@article {12127, title = {Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.}, journal = {Mol Psychiatry}, volume = {26}, year = {2021}, pages = {2111-2125}, abstract = {

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 {\texttimes} 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

}, keywords = {Blood pressure, Epistasis, Genetic, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Polymorphism, Single Nucleotide}, issn = {1476-5578}, doi = {10.1038/s41380-020-0719-3}, author = {de Las Fuentes, Lisa and Yun Ju Sung and Noordam, Raymond and Thomas W Winkler and Feitosa, Mary F and Schwander, Karen and Bentley, Amy R and Brown, Michael R and Guo, Xiuqing and Alisa Manning and Daniel I Chasman and Aschard, Hugues and Traci M Bartz and Bielak, Lawrence F and Campbell, Archie and Cheng, Ching-Yu and Dorajoo, Rajkumar and Hartwig, Fernando P and Horimoto, A R V R and Li, Changwei and Li-Gao, Ruifang and Liu, Yongmei and Marten, Jonathan and Musani, Solomon K and Ntalla, Ioanna and Rankinen, Tuomo and Melissa Richard and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Bamidele O Tayo and Vojinovic, Dina and Warren, Helen R and Xuan, Deng and Alver, Maris and Boissel, Mathilde and Jin-Fang Chai and Chen, Xu and Christensen, Kaare and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Giorgia G Girotto and Sarah E Harris and He, Meian and Hsu, Fang-Chi and K{\"u}hnel, Brigitte and Laguzzi, Federica and Li, Xiaoyin and Lyytik{\"a}inen, Leo-Pekka and Ilja M Nolte and Poveda, Alaitz and Rauramaa, Rainer and Riaz, Muhammad and Rueedi, Rico and Shu, Xiao-Ou and Snieder, Harold and Sofer, Tamar and Takeuchi, Fumihiko and Verweij, Niek and Erin B Ware and Weiss, Stefan and Yanek, Lisa R and Amin, Najaf and Dan E Arking and Donna K Arnett and Bergmann, Sven and Boerwinkle, Eric and Brody, Jennifer A and Broeckel, Ulrich and Brumat, Marco and Burke, Gregory and Cabrera, Claudia P and Canouil, Micka{\"e}l and Chee, Miao Li and Chen, Yii-Der Ida and Cocca, Massimiliano and Connell, John and de Silva, H Janaka and de Vries, Paul S and Eiriksdottir, Gudny and Jessica Faul and Fisher, Virginia and Forrester, Terrence and Fox, Ervin F and Friedlander, Yechiel and Gao, He and Gigante, Bruna and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Tamara B Harris and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven and Ikram, M Arfan and Irvin, Marguerite R and K{\"a}h{\"o}nen, Mika and Kavousi, Maryam and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Komulainen, Pirjo and Kraja, Aldi T and Krieger, J E and Langefeld, Carl D and Li, Yize and Liang, Jingjing and David C Liewald and Liu, Ching-Ti and Liu, Jianjun and Kurt Lohman and M{\"a}gi, Reedik and McKenzie, Colin A and Meitinger, Thomas and Andres Metspalu and Milaneschi, Yuri and Lili Milani and Dennis O Mook-Kanamori and Michael A Nalls and Nelson, Christopher P and Norris, Jill M and Jeff O{\textquoteright}Connell and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmer, Nicholette D and Nancy L Pedersen and Thomas T Perls and Peters, Annette and Petersmann, Astrid and Peyser, Patricia A and Polasek, Ozren and David J Porteous and Raffel, Leslie J and Rice, Treva K and Rotter, Jerome I and Rudan, Igor and Rueda-Ochoa, Oscar-Leonel and Sabanayagam, Charumathi and Babatunde Salako and Schreiner, Pamela J and Shikany, James M and Stephen Sidney and Sims, Mario and Sitlani, Colleen M and Smith, Jennifer A and John M Starr and Strauch, Konstantin and Swertz, Morris A and Teumer, Alexander and Tham, Yih Chung and Andr{\'e} G Uitterlinden and Vaidya, Dhananjay and van der Ende, M Yldau and Waldenberger, Melanie and Wang, Lihua and Wang, Ya-Xing and Wei, Wen-Bin and David R Weir and Wen, Wanqing and Yao, Jie and Yu, Bing and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Alan B Zonderman and Becker, Diane M and Bowden, Donald W and Ian J Deary and D{\"o}rr, Marcus and T{\~o}nu Esko and Freedman, Barry I and Froguel, Philippe and Paolo P. Gasparini and Gieger, Christian and Jost Bruno Jonas and Kammerer, Candace M and Kato, Norihiro and Lakka, Timo A and Leander, Karin and Lehtim{\"a}ki, Terho and Patrik K E Magnusson and Marques-Vidal, Pedro and Brenda W J H Penninx and Nilesh J Samani and van der Harst, Pim and Wagenknecht, Lynne E and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Bouchard, Claude and Cooper, Richard S and Correa, Adolfo and Michele K Evans and Gudnason, Vilmundur and Caroline Hayward and Horta, Bernardo L and Tanika N Kelly and Stephen B Kritchevsky and Levy, Daniel and Walter R Palmas and Pereira, A C and Province, Michael M and Psaty, Bruce M and Ridker, Paul M and Charles N Rotimi and Tai, E Shyong and van Dam, Rob M and Cornelia M van Duijn and Wong, Tien Yin and Kenneth Rice and Gauderman, W James and Alanna C Morrison and Kari E North and Sharon L R Kardia and Caulfield, Mark J and Elliott, Paul and Munroe, Patricia B and Franks, Paul W and Rao, Dabeeru C and Myriam Fornage} } @article {12122, title = {Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.}, journal = {Nature Genetics}, volume = {51}, year = {2019}, pages = {237-244}, abstract = {

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders. They are heritable and etiologically related behaviors that have been resistant to gene discovery efforts. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

}, keywords = {Alcohol Drinking, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Phenotype, Risk, Smoking, Tobacco, Tobacco Use Disorder}, issn = {1546-1718}, doi = {10.1038/s41588-018-0307-5}, author = {Liu, Mengzhen and Jiang, Yu and Wedow, Robbee and Li, Yue and Brazel, David M and Chen, Fang and Datta, Gargi and Davila-Velderrain, Jose and McGuire, Daniel and Tian, Chao and Zhan, Xiaowei and Choquet, H{\'e}l{\`e}ne and Docherty, Anna R and Jessica Faul and Foerster, Johanna R and Fritsche, Lars G and Gabrielsen, Maiken Elvestad and Gordon, Scott D and Jeffrey Haessler and Jouke-Jan Hottenga and Huang, Hongyan and Jang, Seon-Kyeong and Philip R Jansen and Ling, Yueh and M{\"a}gi, Reedik and Matoba, Nana and McMahon, George and Mulas, Antonella and Orr{\`u}, Valeria and Palviainen, Teemu and Anita Pandit and Reginsson, Gunnar W and Skogholt, Anne Heidi and Smith, Jennifer A and Taylor, Amy E and Turman, Constance and Gonneke Willemsen and Young, Hannah and Young, Kendra A and Zajac, Gregory J M and Zhao, Wei and Zhou, Wei and Bjornsdottir, Gyda and Boardman, Jason D and Boehnke, Michael and Dorret I Boomsma and Chen, Chu and Francesco Cucca and Davies, Gareth E and Charles B Eaton and Ehringer, Marissa A and T{\~o}nu Esko and Fiorillo, Edoardo and Gillespie, Nathan A and Gudbjartsson, Daniel F and Haller, Toomas and Kathleen Mullan Harris and Andrew C Heath and Hewitt, John K and Hickie, Ian B and Hokanson, John E and Hopfer, Christian J and Hunter, David J and Iacono, William G and Johnson, Eric O and Kamatani, Yoichiro and Sharon L R Kardia and Matthew C Keller and Kellis, Manolis and Charles Kooperberg and Kraft, Peter and Krauter, Kenneth S and Laakso, Markku and Penelope A Lind and Loukola, Anu and Lutz, Sharon M and Pamela A F Madden and Nicholas G Martin and McGue, Matt and Matthew B McQueen and Sarah E Medland and Andres Metspalu and Mohlke, Karen L and Nielsen, Jonas B and Okada, Yukinori and Peters, Ulrike and Tinca J Polderman and Posthuma, Danielle and Reiner, Alexander P and Rice, John P and Rimm, Eric and Rose, Richard J and Runarsdottir, Valgerdur and Stallings, Michael C and Stan{\v c}{\'a}kov{\'a}, Alena and Stefansson, Hreinn and Thai, Khanh K and Hilary A Tindle and Tyrfingsson, Thorarinn and Wall, Tamara L and David R Weir and Weisner, Constance and Whitfield, John B and Winsvold, Bendik Slagsvold and Yin, Jie and Zuccolo, Luisa and Laura Bierut and Hveem, Kristian and Lee, James J and Munaf{\`o}, Marcus R and Saccone, Nancy L and Willer, Cristen J and Marilyn C Cornelis and David, Sean P and Hinds, David A and Jorgenson, Eric and Kaprio, Jaakko and Stitzel, Jerry A and Stefansson, Kari and Thorgeirsson, Thorgeir E and Gon{\c c}alo R Abecasis and Liu, Dajiang J and Scott Vrieze} } @article {12128, title = {Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.}, journal = {Nature Communications}, volume = {10}, year = {2019}, pages = {376}, abstract = {

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Asians, Blacks, Brazil, Calcium-Binding Proteins, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, Exercise, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Hispanic or Latino, Humans, LIM-Homeodomain Proteins, Lipid Metabolism, Lipids, Male, Membrane Proteins, Microtubule-Associated Proteins, Middle Aged, Muscle Proteins, Nerve Tissue Proteins, Transcription Factors, Triglycerides, Whites, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-018-08008-w}, author = {Kilpel{\"a}inen, Tuomas O and Bentley, Amy R and Noordam, Raymond and Yun Ju Sung and Schwander, Karen and Thomas W Winkler and Jakupovi{\'c}, Hermina and Daniel I Chasman and Alisa Manning and Ntalla, Ioanna and Aschard, Hugues and Brown, Michael R and de Las Fuentes, Lisa and Franceschini, Nora and Guo, Xiuqing and Vojinovic, Dina and Aslibekyan, Stella and Feitosa, Mary F and Kho, Minjung and Musani, Solomon K and Melissa Richard and Wang, Heming and Wang, Zhe and Traci M Bartz and Bielak, Lawrence F and Campbell, Archie and Dorajoo, Rajkumar and Fisher, Virginia and Hartwig, Fernando P and Horimoto, Andrea R V R and Li, Changwei and Kurt Lohman and Marten, Jonathan and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Alver, Maris and Amini, Marzyeh and Boissel, Mathilde and Jin-Fang Chai and Chen, Xu and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Graff, Mariaelisa and Sarah E Harris and He, Meian and Hsu, Fang-Chi and Jackson, Anne U and Jing Hua Zhao and Kraja, Aldi T and K{\"u}hnel, Brigitte and Laguzzi, Federica and Lyytik{\"a}inen, Leo-Pekka and Ilja M Nolte and Rauramaa, Rainer and Riaz, Muhammad and Robino, Antonietta and Rueedi, Rico and Heather M Stringham and Takeuchi, Fumihiko and van der Most, Peter J and Varga, Tibor V and Verweij, Niek and Erin B Ware and Wen, Wanqing and Li, Xiaoyin and Yanek, Lisa R and Amin, Najaf and Donna K Arnett and Boerwinkle, Eric and Brumat, Marco and Brian E Cade and Canouil, Micka{\"e}l and Chen, Yii-Der Ida and Concas, Maria Pina and Connell, John and de Mutsert, Ren{\'e}e and de Silva, H Janaka and de Vries, Paul S and Demirkan, Ayse and Ding, Jingzhong and Charles B Eaton and Jessica Faul and Friedlander, Yechiel and Gabriel, Kelley P and Ghanbari, Mohsen and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Tamara B Harris and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven C and Ikram, M Arfan and Jost Bruno Jonas and Koh, Woon-Puay and Komulainen, Pirjo and Krieger, Jose E and Stephen B Kritchevsky and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langefeld, Carl D and Langenberg, Claudia and Lenore J Launer and Leander, Karin and Lemaitre, Rozenn N and Lewis, Cora E and Liang, Jingjing and Liu, Jianjun and M{\"a}gi, Reedik and Manichaikul, Ani and Meitinger, Thomas and Andres Metspalu and Milaneschi, Yuri and Mohlke, Karen L and Thomas H Mosley and Murray, Alison D and Michael A Nalls and Nang, Ei-Ei Khaing and Nelson, Christopher P and Nona, Sotoodehnia and Norris, Jill M and Nwuba, Chiamaka Vivian and Jeff O{\textquoteright}Connell and Palmer, Nicholette D and Papanicolau, George J and Pazoki, Raha and Nancy L Pedersen and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and David J Porteous and Poveda, Alaitz and Olli T Raitakari and Rich, Stephen S and Neil Risch and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Schreiner, Pamela J and Scott, Robert A and Stephen Sidney and Sims, Mario and Smith, Jennifer A and Snieder, Harold and Sofer, Tamar and John M Starr and Sternfeld, Barbara and Strauch, Konstantin and Tang, Hua and Kent D Taylor and Tsai, Michael Y and Tuomilehto, Jaakko and Andr{\'e} G Uitterlinden and van der Ende, M Yldau and van Heemst, Diana and Voortman, Trudy and Waldenberger, Melanie and Wennberg, Patrik and Wilson, Gregory and Xiang, Yong-Bing and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Alan B Zonderman and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and de Faire, Ulf and Ian J Deary and Elliott, Paul and T{\~o}nu Esko and Freedman, Barry I and Froguel, Philippe and Paolo P. Gasparini and Gieger, Christian and Kato, Norihiro and Laakso, Markku and Lakka, Timo A and Lehtim{\"a}ki, Terho and Patrik K E Magnusson and Oldehinkel, Albertine J and Brenda W J H Penninx and Nilesh J Samani and Shu, Xiao-Ou and van der Harst, Pim and Jana V. van Vliet-Ostaptchouk and Vollenweider, Peter and Wagenknecht, Lynne E and Wang, Ya X and Wareham, Nicholas J and David R Weir and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Michele K Evans and Franks, Paul W and Gudnason, Vilmundur and Caroline Hayward and Horta, Bernardo L and Tanika N Kelly and Liu, Yongmei and Kari E North and Pereira, Alexandre C and Ridker, Paul M and Tai, E Shyong and van Dam, Rob M and Fox, Ervin R and Sharon L R Kardia and Liu, Ching-Ti and Dennis O Mook-Kanamori and Province, Michael A and Redline, Susan and Cornelia M van Duijn and Rotter, Jerome I and Charles Kooperberg and Gauderman, W James and Psaty, Bruce M and Kenneth Rice and Munroe, Patricia B and Myriam Fornage and Cupples, L Adrienne and Charles N Rotimi and Alanna C Morrison and Rao, Dabeeru C and Ruth J F Loos} } @article {10712, title = {Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.}, journal = {Nature Genetics}, volume = {50}, year = {2018}, month = {2018 07 23}, pages = {1112-1121}, abstract = {

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3\% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13\% of the variance in educational attainment and 7-10\% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

}, keywords = {Adult, Aged, Aged, 80 and over, Cohort Studies, Educational Status, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/s41588-018-0147-3}, author = {Lee, James J and Wedow, Robbee and Okbay, Aysu and Kong, Edward and Maghzian, Omeed and Zacher, Meghan and Nguyen-Viet, Tuan Anh and Bowers, Peter and Sidorenko, Julia and Richard Karlsson Linn{\'e}r and Mark Alan Fontana and Kundu, Tushar and Lee, Chanwook and Hui Liu and Li, Ruoxi and Royer, Rebecca and Pascal N Timshel and Walters, Raymond K and Willoughby, Emily A and Yengo, Loic and Alver, Maris and Bao, Yanchun and Clark, David W and Day, Felix R and Furlotte, Nicholas A and Joshi, Peter K and Kathryn E Kemper and Kleinman, Aaron and Langenberg, Claudia and M{\"a}gi, Reedik and Joey W Trampush and Verma, Shefali Setia and Wu, Yang and Lam, Max and Jing Hua Zhao and Zheng, Zhili and Jason D Boardman and Campbell, Harry and Freese, Jeremy and Kathleen Mullan Harris and Caroline Hayward and Herd, Pamela and Kumari, Meena and Lencz, Todd and Luan, Jian{\textquoteright}an and Anil K. Malhotra and Andres Metspalu and Lili Milani and Ong, Ken K and Perry, John R B and David J Porteous and Ritchie, Marylyn D and Smart, Melissa C and Smith, Blair H and Tung, Joyce Y and Wareham, Nicholas J and James F Wilson and Jonathan P. Beauchamp and Dalton C Conley and T{\~o}nu Esko and Lehrer, Steven F and Patrik K E Magnusson and Oskarsson, Sven and Pers, Tune H and Matthew R Robinson and Thom, Kevin and Watson, Chelsea and Chabris, Christopher F and Meyer, Michelle N and David I Laibson and Yang, Jian and Johannesson, Magnus and Philipp D Koellinger and Turley, Patrick and Peter M Visscher and Daniel J. Benjamin and Cesarini, David} } @article {9526, title = {Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Jan}, pages = {26-41}, abstract = {

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5\%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed~to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01\%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI~confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

}, issn = {1546-1718}, doi = {10.1038/s41588-017-0011-x}, author = {Turcot, Val{\'e}rie and Lu, Yingchang and Highland, Heather M and Schurmann, Claudia and Justice, Anne E and Fine, Rebecca S and Bradfield, Jonathan P and T{\~o}nu Esko and Giri, Ayush and Graff, Mariaelisa and Guo, Xiuqing and Hendricks, Audrey E and Karaderi, Tugce and Lempradl, Adelheid and Locke, Adam E and Mahajan, Anubha and Marouli, Eirini and Sivapalaratnam, Suthesh and Young, Kristin L and Alfred, Tamuno and Feitosa, Mary F and Masca, Nicholas G D and Alisa Manning and Medina-Gomez, Carolina and Mudgal, Poorva and Ng, Maggie C Y and Reiner, Alex P and Vedantam, Sailaja and Willems, Sara M and Thomas W Winkler and Gon{\c c}alo R Abecasis and Aben, Katja K and Alam, Dewan S and Alharthi, Sameer E and Matthew A. Allison and Amouyel, Philippe and Asselbergs, Folkert W and Auer, Paul L and Balkau, Beverley and Bang, Lia E and Barroso, In{\^e}s and Bastarache, Lisa and Benn, Marianne and Bergmann, Sven and Bielak, Lawrence F and Bl{\"u}her, Matthias and Boehnke, Michael and Boeing, Heiner and Boerwinkle, Eric and B{\"o}ger, Carsten A and Bork-Jensen, Jette and Bots, Michiel L and Erwin P Bottinger and Bowden, Donald W and Brandslund, Ivan and Breen, Gerome and Brilliant, Murray H and Broer, Linda and Brumat, Marco and Burt, Amber A and Adam S Butterworth and Campbell, Peter T and Cappellani, Stefania and Carey, David J and Catamo, Eulalia and Caulfield, Mark J and Chambers, John C and Daniel I Chasman and Yii-Der I Chen and Chowdhury, Rajiv and Cramer Christensen and Chu, Audrey Y and Cocca, Massimiliano and Collins, Francis S and Cook, James P and Corley, Janie and Jordi Corominas Galbany and Cox, Amanda J and Crosslin, David S and Cuellar-Partida, Gabriel and D{\textquoteright}Eustacchio, Angela and Danesh, John and Gail Davies and Bakker, Paul I W and Groot, Mark C H and Mutsert, Ren{\'e}e and Ian J Deary and George Dedoussis and Ellen W Demerath and Heijer, Martin and Anneke I den Hollander and Hester M den Ruijter and Joe G Dennis and Denny, Josh C and Angelantonio, Emanuele and Drenos, Fotios and Du, Mengmeng and Dub{\'e}, Marie-Pierre and Dunning, Alison M and Easton, Douglas F and Edwards, Todd L and Ellinghaus, David and Ellinor, Patrick T and Elliott, Paul and Evangelou, Evangelos and Farmaki, Aliki-Eleni and Farooqi, I Sadaf and Jessica Faul and Fauser, Sascha and Feng, Shuang and Ferrannini, Ele and Ferri{\`e}res, Jean and Florez, Jose C and Ford, Ian and Myriam Fornage and Franco, Oscar H and Franke, Andre and Franks, Paul W and Friedrich, Nele and Frikke-Schmidt, Ruth and Galesloot, Tessel E and Gan, Wei and Gandin, Ilaria and Paolo P. Gasparini and Gibson, Jane and Giedraitis, Vilmantas and Gjesing, Anette P and Gordon-Larsen, Penny and Gorski, Mathias and Hans-J{\"o}rgen Grabe and Grant, Struan F A and Grarup, Niels and Griffiths, Helen L and Grove, Megan L and Gudnason, Vilmundur and Gustafsson, Stefan and Jeffrey Haessler and Hakonarson, Hakon and Anke R Hammerschlag and Hansen, Torben and Tamara B Harris and Andrew T Hattersley and Have, Christian T and Caroline Hayward and He, Liang and Heard-Costa, Nancy L and Andrew C Heath and Iris M Heid and Helgeland, {\O}yvind and Hernesniemi, Jussi and Hewitt, Alex W and Oddgeir L Holmen and Hovingh, G Kees and Howson, Joanna M M and Hu, Yao and Huang, Paul L and Huffman, Jennifer E and Mohammed Arfan Ikram and Ingelsson, Erik and Jackson, Anne U and Jansson, Jan-H{\r a}kan and Jarvik, Gail P and Jensen, Gorm B and Jia, Yucheng and Johansson, Stefan and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Jukema, J Wouter and Kahali, Bratati and Kahn, Ren{\'e} S and K{\"a}h{\"o}nen, Mika and Kamstrup, Pia R and Kanoni, Stavroula and Kaprio, Jaakko and Karaleftheri, Maria and Sharon L R Kardia and Karpe, Fredrik and Kathiresan, Sekar and Kee, Frank and Lambertus A Kiemeney and Eric S Kim and Kitajima, Hidetoshi and Komulainen, Pirjo and Kooner, Jaspal S and Charles Kooperberg and Korhonen, Tellervo and Kovacs, Peter and Kuivaniemi, Helena and Kutalik, Zolt{\'a}n and Kuulasmaa, Kari and Kuusisto, Johanna and Laakso, Markku and Lakka, Timo A and Lamparter, David and Lange, Ethan M and Leslie A Lange and Langenberg, Claudia and Eric B Larson and Lee, Nanette R and Lehtim{\"a}ki, Terho and Lewis, Cora E and Li, Huaixing and Li, Jin and Li-Gao, Ruifang and Lin, Honghuang and Lin, Keng-Hung and Lin, Li-An and Lin, Xu and Lars Lind and Lindstr{\"o}m, Jaana and Linneberg, Allan and Liu, Ching-Ti and Liu, Dajiang J and Yongmei Liu and Ken Sin Lo and Lophatananon, Artitaya and Lotery, Andrew J and Loukola, Anu and Luan, Jian{\textquoteright}an and Lubitz, Steven A and Lyytik{\"a}inen, Leo-Pekka and M{\"a}nnist{\"o}, Satu and Marenne, Ga{\"e}lle and Mazul, Angela L and McCarthy, Mark I and McKean-Cowdin, Roberta and Sarah E Medland and Meidtner, Karina and Lili Milani and Mistry, Vanisha and Mitchell, Paul and Mohlke, Karen L and Moilanen, Leena and Moitry, Marie and Grant W Montgomery and Dennis O Mook-Kanamori and Moore, Carmel and Mori, Trevor A and Morris, Andrew D and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Munroe, Patricia B and Michael A Nalls and Narisu, Narisu and Nelson, Christopher P and Neville, Matt and Sune Fallgaard Nielsen and Nikus, Kjell and Nj{\o}lstad, P{\r a}l R and B{\o}rge G Nordestgaard and Nyholt, Dale R and Jeff O{\textquoteright}Connell and O{\textquoteright}Donoghue, Michelle L and Ophoff, Roel A and Owen, Katharine R and Packard, Chris J and Padmanabhan, Sandosh and Palmer, Colin N A and Palmer, Nicholette D and Pasterkamp, Gerard and Patel, Aniruddh P and Pattie, Alison and Pedersen, Oluf and Peissig, Peggy L and Peloso, Gina M and Pennell, Craig E and Markus Perola and Perry, James A and Perry, John R B and Pers, Tune H and Person, Thomas N and Peters, Annette and Petersen, Eva R B and Peyser, Patricia A and Pirie, Ailith and Polasek, Ozren and Tinca J Polderman and Puolijoki, Hannu and Olli T Raitakari and Rasheed, Asif and Rauramaa, Rainer and Reilly, Dermot F and Renstrom, Frida and Rheinberger, Myriam and Ridker, Paul M and Rioux, John D and Rivas, Manuel A and Roberts, David J and Neil R Robertson and Robino, Antonietta and Rolandsson, Olov and Rudan, Igor and Ruth, Katherine S and Saleheen, Danish and Veikko Salomaa and Nilesh J Samani and Sapkota, Yadav and Sattar, Naveed and Schoen, Robert E and Schreiner, Pamela J and Schulze, Matthias B and Scott, Robert A and Segura-Lepe, Marcelo P and Svati H Shah and Sheu, Wayne H-H and Sim, Xueling and Slater, Andrew J and Small, Kerrin S and Albert Vernon Smith and Southam, Lorraine and Timothy Spector and Elizabeth K Speliotes and John M Starr and Stefansson, Kari and Steinthorsdottir, Valgerdur and Kathleen E Stirrups and Strauch, Konstantin and Heather M Stringham and Stumvoll, Michael and Sun, Liang and Surendran, Praveen and Swift, Amy J and Tada, Hayato and Tansey, Katherine E and Tardif, Jean-Claude and Kent D Taylor and Teumer, Alexander and Thompson, Deborah J and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Thuesen, Betina H and T{\"o}njes, Anke and Tromp, Gerard and Trompet, Stella and Tsafantakis, Emmanouil and Tuomilehto, Jaakko and Tybjaerg-Hansen, Anne and Tyrer, Jonathan P and Uher, Rudolf and Andr{\'e} G Uitterlinden and Uusitupa, Matti and Laan, Sander W and Duijn, Cornelia M and Leeuwen, Nienke and van Setten, Jessica and Vanhala, Mauno and Varbo, Anette and Varga, Tibor V and Varma, Rohit and Digna R Velez Edwards and Vermeulen, Sita H and Veronesi, Giovanni and Vestergaard, Henrik and Vitart, Veronique and Vogt, Thomas F and V{\"o}lker, Uwe and Vuckovic, Dragana and Wagenknecht, Lynne E and Walker, Mark and Wallentin, Lars and Wang, Feijie and Wang, Carol A and Wang, Shuai and Wang, Yiqin and Erin B Ware and Wareham, Nicholas J and Warren, Helen R and Dawn M Waterworth and Wessel, Jennifer and White, Harvey D and Willer, Cristen J and Wilson, James G and Daniel Witte and Andrew R Wood and Wu, Ying and Yaghootkar, Hanieh and Yao, Jie and Yao, Pang and Laura M Yerges-Armstrong and Young, Robin and Zeggini, Eleftheria and Zhan, Xiaowei and Zhang, Weihua and Wei Zhao and Zhou, Wei and Krina T Zondervan and Rotter, Jerome I and Pospisilik, John A and Fernando Rivadeneira and Ingrid B Borecki and Deloukas, Panos and Timothy M Frayling and Lettre, Guillaume and Kari E North and Lindgren, Cecilia M and Joel N Hirschhron and Ruth J F Loos} } @article {12135, title = {An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.}, journal = {Biological Psychiatry}, volume = {82}, year = {2017}, pages = {322-329}, abstract = {

BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.

METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.

RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 {\texttimes} 10) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 {\texttimes} 10).

CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

}, keywords = {Acid Anhydride Hydrolases, depression, Depressive Disorder, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neoplasm Proteins, Phenotype, Whites}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2016.11.013}, author = {Nese Direk and Williams, Stephanie and Smith, Jennifer A and Ripke, Stephan and Air, Tracy and Amare, Azmeraw T and Amin, Najaf and Baune, Bernhard T and David A Bennett and Blackwood, Douglas H R and Dorret I Boomsma and Breen, Gerome and Buttensch{\o}n, Henriette N and Byrne, Enda M and B{\o}rglum, Anders D and Castelao, Enrique and Cichon, Sven and Clarke, Toni-Kim and Marilyn C Cornelis and Dannlowski, Udo and Philip L de Jager and Demirkan, Ayse and Domenici, Enrico and Cornelia M van Duijn and Dunn, Erin C and Johan G Eriksson and T{\~o}nu Esko and Jessica Faul and Luigi Ferrucci and Myriam Fornage and Eco J. C. de Geus and Gill, Michael and Gordon, Scott D and Hans-J{\"o}rgen Grabe and van Grootheest, Gerard and Hamilton, Steven P and Catharina A Hartman and Andrew C Heath and Karin Hek and Hofman, Albert and Homuth, Georg and Horn, Carsten and Jouke-Jan Hottenga and Sharon L R Kardia and Kloiber, Stefan and Karestan C Koenen and Kutalik, Zolt{\'a}n and Ladwig, Karl-Heinz and Lahti, Jari and Douglas F Levinson and Lewis, Cathryn M and Lewis, Glyn and Li, Qingqin S and David J Llewellyn and Lucae, Susanne and Kathryn L Lunetta and MacIntyre, Donald J and Pamela A F Madden and Nicholas G Martin and McIntosh, Andrew M and Andres Metspalu and Milaneschi, Yuri and Grant W Montgomery and Mors, Ole and Thomas H Mosley and Joanne M Murabito and M{\"u}ller-Myhsok, Bertram and Markus M N{\"o}then and Nyholt, Dale R and O{\textquoteright}Donovan, Michael C and Brenda W J H Penninx and Pergadia, Michele L and Perlis, Roy and Potash, James B and Preisig, Martin and Shaun M Purcell and Quiroz, Jorge A and Katri R{\"a}ikk{\"o}nen and Rice, John P and Rietschel, Marcella and Rivera, Margarita and Schulze, Thomas G and Shi, Jianxin and Shyn, Stanley and Sinnamon, Grant C and Johannes H Smit and Smoller, Jordan W and Snieder, Harold and Toshiko Tanaka and Tansey, Katherine E and Teumer, Alexander and Uher, Rudolf and Umbricht, Daniel and Van der Auwera, Sandra and Erin B Ware and David R Weir and Weissman, Myrna M and Gonneke Willemsen and Yang, Jingyun and Zhao, Wei and Henning Tiemeier and Patrick F. Sullivan} } @article {12131, title = {Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.}, journal = {Nature Communications}, volume = {8}, year = {2017}, pages = {910}, abstract = {

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents{\textquoteright} survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

}, keywords = {Alleles, Body Mass Index, Coronary Disease, Education, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DQ alpha-Chains, HLA-DRB1 Chains, Humans, Insulin Resistance, Life Style, Lipoprotein(a), Lipoproteins, HDL, Longevity, Lung Neoplasms, Obesity, Polymorphism, Single Nucleotide, Smoking, Socioeconomic factors}, issn = {2041-1723}, doi = {10.1038/s41467-017-00934-5}, author = {Joshi, Peter K and Nicola Pirastu and Kentistou, Katherine A and Fischer, Krista and Edith Hofer and Schraut, Katharina E and Clark, David W and Nutile, Teresa and Barnes, Catriona L K and Paul Rhj Timmers and Shen, Xia and Gandin, Ilaria and McDaid, Aaron F and Hansen, Thomas Folkmann and Gordon, Scott D and Giulianini, Franco and Boutin, Thibaud S and Abdellaoui, Abdel and Zhao, Wei and Medina-Gomez, Carolina and Traci M Bartz and Trompet, Stella and Leslie A Lange and Raffield, Laura and van der Spek, Ashley and Galesloot, Tessel E and Proitsi, Petroula and Yanek, Lisa R and Bielak, Lawrence F and Payton, Antony and Murgia, Federico and Concas, Maria Pina and Biino, Ginevra and Tajuddin, Salman M and Sepp{\"a}l{\"a}, Ilkka and Amin, Najaf and Boerwinkle, Eric and B{\o}rglum, Anders D and Campbell, Archie and Ellen W Demerath and Demuth, Ilja and Jessica Faul and Ford, Ian and Gialluisi, Alessandro and G{\"o}gele, Martin and Graff, Mariaelisa and Aroon Hingorani and Jouke-Jan Hottenga and Hougaard, David M and Hurme, Mikko A and Ikram, M Arfan and Jylh{\"a}, Marja and Kuh, Diana and Ligthart, Lannie and Lill, Christina M and Lindenberger, Ulman and Lumley, Thomas and M{\"a}gi, Reedik and Marques-Vidal, Pedro and Sarah E Medland and Lili Milani and Nagy, Reka and William E R Ollier and Peyser, Patricia A and Pramstaller, Peter P and Ridker, Paul M and Fernando Rivadeneira and Ruggiero, Daniela and Saba, Yasaman and Schmidt, Reinhold and Schmidt, Helena and Slagboom, P Eline and Smith, Blair H and Smith, Jennifer A and Sotoodehnia, Nona and Steinhagen-Thiessen, Elisabeth and van Rooij, Frank J A and Verbeek, Andr{\'e} L and Vermeulen, Sita H and Vollenweider, Peter and Wang, Yunpeng and Werge, Thomas and Whitfield, John B and Alan B Zonderman and Lehtim{\"a}ki, Terho and Michele K Evans and Pirastu, Mario and Fuchsberger, Christian and Bertram, Lars and Pendleton, Neil and Sharon L R Kardia and Ciullo, Marina and Becker, Diane M and Wong, Andrew and Psaty, Bruce M and Cornelia M van Duijn and Wilson, James G and Jukema, J Wouter and Lambertus A Kiemeney and Andr{\'e} G Uitterlinden and Franceschini, Nora and Kari E North and David R Weir and Andres Metspalu and Dorret I Boomsma and Caroline Hayward and Daniel I Chasman and Nicholas G Martin and Sattar, Naveed and Campbell, Harry and T{\~o}nu Esko and Kutalik, Zolt{\'a}n and James F Wilson} } @article {9262, title = {Genotype{\textendash}covariate interaction effects and the heritability of adult body mass index}, journal = {Nature Genetics}, volume = {49}, year = {2017}, pages = {1174-1181}, abstract = {Obesity is a worldwide epidemie, with major health and economic costs. Here we estimate heritability for body mass index (BMI) in 172,000 sibling pairs and 150,832 unrelated individuals and explore the contribution of genotype-covariate interaction effects at common SNP loci. We find evidence for genotype-age interaction (likelihood ratio test (LRT) = 73.58, degrees of freedom (df) = 1, P = 4.83 x 10-18), which contributed 8.1 \% (1.4\% s.e.) to BMI variation. Across eight self-reported lifestyle factors, including diet and exercise, we find genotype-environment interaction only for smoking behavior (LRT = 19.70, P = 5.03 x 10-5 and LRT = 30.80, P = 1.42 x 10-8), which contributed 4.0\% (0.8\% s.e.) to BMI variation. Bayesian association analysis suggests that BMI is highly polygenic, with 75\% of the SNP heritability attributable to loci that each explain <0.01 \% of the phenotypic variance. Our findings imply that substantially larger sample sizes across ages and lifestyles are required to understand the full genetic architecture of BMI.}, keywords = {BMI, Genetics, GWAS}, issn = {1061-4036}, doi = {10.1038/ng.3912}, author = {Matthew R Robinson and English, Geoffrey and Moser, Gerhard and Lloyd-Jones, Luke R. and Triplett, Marcus A. and Zhihong Zhu and Ilja M Nolte and Jana V. van Vliet-Ostaptchouk and Snieder, Harold and T{\~o}nu Esko and Lili Milani and M{\"a}gi, Reedik and Andres Metspalu and Patrik K E Magnusson and Nancy L Pedersen and Ingelsson, Erik and Johannesson, Magnus and Yang, Jian and Cesarini, David and Peter M Visscher} } @article {12138, title = {New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.}, journal = {Circulation: Cardiovascular Genetics}, volume = {10}, year = {2017}, pages = {e001778}, abstract = {

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (<5{\texttimes}10) for BP, of which 4 are new BP loci: rs9678851 (missense, ), rs7437940 (), rs13303 (missense, ), and rs1055144 (). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, ) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at ) was genome-wide significant.

CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

}, keywords = {Antiporters, Blood pressure, Cell Adhesion Molecules, Neuronal, Databases, Factual, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Microfilament Proteins, Phenotype, Polymorphism, Single Nucleotide, Receptors, Lymphocyte Homing}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.117.001778}, author = {Kraja, Aldi T and Cook, James P and Warren, Helen R and Surendran, Praveen and Liu, Chunyu and Evangelou, Evangelos and Alisa Manning and Grarup, Niels and Drenos, Fotios and Sim, Xueling and Smith, Albert Vernon and Amin, Najaf and Alexandra I Blakemore and Bork-Jensen, Jette and Brandslund, Ivan and Farmaki, Aliki-Eleni and Fava, Cristiano and Ferreira, Teresa and Herzig, Karl-Heinz and Giri, Ayush and Giulianini, Franco and Grove, Megan L and Guo, Xiuqing and Sarah E Harris and Have, Christian T and Havulinna, Aki S and Zhang, He and J{\o}rgensen, Marit E and K{\"a}r{\"a}j{\"a}m{\"a}ki, AnneMari and Charles Kooperberg and Linneberg, Allan and Little, Louis and Liu, Yongmei and Bonnycastle, Lori L and Lu, Yingchang and M{\"a}gi, Reedik and Mahajan, Anubha and Malerba, Giovanni and Riccardo E Marioni and Mei, Hao and Menni, Cristina and Alanna C Morrison and Padmanabhan, Sandosh and Walter R Palmas and Poveda, Alaitz and Rauramaa, Rainer and Nigel W Rayner and Riaz, Muhammad and Rice, Ken and Melissa Richard and Smith, Jennifer A and Southam, Lorraine and Stan{\v c}{\'a}kov{\'a}, Alena and Kathleen E Stirrups and Tragante, Vinicius and Tuomi, Tiinamaija and Tzoulaki, Ioanna and Varga, Tibor V and Weiss, Stefan and Yiorkas, Andrianos M and Young, Robin and Zhang, Weihua and Barnes, Michael R and Cabrera, Claudia P and Gao, He and Boehnke, Michael and Boerwinkle, Eric and Chambers, John C and Connell, John M and Cramer Christensen and de Boer, Rudolf A and Ian J Deary and George Dedoussis and Deloukas, Panos and Dominiczak, Anna F and D{\"o}rr, Marcus and Joehanes, Roby and Edwards, Todd L and T{\~o}nu Esko and Myriam Fornage and Franceschini, Nora and Franks, Paul W and Gambaro, Giovanni and Leif C Groop and Hallmans, G{\"o}ran and Hansen, Torben and Caroline Hayward and Heikki, Oksa and Ingelsson, Erik and Tuomilehto, Jaakko and J{\"a}rvelin, Marjo-Riitta and Sharon L R Kardia and Karpe, Fredrik and Kooner, Jaspal S and Lakka, Timo A and Langenberg, Claudia and Lars Lind and Ruth J F Loos and Laakso, Markku and McCarthy, Mark I and Melander, Olle and Mohlke, Karen L and Morris, Andrew P and Palmer, Colin N A and Pedersen, Oluf and Polasek, Ozren and Neil Poulter and Province, Michael A and Psaty, Bruce M and Ridker, Paul M and Rotter, Jerome I and Rudan, Igor and Veikko Salomaa and Nilesh J Samani and Peter Sever and Skaaby, Tea and Stafford, Jeanette M and John M Starr and van der Harst, Pim and van der Meer, Peter and Cornelia M van Duijn and Vergnaud, Anne-Claire and Gudnason, Vilmundur and Wareham, Nicholas J and Wilson, James G and Willer, Cristen J and Daniel Witte and Zeggini, Eleftheria and Saleheen, Danish and Adam S Butterworth and Danesh, John and Asselbergs, Folkert W and Wain, Louise V and Georg B Ehret and Daniel I Chasman and Caulfield, Mark J and Elliott, Paul and Lindgren, Cecilia M and Levy, Daniel and Newton-Cheh, Christopher and Munroe, Patricia B and Howson, Joanna M M} } @article {8886, title = {Rare and low-frequency coding variants alter human adult height.}, journal = {Nature}, volume = {542}, year = {2017}, month = {2017 Feb 09}, pages = {186-190}, abstract = {

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8\%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

}, issn = {1476-4687}, doi = {10.1038/nature21039}, author = {Marouli, Eirini and Graff, Mariaelisa and Medina-Gomez, Carolina and Ken Sin Lo and Andrew R Wood and Kjaer, Troels R and Fine, Rebecca S and Lu, Yingchang and Schurmann, Claudia and Highland, Heather M and R{\"u}eger, Sina and Thorleifsson, Gudmar and Justice, Anne E and Lamparter, David and Kathleen E Stirrups and Turcot, Val{\'e}rie and Young, Kristin L and Thomas W Winkler and T{\~o}nu Esko and Karaderi, Tugce and Locke, Adam E and Masca, Nicholas G D and Ng, Maggie C Y and Mudgal, Poorva and Rivas, Manuel A and Vedantam, Sailaja and Mahajan, Anubha and Guo, Xiuqing and Gon{\c c}alo R Abecasis and Aben, Katja K and Adair, Linda S and Alam, Dewan S and Albrecht, Eva and Allin, Kristine H and Matthew A. Allison and Amouyel, Philippe and Appel, Emil V and Arveiler, Dominique and Asselbergs, Folkert W and Auer, Paul L and Balkau, Beverley and Banas, Bernhard and Bang, Lia E and Benn, Marianne and Bergmann, Sven and Bielak, Lawrence F and Bl{\"u}her, Matthias and Boeing, Heiner and Boerwinkle, Eric and B{\"o}ger, Carsten A and Bonnycastle, Lori L and Bork-Jensen, Jette and Bots, Michiel L and Erwin P Bottinger and Bowden, Donald W and Brandslund, Ivan and Breen, Gerome and Brilliant, Murray H and Broer, Linda and Burt, Amber A and Adam S Butterworth and Carey, David J and Caulfield, Mark J and Chambers, John C and Daniel I Chasman and Yii-Der I Chen and Chowdhury, Rajiv and Cramer Christensen and Chu, Audrey Y and Cocca, Massimiliano and Collins, Francis S and Cook, James P and Corley, Janie and Jordi Corominas Galbany and Cox, Amanda J and Cuellar-Partida, Gabriel and Danesh, John and Gail Davies and de Bakker, Paul I W and de Borst, Gert J and de Denus, Simon and de Groot, Mark C H and de Mutsert, Ren{\'e}e and Ian J Deary and George Dedoussis and Ellen W Demerath and Anneke I den Hollander and Joe G Dennis and Di Angelantonio, Emanuele and Drenos, Fotios and Du, Mengmeng and Dunning, Alison M and Easton, Douglas F and Ebeling, Tapani and Edwards, Todd L and Ellinor, Patrick T and Elliott, Paul and Evangelou, Evangelos and Farmaki, Aliki-Eleni and Jessica Faul and Feitosa, Mary F and Feng, Shuang and Ferrannini, Ele and Marco M Ferrario and Ferri{\`e}res, Jean and Florez, Jose C and Ford, Ian and Myriam Fornage and Franks, Paul W and Frikke-Schmidt, Ruth and Galesloot, Tessel E and Gan, Wei and Gandin, Ilaria and Paolo P. Gasparini and Giedraitis, Vilmantas and Giri, Ayush and Giorgia G Girotto and Gordon, Scott D and Gordon-Larsen, Penny and Gorski, Mathias and Grarup, Niels and Grove, Megan L and Gudnason, Vilmundur and Gustafsson, Stefan and Hansen, Torben and Kathleen Mullan Harris and Tamara B Harris and Andrew T Hattersley and Caroline Hayward and He, Liang and Iris M Heid and Heikkil{\"a}, Kauko and Helgeland, {\O}yvind and Hernesniemi, Jussi and Hewitt, Alex W and Lynne J Hocking and Hollensted, Mette and Oddgeir L Holmen and Hovingh, G Kees and Howson, Joanna M M and Hoyng, Carel B and Huang, Paul L and Hveem, Kristian and Mohammed Arfan Ikram and Ingelsson, Erik and Jackson, Anne U and Jansson, Jan-H{\r a}kan and Jarvik, Gail P and Jensen, Gorm B and Jhun, Min A and Jia, Yucheng and Jiang, Xuejuan and Johansson, Stefan and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Jousilahti, Pekka and Jukema, J Wouter and Kahali, Bratati and Kahn, Ren{\'e} S and K{\"a}h{\"o}nen, Mika and Kamstrup, Pia R and Kanoni, Stavroula and Kaprio, Jaakko and Karaleftheri, Maria and Sharon L R Kardia and Karpe, Fredrik and Kee, Frank and Keeman, Renske and Lambertus A Kiemeney and Kitajima, Hidetoshi and Kluivers, Kirsten B and Kocher, Thomas and Komulainen, Pirjo and Kontto, Jukka and Kooner, Jaspal S and Charles Kooperberg and Kovacs, Peter and Kriebel, Jennifer and Kuivaniemi, Helena and K{\"u}ry, S{\'e}bastien and Kuusisto, Johanna and La Bianca, Martina and Laakso, Markku and Lakka, Timo A and Lange, Ethan M and Leslie A Lange and Langefeld, Carl D and Langenberg, Claudia and Eric B Larson and Lee, I-Te and Lehtim{\"a}ki, Terho and Lewis, Cora E and Li, Huaixing and Li, Jin and Li-Gao, Ruifang and Lin, Honghuang and Lin, Li-An and Lin, Xu and Lars Lind and Lindstr{\"o}m, Jaana and Linneberg, Allan and Liu, Yeheng and Yongmei Liu and Lophatananon, Artitaya and Luan, Jian{\textquoteright}an and Lubitz, Steven A and Lyytik{\"a}inen, Leo-Pekka and Mackey, David A and Pamela A F Madden and Alisa Manning and M{\"a}nnist{\"o}, Satu and Marenne, Ga{\"e}lle and Marten, Jonathan and Nicholas G Martin and Mazul, Angela L and Meidtner, Karina and Andres Metspalu and Mitchell, Paul and Mohlke, Karen L and Dennis O Mook-Kanamori and Morgan, Anna and Morris, Andrew D and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Munroe, Patricia B and Michael A Nalls and Nauck, Matthias and Nelson, Christopher P and Neville, Matt and Sune Fallgaard Nielsen and Nikus, Kjell and Nj{\o}lstad, P{\r a}l R and B{\o}rge G Nordestgaard and Ntalla, Ioanna and Jeff O{\textquoteright}Connell and Oksa, Heikki and Loes M Olde Loohuis and Ophoff, Roel A and Owen, Katharine R and Packard, Chris J and Padmanabhan, Sandosh and Palmer, Colin N A and Pasterkamp, Gerard and Patel, Aniruddh P and Pattie, Alison and Pedersen, Oluf and Peissig, Peggy L and Peloso, Gina M and Pennell, Craig E and Markus Perola and Perry, James A and Perry, John R B and Person, Thomas N and Pirie, Ailith and Polasek, Ozren and Posthuma, Danielle and Olli T Raitakari and Rasheed, Asif and Rauramaa, Rainer and Reilly, Dermot F and Reiner, Alex P and Renstrom, Frida and Ridker, Paul M and Rioux, John D and Neil R Robertson and Robino, Antonietta and Rolandsson, Olov and Rudan, Igor and Ruth, Katherine S and Saleheen, Danish and Veikko Salomaa and Nilesh J Samani and Sandow, Kevin and Sapkota, Yadav and Sattar, Naveed and Schmidt, Marjanka K and Schreiner, Pamela J and Schulze, Matthias B and Scott, Robert A and Segura-Lepe, Marcelo P and Svati H Shah and Sim, Xueling and Sivapalaratnam, Suthesh and Small, Kerrin S and Albert Vernon Smith and Jennifer A Smith and Southam, Lorraine and Timothy Spector and Elizabeth K Speliotes and John M Starr and Steinthorsdottir, Valgerdur and Heather M Stringham and Stumvoll, Michael and Surendran, Praveen and {\textquoteright}t Hart, Leen M and Tansey, Katherine E and Tardif, Jean-Claude and Kent D Taylor and Teumer, Alexander and Thompson, Deborah J and Thorsteinsdottir, Unnur and Thuesen, Betina H and T{\"o}njes, Anke and Tromp, Gerard and Trompet, Stella and Tsafantakis, Emmanouil and Tuomilehto, Jaakko and Tybjaerg-Hansen, Anne and Tyrer, Jonathan P and Uher, Rudolf and Andr{\'e} G Uitterlinden and Ulivi, Sheila and van der Laan, Sander W and Van Der Leij, Andries R and Cornelia M van Duijn and van Schoor, Natasja M and van Setten, Jessica and Varbo, Anette and Varga, Tibor V and Varma, Rohit and Digna R Velez Edwards and Vermeulen, Sita H and Vestergaard, Henrik and Vitart, Veronique and Vogt, Thomas F and Vozzi, Diego and Walker, Mark and Wang, Feijie and Wang, Carol A and Wang, Shuai and Wang, Yiqin and Wareham, Nicholas J and Warren, Helen R and Wessel, Jennifer and Willems, Sara M and Wilson, James G and Daniel Witte and Woods, Michael O and Wu, Ying and Yaghootkar, Hanieh and Yao, Jie and Yao, Pang and Laura M Yerges-Armstrong and Young, Robin and Zeggini, Eleftheria and Zhan, Xiaowei and Zhang, Weihua and Jing Hua Zhao and Wei Zhao and Wei Zhao and Zheng, He and Zhou, Wei and Rotter, Jerome I and Boehnke, Michael and Kathiresan, Sekar and McCarthy, Mark I and Willer, Cristen J and Stefansson, Kari and Ingrid B Borecki and Liu, Dajiang J and Kari E North and Heard-Costa, Nancy L and Pers, Tune H and Lindgren, Cecilia M and Oxvig, Claus and Kutalik, Zolt{\'a}n and Fernando Rivadeneira and Ruth J F Loos and Timothy M Frayling and Joel N Hirschhron and Deloukas, Panos and Lettre, Guillaume} } @article {12133, title = {SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.}, journal = {Journal of the American Society of Nephrology }, volume = {28}, year = {2017}, pages = {981-994}, abstract = {

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7{\texttimes}10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4{\texttimes}10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

}, keywords = {Animals, Exome, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, kidney, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins, Son of Sevenless Proteins, Zebrafish}, issn = {1533-3450}, doi = {10.1681/ASN.2016020131}, author = {Li, Man and Li, Yong and Weeks, Olivia and Mijatovic, Vladan and Teumer, Alexander and Huffman, Jennifer E and Tromp, Gerard and Fuchsberger, Christian and Gorski, Mathias and Lyytik{\"a}inen, Leo-Pekka and Nutile, Teresa and Sedaghat, Sanaz and Sorice, Rossella and Tin, Adrienne and Yang, Qiong and Ahluwalia, Tarunveer S and Dan E Arking and Bihlmeyer, Nathan A and B{\"o}ger, Carsten A and Carroll, Robert J and Daniel I Chasman and Marilyn C Cornelis and Dehghan, Abbas and Jessica Faul and Feitosa, Mary F and Gambaro, Giovanni and Paolo P. Gasparini and Giulianini, Franco and Iris M Heid and Huang, Jinyan and Imboden, Medea and Jackson, Anne U and Janina Jeff and Jhun, Min A and Katz, Ronit and Kifley, Annette and Kilpel{\"a}inen, Tuomas O and Kumar, Ashish and Laakso, Markku and Li-Gao, Ruifang and Kurt Lohman and Lu, Yingchang and M{\"a}gi, Reedik and Malerba, Giovanni and Mihailov, Evelin and Mohlke, Karen L and Dennis O Mook-Kanamori and Robino, Antonietta and Ruderfer, Douglas and Salvi, Erika and Schick, Ursula M and Schulz, Christina-Alexandra and Smith, Albert V and Smith, Jennifer A and Traglia, Michela and Laura M Yerges-Armstrong and Zhao, Wei and Goodarzi, Mark O and Kraja, Aldi T and Liu, Chunyu and Wessel, Jennifer and Boerwinkle, Eric and Ingrid B Borecki and Bork-Jensen, Jette and Erwin P Bottinger and Braga, Daniele and Brandslund, Ivan and Brody, Jennifer A and Campbell, Archie and Carey, David J and Cramer Christensen and Coresh, Josef and Crook, Errol and Curhan, Gary C and Cusi, Daniele and de Boer, Ian H and de Vries, Aiko P J and Denny, Joshua C and Devuyst, Olivier and Dreisbach, Albert W and Endlich, Karlhans and T{\~o}nu Esko and Franco, Oscar H and Fulop, Tibor and Gerhard, Glenn S and Gl{\"u}mer, Charlotte and Gottesman, Omri and Grarup, Niels and Gudnason, Vilmundur and Hansen, Torben and Tamara B Harris and Caroline Hayward and Lynne J Hocking and Hofman, Albert and Hu, Frank B and Husemoen, Lise Lotte N and Jackson, Rebecca D and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and K{\"a}h{\"o}nen, Mika and Sharon L R Kardia and K{\"o}nig, Wolfgang and Charles Kooperberg and Kriebel, Jennifer and Lenore J Launer and Lauritzen, Torsten and Lehtim{\"a}ki, Terho and Levy, Daniel and Linksted, Pamela and Linneberg, Allan and Liu, Yongmei and Ruth J F Loos and Lupo, Antonio and Meisinger, Christine and Melander, Olle and Andres Metspalu and Mitchell, Paul and Nauck, Matthias and N{\"u}rnberg, Peter and Orho-Melander, Marju and Parsa, Afshin and Pedersen, Oluf and Peters, Annette and Peters, Ulrike and Polasek, Ozren and David J Porteous and Nicole M Probst-Hensch and Psaty, Bruce M and Qi, Lu and Olli T Raitakari and Reiner, Alex P and Rettig, Rainer and Ridker, Paul M and Fernando Rivadeneira and Rossouw, Jacques E and Schmidt, Frank and David S Siscovick and Soranzo, Nicole and Strauch, Konstantin and Toniolo, Daniela and Stephen T Turner and Andr{\'e} G Uitterlinden and Ulivi, Sheila and Velayutham, Dinesh and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wang, Jie Jin and David R Weir and Daniel Witte and Kuivaniemi, Helena and Caroline S Fox and Franceschini, Nora and Goessling, Wolfram and K{\"o}ttgen, Anna and Chu, Audrey Y} } @article {8879, title = {Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016 Jan 21}, pages = {10023}, abstract = {

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

}, keywords = {Chronic disease, Genome-Wide Association Study, Genotype, Humans}, issn = {2041-1723}, doi = {10.1038/ncomms10023}, author = {Pattaro, Cristian and Teumer, Alexander and Gorski, Mathias and Chu, Audrey Y and Li, Man and Mijatovic, Vladan and Garnaas, Maija and Tin, Adrienne and Sorice, Rossella and Yong Li and Taliun, Daniel and Olden, Matthias and Foster, Meredith and Qiong Yang and Chen, Ming-Huei and Pers, Tune H and Andrew D Johnson and Ko, Yi-An and Fuchsberger, Christian and Bamidele O Tayo and Michael A Nalls and Feitosa, Mary F and Isaacs, Aaron and Dehghan, Abbas and d{\textquoteright}Adamo, Pio and Adebawole Adeyemo and Dieffenbach, Aida Karina and Alan B Zonderman and Ilja M Nolte and van der Most, Peter J and Alan F Wright and Alan R Shuldiner and Alanna C Morrison and Hofman, Albert and Albert Vernon Smith and Dreisbach, Albert W and Franke, Andre and Andr{\'e} G Uitterlinden and Andres Metspalu and T{\"o}njes, Anke and Lupo, Antonio and Robino, Antonietta and Johansson, {\r A}sa and Demirkan, Ayse and Kollerits, Barbara and Freedman, Barry I and Ponte, Belen and Ben A Oostra and Paulweber, Bernhard and Kr{\"a}mer, Bernhard K and Mitchell, Braxton D and Buckley, Brendan M and Peralta, Carmen A and Caroline Hayward and Helmer, Catherine and Charles N Rotimi and Shaffer, Christian M and M{\"u}ller, Christian and Cinzia Felicita Sala and Cornelia M van Duijn and Saint-Pierre, Aude and Daniel Ackermann and Daniel Shriner and Ruggiero, Daniela and Toniolo, Daniela and Lu, Yingchang and Cusi, Daniele and Czamara, Darina and Ellinghaus, David and David S Siscovick and Ruderfer, Douglas and Gieger, Christian and Grallert, Harald and Rochtchina, Elena and Atkinson, Elizabeth J and Holliday, Elizabeth G and Boerwinkle, Eric and Salvi, Erika and Erwin P Bottinger and Murgia, Federico and Fernando Rivadeneira and Ernst, Florian and Kronenberg, Florian and Hu, Frank B and Navis, Gerjan J and Curhan, Gary C and Georg B Ehret and Homuth, Georg and Coassin, Stefan and Thun, Gian-Andri and Pistis, Giorgio and Gambaro, Giovanni and Malerba, Giovanni and Grant W Montgomery and Gu{\dh}ny Eir{\'\i}ksd{\'o}ttir and Jacobs, Gunnar and Guo Li and Wichmann, H-Erich and Campbell, Harry and Schmidt, Helena and Wallaschofski, Henri and V{\"o}lzke, Henry and Brenner, Hermann and Kroemer, Heyo K and Kramer, Holly and Lin, Honghuang and Irene Mateo Leach and Ford, Ian and Guessous, Idris and Rudan, Igor and Prokopenko, Inga and Ingrid B Borecki and Iris M Heid and Kolcic, Ivana and Persico, Ivana and Jukema, J Wouter and James F Wilson and Felix, Janine F and Divers, Jasmin and Lambert, Jean-Charles and Stafford, Jeanette M and Gaspoz, Jean-Michel and Jennifer A Smith and Jessica Faul and Wang, Jie Jin and Ding, Jingzhong and Joel N Hirschhron and John R. Attia and Whitfield, John B and Chalmers, John and Viikari, Jorma and Coresh, Josef and Denny, Joshua C and Karjalainen, Juha and Fernandes, Jyotika K and Endlich, Karlhans and Butterbach, Katja and Keene, Keith L and Kurt Lohman and Portas, Laura and Lenore J Launer and Lyytik{\"a}inen, Leo-Pekka and Yengo, Loic and Lude L Franke and Luigi Ferrucci and Rose, Lynda M and Kedenko, Lyudmyla and Rao, Madhumathi and Struchalin, Maksim and Kleber, Marcus E and Cavalieri, Margherita and Haun, Margot and Marilyn C Cornelis and Ciullo, Marina and Pirastu, Mario and de Andrade, Mariza and McEvoy, Mark A and Woodward, Mark and Adam, Martin and Cocca, Massimiliano and Nauck, Matthias and Imboden, Medea and Waldenberger, Melanie and Pruijm, Menno and Metzger, Marie and Stumvoll, Michael and Michele K Evans and Sale, Michele M and K{\"a}h{\"o}nen, Mika and Boban, Mladen and Bochud, Murielle and Rheinberger, Myriam and Verweij, Niek and Bouatia-Naji, Nabila and Nicholas G Martin and Nicholas D Hastie and Nicole M Probst-Hensch and Soranzo, Nicole and Devuyst, Olivier and Olli T Raitakari and Gottesman, Omri and Franco, Oscar H and Polasek, Ozren and Paolo P. Gasparini and Munroe, Patricia B and Ridker, Paul M and Mitchell, Paul and Muntner, Paul and Meisinger, Christa and Johannes H Smit and Kovacs, Peter and Wild, Philipp S and Froguel, Philippe and Rettig, Rainer and M{\"a}gi, Reedik and Biffar, Reiner and Schmidt, Reinhold and Middelberg, Rita P S and Carroll, Robert J and Brenda W J H Penninx and Rodney J Scott and Katz, Ronit and Sedaghat, Sanaz and Sarah Wild and Sharon L R Kardia and Ulivi, Sheila and Hwang, Shih-Jen and Enroth, Stefan and Kloiber, Stefan and Trompet, Stella and Stengel, Benedicte and Hancock, Stephen J and Stephen T Turner and Rosas, Sylvia E and Stracke, Sylvia and Tamara B Harris and Zeller, Tanja and Zemunik, Tatijana and Lehtim{\"a}ki, Terho and Illig, Thomas and Aspelund, Thor and Nikopensius, Tiit and T{\~o}nu Esko and Toshiko Tanaka and Gyllensten, Ulf and V{\"o}lker, Uwe and Emilsson, Valur and Vitart, Veronique and Aalto, Ville and Gudnason, Vilmundur and Chouraki, Vincent and Chen, Wei-Min and Igl, Wilmar and M{\"a}rz, Winfried and Koenig, Wolfgang and Lieb, Wolfgang and Ruth J F Loos and Yongmei Liu and Snieder, Harold and Pramstaller, Peter P and Parsa, Afshin and Jeff O{\textquoteright}Connell and Susztak, Katalin and Hamet, Pavel and Tremblay, Johanne and de Boer, Ian H and B{\"o}ger, Carsten A and Goessling, Wolfram and Daniel I Chasman and K{\"o}ttgen, Anna and Kao, W H Linda and Caroline S Fox} } @article {8618, title = {Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 06}, pages = {624-33}, abstract = {

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

}, keywords = {Anxiety Disorders, Bayes Theorem, depression, Genome-Wide Association Study, Humans, Neuroticism, Phenotype, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.3552}, author = {Okbay, Aysu and Baselmans, Bart M L and De Neve, Jan-Emmanuel and Turley, Patrick and Nivard, Michel G and Mark Alan Fontana and Meddens, S Fleur W and Richard Karlsson Linn{\'e}r and Cornelius A Rietveld and Derringer, Jaime and Gratten, Jacob and Lee, James J and Liu, Jimmy Z and de Vlaming, Ronald and Ahluwalia, Tarunveer S and Buchwald, Jadwiga and Cavadino, Alana and Frazier-Wood, Alexis C and Furlotte, Nicholas A and Garfield, Victoria and Geisel, Marie Henrike and Gonzalez, Juan R and Haitjema, Saskia and Karlsson, Robert and van der Laan, Sander W and Ladwig, Karl-Heinz and J. Lahti and Sven J van der Lee and Penelope A Lind and Tian Liu and Lindsay K Matteson and Mihailov, Evelin and Michael B Miller and Minica, Camelia C and Ilja M Nolte and Dennis O Mook-Kanamori and van der Most, Peter J and Christopher J Oldmeadow and Qian, Yong and Olli T Raitakari and Rawal, Rajesh and Realo, Anu and Rueedi, Rico and Schmidt, B{\"o}rge and Albert Vernon Smith and Stergiakouli, Evie and Toshiko Tanaka and Kent D Taylor and Wedenoja, Juho and J{\"u}rgen Wellmann and Westra, Harm-Jan and Willems, Sara M and Wei Zhao and Amin, Najaf and Bakshi, Andrew and Patricia A. Boyle and Cherney, Samantha and Cox, Simon R and Gail Davies and Davis, Oliver S P and Ding, Jun and Nese Direk and Eibich, Peter and Emeny, Rebecca T and Fatemifar, Ghazaleh and Jessica Faul and Luigi Ferrucci and Andreas J Forstner and Gieger, Christian and Gupta, Richa and Tamara B Harris and Harris, Juliette M and Holliday, Elizabeth G and Jouke-Jan Hottenga and Philip L de Jager and Marika A Kaakinen and Kajantie, Eero and Karhunen, Ville and Kolcic, Ivana and Kumari, Meena and Lenore J Launer and Lude L Franke and Li-Gao, Ruifang and Koini, Marisa and Loukola, Anu and Marques-Vidal, Pedro and Grant W Montgomery and Mosing, Miriam A and Paternoster, Lavinia and Pattie, Alison and Katja E Petrovic and Pulkki-Raback, Laura and Quaye, Lydia and Katri R{\"a}ikk{\"o}nen and Rudan, Igor and Rodney J Scott and Jennifer A Smith and Angelina R Sutin and Trzaskowski, Maciej and Anna A E Vinkhuyzen and Lei Yu and Zabaneh, Delilah and John R. Attia and David A Bennett and Klaus Berger and Bertram, Lars and Dorret I Boomsma and Snieder, Harold and Chang, Shun-Chiao and Francesco Cucca and Ian J Deary and Cornelia M van Duijn and Johan G Eriksson and B{\"u}ltmann, Ute and Eco J. C. de Geus and Groenen, Patrick J F and Gudnason, Vilmundur and Hansen, Torben and Catharina A Hartman and Haworth, Claire M A and Caroline Hayward and Andrew C Heath and Hinds, David A and Hypp{\"o}nen, Elina and Iacono, William G and J{\"a}rvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Kaprio, Jaakko and Sharon L R Kardia and Keltikangas-J{\"a}rvinen, Liisa and Kraft, Peter and Laura D Kubzansky and Lehtim{\"a}ki, Terho and Patrik K E Magnusson and Nicholas G Martin and McGue, Matt and Andres Metspalu and Melinda C Mills and de Mutsert, Ren{\'e}e and Oldehinkel, Albertine J and Pasterkamp, Gerard and Nancy L Pedersen and Plomin, Robert and Polasek, Ozren and Power, Christine and Rich, Stephen S and Rosendaal, Frits R and Hester M. den Ruijter and Schlessinger, David and Schmidt, Helena and Svento, Rauli and Schmidt, Reinhold and Alizadeh, Behrooz Z and Thorkild I. A. S{\o}rensen and Timothy Spector and Andrew Steptoe and Antonio Terracciano and A. Roy Thurik and Nicholas J Timpson and Henning Tiemeier and Andr{\'e} G Uitterlinden and Vollenweider, Peter and Wagner, Gert G and David R Weir and Yang, Jian and Dalton C Conley and Hofman, Albert and Johannesson, Magnus and David I Laibson and Sarah E Medland and Meyer, Michelle N and Pickrell, Joseph K and T{\~o}nu Esko and Krueger, Robert F and Jonathan P. Beauchamp and Philipp D Koellinger and Daniel J. Benjamin and Bartels, Meike and Cesarini, David} } @article {8881, title = {Genome-wide analysis identifies 12 loci influencing human reproductive behavior.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 Dec}, pages = {1462-1472}, abstract = {

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

}, issn = {1546-1718}, doi = {10.1038/ng.3698}, author = {Nicola Barban and Jansen, Rick and de Vlaming, Ronald and Vaez, Ahmad and Mandemakers, Jornt J and Felix C Tropf and Shen, Xia and James F Wilson and Daniel I Chasman and Ilja M Nolte and Tragante, Vinicius and van der Laan, Sander W and Perry, John R B and Kong, Augustine and Ahluwalia, Tarunveer S and Albrecht, Eva and Laura M Yerges-Armstrong and Atzmon, Gil and Auro, Kirsi and Kristin L. Ayers and Bakshi, Andrew and Ben-Avraham, Danny and Klaus Berger and Bergman, Aviv and Bertram, Lars and Bielak, Lawrence F and Bjornsdottir, Gyda and Bonder, Marc Jan and Broer, Linda and Bui, Minh and Barbieri, Caterina and Cavadino, Alana and Chavarro, Jorge E and Turman, Constance and Maria Pina Concas and Cordell, Heather J and Gail Davies and Eibich, Peter and Eriksson, Nicholas and T{\~o}nu Esko and Eriksson, Joel and Falahi, Fahimeh and Felix, Janine F and Mark Alan Fontana and Lude L Franke and Gandin, Ilaria and Gaskins, Audrey J and Gieger, Christian and Gunderson, Erica P and Guo, Xiuqing and Caroline Hayward and He, Chunyan and Edith Hofer and Huang, Hongyan and Joshi, Peter K and Kanoni, Stavroula and Karlsson, Robert and Kiechl, Stefan and Kifley, Annette and Kluttig, Alexander and Kraft, Peter and Lagou, Vasiliki and Lecoeur, Cecile and Lahti, Jari and Li-Gao, Ruifang and Penelope A Lind and Tian Liu and Makalic, Enes and Mamasoula, Crysovalanto and Lindsay K Matteson and Mbarek, Hamdi and McArdle, Patrick F and McMahon, George and Meddens, S Fleur W and Mihailov, Evelin and Michael B Miller and Missmer, Stacey A and Monnereau, Claire and van der Most, Peter J and Myhre, Ronny and Michael A Nalls and Nutile, Teresa and Ioanna Panagiota Kalafati and Porcu, Eleonora and Prokopenko, Inga and Rajan, Kumar B and Rich-Edwards, Janet and Cornelius A Rietveld and Robino, Antonietta and Rose, Lynda M and Rueedi, Rico and Ryan, Kathleen A and Saba, Yasaman and Schmidt, Daniel and Jennifer A Smith and Stolk, Lisette and Streeten, Elizabeth and T{\"o}njes, Anke and Thorleifsson, Gudmar and Ulivi, Sheila and Wedenoja, Juho and J{\"u}rgen Wellmann and Willeit, Peter and Yao, Jie and Yengo, Loic and Jing Hua Zhao and Wei Zhao and Zhernakova, Daria V and Amin, Najaf and Andrews, Howard and Balkau, Beverley and Barzilai, Nir and Bergmann, Sven and Biino, Ginevra and Bisgaard, Hans and B{\o}nnelykke, Klaus and Dorret I Boomsma and Buring, Julie E and Campbell, Harry and Cappellani, Stefania and Ciullo, Marina and Cox, Simon R and Francesco Cucca and Toniolo, Daniela and Davey-Smith, George and Ian J Deary and George Dedoussis and Deloukas, Panos and Cornelia M van Duijn and Eco J. C. de Geus and Johan G Eriksson and Jessica Faul and Cinzia Felicita Sala and Froguel, Philippe and Paolo P. Gasparini and Giorgia G Girotto and Hans-J{\"o}rgen Grabe and Greiser, Karin Halina and Groenen, Patrick J F and de Haan, Hugoline G and Haerting, Johannes and Tamara B Harris and Andrew C Heath and Heikkil{\"a}, Kauko and Hofman, Albert and Homuth, Georg and Holliday, Elizabeth G and John L Hopper and Hypp{\"o}nen, Elina and Jacobsson, Bo and Vincent Jaddoe and Johannesson, Magnus and Jugessur, Astanand and K{\"a}h{\"o}nen, Mika and Kajantie, Eero and Sharon L R Kardia and Keavney, Bernard and Kolcic, Ivana and Koponen, P{\"a}ivikki and Kovacs, Peter and Kronenberg, Florian and Kutalik, Zolt{\'a}n and La Bianca, Martina and Lachance, Genevieve and Iacono, William G and Lai, Sandra and Lehtim{\"a}ki, Terho and David C Liewald and Lindgren, Cecilia M and Yongmei Liu and Luben, Robert and Lucht, Michael and Luoto, Riitta and Magnus, Per and Patrik K E Magnusson and Nicholas G Martin and McGue, Matt and McQuillan, Ruth and Sarah E Medland and Meisinger, Christa and Mellstr{\"o}m, Dan and Andres Metspalu and Traglia, Michela and Lili Milani and Mitchell, Paul and Grant W Montgomery and Dennis O Mook-Kanamori and de Mutsert, Ren{\'e}e and Nohr, Ellen A and Ohlsson, Claes and Olsen, J{\o}rn and Ong, Ken K and Paternoster, Lavinia and Pattie, Alison and Brenda W J H Penninx and Markus Perola and Peyser, Patricia A and Pirastu, Mario and Polasek, Ozren and Power, Chris and Kaprio, Jaakko and Raffel, Leslie J and Katri R{\"a}ikk{\"o}nen and Olli T Raitakari and Ridker, Paul M and Ring, Susan M and Roll, Kathryn and Rudan, Igor and Ruggiero, Daniela and Rujescu, Dan and Veikko Salomaa and Schlessinger, David and Schmidt, Helena and Schmidt, Reinhold and Schupf, Nicole and Johannes H Smit and Sorice, Rossella and Timothy Spector and John M Starr and St{\"o}ckl, Doris and Strauch, Konstantin and Stumvoll, Michael and Swertz, Morris A and Thorsteinsdottir, Unnur and A. Roy Thurik and Nicholas J Timpson and Tung, Joyce Y and Andr{\'e} G Uitterlinden and Vaccargiu, Simona and Viikari, Jorma and Vitart, Veronique and V{\"o}lzke, Henry and Vollenweider, Peter and Vuckovic, Dragana and Waage, Johannes and Wagner, Gert G and Wang, Jie Jin and Wareham, Nicholas J and David R Weir and Gonneke Willemsen and Willeit, Johann and Alan F Wright and Krina T Zondervan and Stefansson, Kari and Krueger, Robert F and Lee, James J and Daniel J. Benjamin and Cesarini, David and Philipp D Koellinger and den Hoed, Marcel and Snieder, Harold and Melinda C Mills} } @article {8883, title = {Genome-wide association study identifies 74 loci associated with educational attainment.}, journal = {Nature}, volume = {533}, year = {2016}, month = {2016 05 26}, pages = {539-42}, abstract = {

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20\% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

}, keywords = {Alzheimer{\textquoteright}s disease, Bipolar Disorder, Cognitive Ability, Education, Fetus, Genome-Wide Association Study, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Schizophrenia, United Kingdom}, issn = {1476-4687}, doi = {10.1038/nature17671}, author = {Okbay, Aysu and Jonathan P. Beauchamp and Mark Alan Fontana and Lee, James J and Pers, Tune H and Cornelius A Rietveld and Turley, Patrick and Chen, Guo-Bo and Emilsson, Valur and Meddens, S Fleur W and Oskarsson, Sven and Pickrell, Joseph K and Thom, Kevin and Pascal N Timshel and de Vlaming, Ronald and Abdel Abdellaoui and Ahluwalia, Tarunveer S and Bacelis, Jonas and Baumbach, Clemens and Bjornsdottir, Gyda and Brandsma, Johannes H and Maria Pina Concas and Derringer, Jaime and Furlotte, Nicholas A and Galesloot, Tessel E and Giorgia G Girotto and Gupta, Richa and Hall, Leanne M and Sarah E Harris and Edith Hofer and Horikoshi, Momoko and Huffman, Jennifer E and Kaasik, Kadri and Ioanna Panagiota Kalafati and Karlsson, Robert and Kong, Augustine and Lahti, Jari and Sven J van der Lee and Christiaan de Leeuw and Penelope A Lind and Lindgren, Karl-Oskar and Tian Liu and Mangino, Massimo and Marten, Jonathan and Mihailov, Evelin and Michael B Miller and van der Most, Peter J and Christopher J Oldmeadow and Payton, Antony and Pervjakova, Natalia and Wouter J Peyrot and Qian, Yong and Olli T Raitakari and Rueedi, Rico and Salvi, Erika and Schmidt, B{\"o}rge and Schraut, Katharina E and Jianxin Shi and Albert Vernon Smith and Poot, Raymond A and St Pourcain, Beate and Teumer, Alexander and Thorleifsson, Gudmar and Verweij, Niek and Vuckovic, Dragana and J{\"u}rgen Wellmann and Westra, Harm-Jan and Yang, Jingyun and Wei Zhao and Zhihong Zhu and Alizadeh, Behrooz Z and Amin, Najaf and Bakshi, Andrew and Baumeister, Sebastian E and Biino, Ginevra and B{\o}nnelykke, Klaus and Patricia A. Boyle and Campbell, Harry and Cappuccio, Francesco P and Gail Davies and De Neve, Jan-Emmanuel and Deloukas, Panos and Demuth, Ilja and Ding, Jun and Eibich, Peter and Eisele, Lewin and Eklund, Niina and Jessica Faul and Feitosa, Mary F and Andreas J Forstner and Gandin, Ilaria and Gunnarsson, Bjarni and Halld{\'o}rsson, Bjarni V and Tamara B Harris and Andrew C Heath and Lynne J Hocking and Holliday, Elizabeth G and Homuth, Georg and Horan, Michael A and Jouke-Jan Hottenga and Philip L de Jager and Joshi, Peter K and Jugessur, Astanand and Marika A Kaakinen and K{\"a}h{\"o}nen, Mika and Kanoni, Stavroula and Keltigangas-J{\"a}rvinen, Liisa and Lambertus A Kiemeney and Kolcic, Ivana and Koskinen, Seppo and Kraja, Aldi T and Kroh, Martin and Kutalik, Zolt{\'a}n and Latvala, Antti and Lenore J Launer and Lebreton, Ma{\"e}l P and Douglas F Levinson and Paul Lichtenstein and Lichtner, Peter and David C Liewald and Loukola, Anu and Pamela A F Madden and M{\"a}gi, Reedik and M{\"a}ki-Opas, Tomi and Riccardo E Marioni and Marques-Vidal, Pedro and Meddens, Gerardus A and McMahon, George and Meisinger, Christa and Meitinger, Thomas and Milaneschi, Yusplitri and Lili Milani and Grant W Montgomery and Myhre, Ronny and Nelson, Christopher P and Nyholt, Dale R and William E R Ollier and Aarno Palotie and Paternoster, Lavinia and Nancy L Pedersen and Katja E Petrovic and David J Porteous and Katri R{\"a}ikk{\"o}nen and Ring, Susan M and Robino, Antonietta and Rostapshova, Olga and Rudan, Igor and Rustichini, Aldo and Veikko Salomaa and Sanders, Alan R and Sarin, Antti-Pekka and Schmidt, Helena and Rodney J Scott and Smith, Blair H and Jennifer A Smith and Staessen, Jan A and Steinhagen-Thiessen, Elisabeth and Strauch, Konstantin and Antonio Terracciano and Tobin, Martin D and Ulivi, Sheila and Vaccargiu, Simona and Quaye, Lydia and van Rooij, Frank J A and Venturini, Cristina and Anna A E Vinkhuyzen and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Vonk, Judith M and Vozzi, Diego and Waage, Johannes and Erin B Ware and Gonneke Willemsen and John R. Attia and David A Bennett and Klaus Berger and Bertram, Lars and Bisgaard, Hans and Dorret I Boomsma and Ingrid B Borecki and B{\"u}ltmann, Ute and Chabris, Christopher F and Francesco Cucca and Cusi, Daniele and Ian J Deary and George Dedoussis and Cornelia M van Duijn and Johan G Eriksson and Franke, Barbara and Lude L Franke and Paolo P. Gasparini and Gejman, Pablo V and Gieger, Christian and Hans-J{\"o}rgen Grabe and Gratten, Jacob and Groenen, Patrick J F and Gudnason, Vilmundur and van der Harst, Pim and Caroline Hayward and Hinds, David A and Hoffmann, Wolfgang and Hypp{\"o}nen, Elina and Iacono, William G and Jacobsson, Bo and J{\"a}rvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Kaprio, Jaakko and Sharon L R Kardia and Lehtim{\"a}ki, Terho and Lehrer, Steven F and Patrik K E Magnusson and Nicholas G Martin and McGue, Matt and Andres Metspalu and Pendleton, Neil and Brenda W J H Penninx and Markus Perola and Nicola Pirastu and Pirastu, Mario and Polasek, Ozren and Posthuma, Danielle and Power, Christine and Province, Michael A and Nilesh J Samani and Schlessinger, David and Schmidt, Reinhold and Thorkild I. A. S{\o}rensen and Timothy Spector and Stefansson, Kari and Thorsteinsdottir, Unnur and A. Roy Thurik and Nicholas J Timpson and Henning Tiemeier and Tung, Joyce Y and Andr{\'e} G Uitterlinden and Vitart, Veronique and Vollenweider, Peter and David R Weir and James F Wilson and Alan F Wright and Dalton C Conley and Krueger, Robert F and George Davey Smith and Hofman, Albert and David I Laibson and Sarah E Medland and Meyer, Michelle N and Yang, Jian and Johannesson, Magnus and Peter M Visscher and T{\~o}nu Esko and Philipp D Koellinger and Cesarini, David and Daniel J. Benjamin} } @article {8619, title = {The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25,000 subjects.}, journal = {Mol Psychiatry}, volume = {20}, year = {2015}, month = {2015 Jun}, pages = {735-43}, abstract = {

An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14,949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15,138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884,105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on ~120,000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status.

}, keywords = {Adult, Aged, Cohort Studies, Depressive Disorder, Major, Educational Status, Estonia, Female, Gene-Environment Interaction, Genetic Association Studies, Genotype, Humans, Likelihood Functions, Male, Middle Aged, Netherlands, Odds Ratio, Polymorphism, Single Nucleotide, Psychiatric Status Rating Scales, Regression Analysis}, issn = {1476-5578}, doi = {10.1038/mp.2015.50}, author = {Wouter J Peyrot and Lee, S H and Milaneschi, Y and Abdel Abdellaoui and Byrne, E M and T{\~o}nu Esko and Eco J. C. de Geus and Hemani, G and Jouke-Jan Hottenga and Kloiber, S and Douglas F Levinson and Lucae, S and Nicholas G Martin and Sarah E Medland and Andres Metspalu and Lili Milani and Markus M N{\"o}then and Potash, J B and Rietschel, M and Cornelius A Rietveld and Ripke, S and Jianxin Shi and Gonneke Willemsen and Zhihong Zhu and Dorret I Boomsma and Naomi R. Wray and Brenda W J H Penninx} } @article {8884, title = {Directional dominance on stature and cognition in~diverse human populations.}, journal = {Nature}, volume = {523}, year = {2015}, month = {2015 Jul 23}, pages = {459-62}, abstract = {

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs~of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 {\texttimes} 10(-300), 2.1 {\texttimes} 10(-6), 2.5 {\texttimes} 10(-10) and 1.8 {\texttimes} 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months{\textquoteright} less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

}, keywords = {Biological Evolution, Blood pressure, Body Height, Cholesterol, Cognitive Ability, Cohort Studies, Education, Female, Forced Expiratory Volume, Genome, Homozygote, Humans, Lung Volume Measurements, Male, Phenotype}, issn = {1476-4687}, doi = {10.1038/nature14618}, author = {Joshi, Peter K and T{\~o}nu Esko and Mattsson, Hannele and Eklund, Niina and Gandin, Ilaria and Nutile, Teresa and Jackson, Anne U and Schurmann, Claudia and Albert Vernon Smith and Zhang, Weihua and Okada, Yukinori and Stan{\v c}{\'a}kov{\'a}, Alena and Jessica Faul and Wei Zhao and Traci M Bartz and Maria Pina Concas and Franceschini, Nora and Enroth, Stefan and Vitart, Veronique and Trompet, Stella and Guo, Xiuqing and Daniel I Chasman and Jeff O{\textquoteright}Connell and Corre, Tanguy and Nongmaithem, Suraj S and Chen, Yuning and Mangino, Massimo and Ruggiero, Daniela and Traglia, Michela and Farmaki, Aliki-Eleni and Kacprowski, Tim and Bjonnes, Andrew and van der Spek, Ashley and Wu, Ying and Giri, Anil K and Yanek, Lisa R and Wang, Lihua and Edith Hofer and Cornelius A Rietveld and McLeod, Olga and Marilyn C Cornelis and Pattaro, Cristian and Verweij, Niek and Baumbach, Clemens and Abdel Abdellaoui and Warren, Helen R and Vuckovic, Dragana and Mei, Hao and Bouchard, Claude and Perry, John R B and Cappellani, Stefania and Saira S Mirza and Benton, Miles C and Broeckel, Ulrich and Sarah E Medland and Penelope A Lind and Malerba, Giovanni and Alexander W Drong and Yengo, Loic and Bielak, Lawrence F and Zhi, Degui and van der Most, Peter J and Daniel Shriner and M{\"a}gi, Reedik and Hemani, Gibran and Karaderi, Tugce and Wang, Zhaoming and Tian Liu and Demuth, Ilja and Jing Hua Zhao and Meng, Weihua and Lataniotis, Lazaros and van der Laan, Sander W and Bradfield, Jonathan P and Andrew R Wood and Bonnefond, Amelie and Ahluwalia, Tarunveer S and Hall, Leanne M and Salvi, Erika and Yazar, Seyhan and Carstensen, Lisbeth and de Haan, Hugoline G and Abney, Mark and Afzal, Uzma and Matthew A. Allison and Amin, Najaf and Asselbergs, Folkert W and Bakker, Stephan J L and Barr, R Graham and Baumeister, Sebastian E and Daniel J. Benjamin and Bergmann, Sven and Boerwinkle, Eric and Erwin P Bottinger and Campbell, Archie and Chakravarti, Aravinda and Chan, Yingleong and Chanock, Stephen J and Chen, Constance and Yii-Der I Chen and Collins, Francis S and Connell, John and Correa, Adolfo and Cupples, L Adrienne and Gail Davies and D{\"o}rr, Marcus and Georg B Ehret and Ellis, Stephen B and Feenstra, Bjarke and Feitosa, Mary F and Ford, Ian and Caroline S Fox and Timothy M Frayling and Friedrich, Nele and Geller, Frank and Scotland, Generation and Gillham-Nasenya, Irina and Gottesman, Omri and Graff, Misa and Grodstein, Francine and Gu, Charles and Haley, Chris and Hammond, Christopher J and Sarah E Harris and Tamara B Harris and Nicholas D Hastie and Heard-Costa, Nancy L and Heikkil{\"a}, Kauko and Lynne J Hocking and Homuth, Georg and Jouke-Jan Hottenga and Huang, Jinyan and Huffman, Jennifer E and Hysi, Pirro G and Mohammed Arfan Ikram and Ingelsson, Erik and Joensuu, Anni and Johansson, {\r A}sa and Jousilahti, Pekka and Jukema, J Wouter and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanoni, Stavroula and Kerr, Shona M and Khan, Nazir M and Philipp D Koellinger and Koistinen, Heikki A and Kooner, Manraj K and Kubo, Michiaki and Kuusisto, Johanna and Lahti, Jari and Lenore J Launer and Lea, Rodney A and Lehne, Benjamin and Lehtim{\"a}ki, Terho and David C Liewald and Lars Lind and Loh, Marie and Lokki, Marja-Liisa and London, Stephanie J and Loomis, Stephanie J and Loukola, Anu and Lu, Yingchang and Lumley, Thomas and Lundqvist, Annamari and M{\"a}nnist{\"o}, Satu and Marques-Vidal, Pedro and Masciullo, Corrado and Matchan, Angela and Mathias, Rasika A and Matsuda, Koichi and Meigs, James B and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Mentch, Frank D and Mihailov, Evelin and Lili Milani and Montasser, May E and Grant W Montgomery and Alanna C Morrison and Myers, Richard H and Nadukuru, Rajiv and Navarro, Pau and Nelis, Mari and Nieminen, Markku S and Ilja M Nolte and O{\textquoteright}Connor, George T and Ogunniyi, Adesola and Padmanabhan, Sandosh and Walter R Palmas and Pankow, James S and Patarcic, Inga and Pavani, Francesca and Peyser, Patricia A and Pietilainen, Kirsi and Neil Poulter and Prokopenko, Inga and Ralhan, Sarju and Redmond, Paul and Rich, Stephen S and Rissanen, Harri and Robino, Antonietta and Rose, Lynda M and Rose, Richard and Cinzia Felicita Sala and Babatunde Salako and Veikko Salomaa and Sarin, Antti-Pekka and Saxena, Richa and Schmidt, Helena and Scott, Laura J and Scott, William R and Sennblad, Bengt and Seshadri, Sudha and Peter Sever and Shrestha, Smeeta and Smith, Blair H and Jennifer A Smith and Soranzo, Nicole and Sotoodehnia, Nona and Southam, Lorraine and Stanton, Alice V and Stathopoulou, Maria G and Strauch, Konstantin and Strawbridge, Rona J and Suderman, Matthew J and Tandon, Nikhil and Tang, Sian-Tsun and Kent D Taylor and Bamidele O Tayo and T{\"o}glhofer, Anna Maria and Tomaszewski, Maciej and T{\v s}ernikova, Natalia and Tuomilehto, Jaakko and Andr{\'e} G Uitterlinden and Vaidya, Dhananjay and van Hylckama Vlieg, Astrid and van Setten, Jessica and Vasankari, Tuula and Vedantam, Sailaja and Vlachopoulou, Efthymia and Vozzi, Diego and Vuoksimaa, Eero and Waldenberger, Melanie and Erin B Ware and Wentworth-Shields, William and Whitfield, John B and Sarah Wild and Gonneke Willemsen and Yajnik, Chittaranjan S and Yao, Jie and Zaza, Gianluigi and Zhu, Xiaofeng and Salem, Rany M and Melbye, Mads and Bisgaard, Hans and Nilesh J Samani and Cusi, Daniele and Mackey, David A and Cooper, Richard S and Froguel, Philippe and Pasterkamp, Gerard and Grant, Struan F A and Hakonarson, Hakon and Luigi Ferrucci and Scott, Robert A and Morris, Andrew D and Palmer, Colin N A and George Dedoussis and Deloukas, Panos and Bertram, Lars and Lindenberger, Ulman and Berndt, Sonja I and Lindgren, Cecilia M and Nicholas J Timpson and T{\"o}njes, Anke and Munroe, Patricia B and Thorkild I. A. S{\o}rensen and Charles N Rotimi and Donna K Arnett and Oldehinkel, Albertine J and Sharon L R Kardia and Balkau, Beverley and Gambaro, Giovanni and Morris, Andrew P and Johan G Eriksson and Margaret J Wright and Nicholas G Martin and Hunt, Steven C and John M Starr and Ian J Deary and Griffiths, Lyn R and Henning Tiemeier and Nicola Pirastu and Kaprio, Jaakko and Wareham, Nicholas J and P{\'e}russe, Louis and Wilson, James G and Giorgia G Girotto and Caulfield, Mark J and Olli T Raitakari and Dorret I Boomsma and Gieger, Christian and van der Harst, Pim and Hicks, Andrew A and Kraft, Peter and Sinisalo, Juha and Knekt, Paul and Johannesson, Magnus and Patrik K E Magnusson and Hamsten, Anders and Schmidt, Reinhold and Ingrid B Borecki and Vartiainen, Erkki and Becker, Diane M and Bharadwaj, Dwaipayan and Mohlke, Karen L and Boehnke, Michael and Cornelia M van Duijn and Sanghera, Dharambir K and Teumer, Alexander and Zeggini, Eleftheria and Andres Metspalu and Paolo P. Gasparini and Ulivi, Sheila and Ober, Carole and Toniolo, Daniela and Rudan, Igor and David J Porteous and Ciullo, Marina and Timothy Spector and Caroline Hayward and Dupuis, Jos{\'e}e and Ruth J F Loos and Alan F Wright and Chandak, Giriraj R and Vollenweider, Peter and Alan R Shuldiner and Ridker, Paul M and Rotter, Jerome I and Sattar, Naveed and Gyllensten, Ulf and Kari E North and Pirastu, Mario and Psaty, Bruce M and David R Weir and Laakso, Markku and Gudnason, Vilmundur and Takahashi, Atsushi and Chambers, John C and Kooner, Jaspal S and David P Strachan and Campbell, Harry and Joel N Hirschhron and Markus Perola and Polasek, Ozren and James F Wilson} } @article {8882, title = {Genetic studies of body mass index yield new insights for obesity biology.}, journal = {Nature}, volume = {518}, year = {2015}, month = {2015 Feb 12}, pages = {197-206}, abstract = {

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P~<~5~{\texttimes}~10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for \~{}2.7\% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20\% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

}, keywords = {Age Factors, BMI, Continental Population Groups, Energy Metabolism, Europe, Female, Genome-Wide Association Study, Glutamic Acid, Humans, Insulin, Male, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Synapses}, issn = {1476-4687}, doi = {10.1038/nature14177}, author = {Locke, Adam E and Kahali, Bratati and Berndt, Sonja I and Justice, Anne E and Pers, Tune H and Day, Felix R and Powell, Corey and Vedantam, Sailaja and Buchkovich, Martin L and Yang, Jian and Croteau-Chonka, Damien C and T{\~o}nu Esko and Fall, Tove and Ferreira, Teresa and Gustafsson, Stefan and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Randall, Joshua C and Thomas W Winkler and Andrew R Wood and Workalemahu, Tsegaselassie and Jessica Faul and Jennifer A Smith and Jing Hua Zhao and Wei Zhao and Chen, Jin and Rudolf Ferhmann and Hedman, {\r A}sa K and Karjalainen, Juha and Schmidt, Ellen M and Absher, Devin and Amin, Najaf and Anderson, Denise and Beekman, Marian and Bolton, Jennifer L and Bragg-Gresham, Jennifer L and Buyske, Steven and Demirkan, Ayse and Deng, Guohong and Georg B Ehret and Feenstra, Bjarke and Feitosa, Mary F and Fischer, Krista and Goel, Anuj and Gong, Jian and Jackson, Anne U and Kanoni, Stavroula and Kleber, Marcus E and Kristiansson, Kati and Lim, Unhee and Lotay, Vaneet and Mangino, Massimo and Irene Mateo Leach and Medina-Gomez, Carolina and Sarah E Medland and Michael A Nalls and Palmer, Cameron D and Pasko, Dorota and Pechlivanis, Sonali and Peters, Marjolein J and Prokopenko, Inga and Shungin, Dmitry and Stan{\v c}{\'a}kov{\'a}, Alena and Strawbridge, Rona J and Yun Ju Sung and Toshiko Tanaka and Teumer, Alexander and Trompet, Stella and van der Laan, Sander W and van Setten, Jessica and Jana V. van Vliet-Ostaptchouk and Wang, Zhaoming and Yengo, Loic and Zhang, Weihua and Isaacs, Aaron and Albrecht, Eva and {\"A}rnl{\"o}v, Johan and Arscott, Gillian M and Attwood, Antony P and Bandinelli, Stefania and Barrett, Amy and Bas, Isabelita N and Bellis, Claire and Bennett, Amanda J and Berne, Christian and Blagieva, Roza and Bl{\"u}her, Matthias and B{\"o}hringer, Stefan and Bonnycastle, Lori L and B{\"o}ttcher, Yvonne and Boyd, Heather A and Bruinenberg, Marcel and Caspersen, Ida H and Yii-Der I Chen and Robert Clark and Daw, E Warwick and de Craen, Anton J M and Delgado, Graciela and Dimitriou, Maria and Doney, Alex S F and Eklund, Niina and Estrada, Karol and Eury, Elodie and Folkersen, Lasse and Fraser, Ross M and Melissa E Garcia and Geller, Frank and Giedraitis, Vilmantas and Gigante, Bruna and Alan S Go and Golay, Alain and Goodall, Alison H and Gordon, Scott D and Gorski, Mathias and Hans-J{\"o}rgen Grabe and Grallert, Harald and Grammer, Tanja B and Gr{\"a}{\ss}ler, J{\"u}rgen and Gr{\"o}nberg, Henrik and Groves, Christopher J and Gusto, Ga{\"e}lle and Jeffrey Haessler and Hall, Per and Haller, Toomas and Hallmans, G{\"o}ran and Catharina A Hartman and Hassinen, Maija and Caroline Hayward and Heard-Costa, Nancy L and Helmer, Quinta and Hengstenberg, Christian and Oddgeir L Holmen and Jouke-Jan Hottenga and James, Alan L and Janina Jeff and Johansson, {\r A}sa and Jolley, Jennifer and Juliusdottir, Thorhildur and Kinnunen, Leena and Koenig, Wolfgang and Koskenvuo, Markku and Kratzer, Wolfgang and Laitinen, Jaana and Lamina, Claudia and Leander, Karin and Lee, Nanette R and Lichtner, Peter and Lars Lind and Lindstr{\"o}m, Jaana and Ken Sin Lo and Lobbens, St{\'e}phane and Lorbeer, Roberto and Lu, Yingchang and Mach, Fran{\c c}ois and Patrik K E Magnusson and Mahajan, Anubha and McArdle, Wendy L and McLachlan, Stela and Menni, Cristina and Merger, Sigrun and Mihailov, Evelin and Lili Milani and Moayyeri, Alireza and Monda, Keri L and Morken, Mario A and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Musk, Arthur W and Nagaraja, Ramaiah and Markus M N{\"o}then and Ilja M Nolte and Pilz, Stefan and Nigel W Rayner and Renstrom, Frida and Rettig, Rainer and Ried, Janina S and Ripke, Stephan and Neil R Robertson and Rose, Lynda M and Sanna, Serena and Scharnagl, Hubert and Scholtens, Salome and Schumacher, Fredrick R and Scott, William R and Seufferlein, Thomas and Jianxin Shi and Albert Vernon Smith and Smolonska, Joanna and Stanton, Alice V and Steinthorsdottir, Valgerdur and Kathleen E Stirrups and Heather M Stringham and Sundstr{\"o}m, Johan and Swertz, Morris A and Swift, Amy J and Syv{\"a}nen, Ann-Christine and Tan, Sian-Tsung and Bamidele O Tayo and Thorand, Barbara and Thorleifsson, Gudmar and Tyrer, Jonathan P and Uh, Hae-Won and Vandenput, Liesbeth and Verhulst, Frank C and Vermeulen, Sita H and Verweij, Niek and Vonk, Judith M and Lindsay L Waite and Warren, Helen R and Dawn M Waterworth and Michael N Weedon and Wilkens, Lynne R and Willenborg, Christina and Wilsgaard, Tom and Wojczynski, Mary K and Wong, Andrew and Alan F Wright and Zhang, Qunyuan and Brennan, Eoin P and Murim Choi and Dastani, Zari and Alexander W Drong and Eriksson, Per and Franco-Cereceda, Anders and G{\r a}din, Jesper R and Gharavi, Ali G and Goddard, Michael E and Handsaker, Robert E and Huang, Jinyan and Karpe, Fredrik and Kathiresan, Sekar and Keildson, Sarah and Kiryluk, Krzysztof and Kubo, Michiaki and Lee, Jong-Young and Liang, Liming and Lifton, Richard P and Ma, Baoshan and McCarroll, Steven A and McKnight, Amy J and Min, Josine L and Moffatt, Miriam F and Grant W Montgomery and Joanne M Murabito and Nicholson, George and Nyholt, Dale R and Okada, Yukinori and Perry, John R B and Dorajoo, Rajkumar and Reinmaa, Eva and Salem, Rany M and Sandholm, Niina and Scott, Robert A and Stolk, Lisette and Takahashi, Atsushi and Tanaka, Toshihiro and Ferdinand M van {\textquoteright}t Hooft and Anna A E Vinkhuyzen and Westra, Harm-Jan and Wei Zhang and Krina T Zondervan and Andrew C Heath and Arveiler, Dominique and Bakker, Stephan J L and Beilby, John and Bergman, Richard N and Blangero, John and Bovet, Pascal and Campbell, Harry and Caulfield, Mark J and Cesana, Giancarlo and Chakravarti, Aravinda and Daniel I Chasman and Chines, Peter S and Collins, Francis S and Crawford, Dana C and Cupples, L Adrienne and Cusi, Daniele and Danesh, John and de Faire, Ulf and Hester M den Ruijter and Dominiczak, Anna F and Erbel, Raimund and Erdmann, Jeanette and Johan G Eriksson and Farrall, Martin and Felix, Stephan B and Ferrannini, Ele and Ferri{\`e}res, Jean and Ford, Ian and Forouhi, Nita G and Forrester, Terrence and Franco, Oscar H and Gansevoort, Ron T and Gejman, Pablo V and Gieger, Christian and Gottesman, Omri and Gudnason, Vilmundur and Gyllensten, Ulf and Hall, Alistair S and Tamara B Harris and Andrew T Hattersley and Hicks, Andrew A and Hindorff, Lucia A and Aroon Hingorani and Hofman, Albert and Homuth, Georg and Hovingh, G Kees and Humphries, Steve E and Hunt, Steven C and Hypp{\"o}nen, Elina and Illig, Thomas and Jacobs, Kevin B and J{\"a}rvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Johansen, Berit and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti M and Kaprio, Jaakko and Kastelein, John J P and Keinanen-Kiukaanniemi, Sirkka M and Lambertus A Kiemeney and Knekt, Paul and Kooner, Jaspal S and Charles Kooperberg and Kovacs, Peter and Kraja, Aldi T and Kumari, Meena and Kuusisto, Johanna and Lakka, Timo A and Langenberg, Claudia and Loic Le Marchand and Lehtim{\"a}ki, Terho and Lyssenko, Valeriya and M{\"a}nnist{\"o}, Satu and Marette, Andr{\'e} and Matise, Tara C and McKenzie, Colin A and McKnight, Barbara and Moll, Frans L and Morris, Andrew D and Morris, Andrew P and Murray, Jeffrey C and Nelis, Mari and Ohlsson, Claes and Oldehinkel, Albertine J and Ong, Ken K and Pamela A F Madden and Pasterkamp, Gerard and Peden, John F and Peters, Annette and Postma, Dirkje S and Pramstaller, Peter P and Price, Jackie F and Qi, Lu and Olli T Raitakari and Rankinen, Tuomo and Rao, D C and Rice, Treva K and Ridker, Paul M and Rioux, John D and Ritchie, Marylyn D and Rudan, Igor and Veikko Salomaa and Nilesh J Samani and Saramies, Jouko and Sarzynski, Mark A and Schunkert, Heribert and Schwarz, Peter E H and Peter Sever and Alan R Shuldiner and Sinisalo, Juha and Stolk, Ronald P and Strauch, Konstantin and T{\"o}njes, Anke and Tr{\'e}gou{\"e}t, David-Alexandre and Tremblay, Angelo and Tremoli, Elena and Virtamo, Jarmo and Vohl, Marie-Claude and V{\"o}lker, Uwe and Waeber, G{\'e}rard and Gonneke Willemsen and Witteman, Jacqueline C and Zillikens, M Carola and Adair, Linda S and Amouyel, Philippe and Asselbergs, Folkert W and Assimes, Themistocles L and Bochud, Murielle and Boehm, Bernhard O and Boerwinkle, Eric and Bornstein, Stefan R and Erwin P Bottinger and Bouchard, Claude and Cauchi, St{\'e}phane and Chambers, John C and Chanock, Stephen J and Cooper, Richard S and de Bakker, Paul I W and George Dedoussis and Luigi Ferrucci and Franks, Paul W and Froguel, Philippe and Leif C Groop and Christopher A Haiman and Hamsten, Anders and Hui, Jennie and Hunter, David J and Hveem, Kristian and Kaplan, Robert C and Mika Kivim{\"a}ki and Kuh, Diana and Laakso, Markku and Yongmei Liu and Nicholas G Martin and M{\"a}rz, Winfried and Melbye, Mads and Andres Metspalu and Moebus, Susanne and Munroe, Patricia B and Nj{\o}lstad, Inger and Ben A Oostra and Palmer, Colin N A and Nancy L Pedersen and Markus Perola and P{\'e}russe, Louis and Peters, Ulrike and Power, Chris and Quertermous, Thomas and Rauramaa, Rainer and Fernando Rivadeneira and Saaristo, Timo E and Saleheen, Danish and Sattar, Naveed and Eric E Schadt and Schlessinger, David and Eline P Slagboom and Snieder, Harold and Timothy Spector and Thorsteinsdottir, Unnur and Stumvoll, Michael and Tuomilehto, Jaakko and Andr{\'e} G Uitterlinden and Uusitupa, Matti and van der Harst, Pim and Walker, Mark and Wallaschofski, Henri and Wareham, Nicholas J and Watkins, Hugh and David R Weir and Wichmann, H-Erich and James F Wilson and Zanen, Pieter and Ingrid B Borecki and Deloukas, Panos and Caroline S Fox and Iris M Heid and Jeff O{\textquoteright}Connell and David P Strachan and Stefansson, Kari and Cornelia M van Duijn and Gon{\c c}alo R Abecasis and Lude L Franke and Timothy M Frayling and McCarthy, Mark I and Peter M Visscher and Scherag, Andre and Willer, Cristen J and Boehnke, Michael and Mohlke, Karen L and Lindgren, Cecilia M and Beckmann, Jacques S and Barroso, In{\^e}s and Kari E North and Ingelsson, Erik and Joel N Hirschhron and Ruth J F Loos and Elizabeth K Speliotes} } @article {8889, title = {Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Nov}, pages = {1294-303}, abstract = {

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in \~{}70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (\~{}6\% increase in risk per year; P = 3 {\texttimes} 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

}, keywords = {Age Factors, Aging, BRCA1 Protein, Breast Neoplasms, DNA Repair, Female, Genome, Genome-Wide Association Study, Genotype, Humans, Hypothalamus, Menopause, Middle Aged, Models, Genetic, Older Adults, Phenotype, Reproduction, Signal Transduction}, issn = {1546-1718}, doi = {10.1038/ng.3412}, author = {Day, Felix R and Ruth, Katherine S and Thompson, Deborah J and Kathryn L Lunetta and Pervjakova, Natalia and Daniel I Chasman and Stolk, Lisette and Finucane, Hilary K and Sulem, Patrick and Bulik-Sullivan, Brendan and T{\~o}nu Esko and Andrew D Johnson and Elks, Cathy E and Franceschini, Nora and He, Chunyan and Altmaier, Elisabeth and Brody, Jennifer A and Lude L Franke and Huffman, Jennifer E and Keller, Margaux F and McArdle, Patrick F and Nutile, Teresa and Porcu, Eleonora and Robino, Antonietta and Rose, Lynda M and Schick, Ursula M and Jennifer A Smith and Teumer, Alexander and Traglia, Michela and Vuckovic, Dragana and Yao, Jie and Wei Zhao and Albrecht, Eva and Amin, Najaf and Corre, Tanguy and Jouke-Jan Hottenga and Mangino, Massimo and Albert Vernon Smith and Toshiko Tanaka and Gon{\c c}alo R Abecasis and Andrulis, Irene L and Anton-Culver, Hoda and Antoniou, Antonis C and Arndt, Volker and Alice M. Arnold and Barbieri, Caterina and Beckmann, Matthias W and Beeghly-Fadiel, Alicia and Benitez, Javier and Bernstein, Leslie and Bielinski, Suzette J and Blomqvist, Carl and Boerwinkle, Eric and Bogdanova, Natalia V and Bojesen, Stig E and Manjeet K. Bolla and Borresen-Dale, Anne-Lise and Boutin, Thibaud S and Brauch, Hiltrud and Brenner, Hermann and Br{\"u}ning, Thomas and Burwinkel, Barbara and Campbell, Archie and Campbell, Harry and Chanock, Stephen J and Chapman, J Ross and Yii-Der I Chen and Chenevix-Trench, Georgia and Couch, Fergus J and Coviello, Andrea D and Cox, Angela and Czene, Kamila and Darabi, Hatef and De Vivo, Immaculata and Ellen W Demerath and Joe G Dennis and Devilee, Peter and D{\"o}rk, Thilo and Dos-Santos-Silva, Isabel and Dunning, Alison M and John D Eicher and Fasching, Peter A and Jessica Faul and Figueroa, Jonine and Flesch-Janys, Dieter and Gandin, Ilaria and Melissa E Garcia and Garc{\'\i}a-Closas, Montserrat and Giles, Graham G and Giorgia G Girotto and Goldberg, Mark S and Gonz{\'a}lez-Neira, Anna and Goodarzi, Mark O and Grove, Megan L and Gudbjartsson, Daniel F and Gu{\'e}nel, Pascal and Guo, Xiuqing and Christopher A Haiman and Hall, Per and Hamann, Ute and Henderson, Brian E and Lynne J Hocking and Hofman, Albert and Homuth, Georg and Hooning, Maartje J and John L Hopper and Hu, Frank B and Huang, Jinyan and Humphreys, Keith and Hunter, David J and Jakubowska, Anna and Jones, Samuel E and Kabisch, Maria and Karasik, David and Knight, Julia A and Kolcic, Ivana and Charles Kooperberg and Kosma, Veli-Matti and Kriebel, Jennifer and Kristensen, Vessela and Lambrechts, Diether and Langenberg, Claudia and Li, Jingmei and Li, Xin and Lindstr{\"o}m, Sara and Yongmei Liu and Luan, Jian{\textquoteright}an and Lubinski, Jan and M{\"a}gi, Reedik and Mannermaa, Arto and Manz, Judith and Margolin, Sara and Marten, Jonathan and Nicholas G Martin and Masciullo, Corrado and Meindl, Alfons and Michailidou, Kyriaki and Mihailov, Evelin and Lili Milani and Milne, Roger L and M{\"u}ller-Nurasyid, Martina and Michael A Nalls and Neale, Benjamin M and Nevanlinna, Heli and Neven, Patrick and Anne B Newman and B{\o}rge G Nordestgaard and Olson, Janet E and Padmanabhan, Sandosh and Peterlongo, Paolo and Peters, Ulrike and Petersmann, Astrid and Peto, Julian and Pharoah, Paul D P and Nicola Pirastu and Pirie, Ailith and Pistis, Giorgio and Polasek, Ozren and David J Porteous and Psaty, Bruce M and Pylk{\"a}s, Katri and Radice, Paolo and Raffel, Leslie J and Fernando Rivadeneira and Rudan, Igor and Rudolph, Anja and Ruggiero, Daniela and Cinzia Felicita Sala and Sanna, Serena and Sawyer, Elinor J and Schlessinger, David and Schmidt, Marjanka K and Schmidt, Frank and Schmutzler, Rita K and Schoemaker, Minouk J and Scott, Robert A and Seynaeve, Caroline M and Simard, Jacques and Sorice, Rossella and Southey, Melissa C and St{\"o}ckl, Doris and Strauch, Konstantin and Swerdlow, Anthony and Kent D Taylor and Thorsteinsdottir, Unnur and Toland, Amanda E and Tomlinson, Ian and Truong, Th{\'e}r{\`e}se and Tryggvadottir, Laufey and Stephen T Turner and Vozzi, Diego and Wang, Qin and Wellons, Melissa and Gonneke Willemsen and James F Wilson and Winqvist, Robert and Wolffenbuttel, Bruce B H R and Alan F Wright and Yannoukakos, Drakoulis and Zemunik, Tatijana and Wei Zhang and Zygmunt, Marek and Bergmann, Sven and Dorret I Boomsma and Buring, Julie E and Luigi Ferrucci and Grant W Montgomery and Gudnason, Vilmundur and Timothy Spector and Cornelia M van Duijn and Alizadeh, Behrooz Z and Ciullo, Marina and Crisponi, Laura and Easton, Douglas F and Paolo P. Gasparini and Gieger, Christian and Tamara B Harris and Caroline Hayward and Sharon L R Kardia and Kraft, Peter and McKnight, Barbara and Andres Metspalu and Alanna C Morrison and Reiner, Alex P and Ridker, Paul M and Rotter, Jerome I and Toniolo, Daniela and Andr{\'e} G Uitterlinden and Ulivi, Sheila and V{\"o}lzke, Henry and Wareham, Nicholas J and David R Weir and Laura M Yerges-Armstrong and Price, Alkes L and Stefansson, Kari and Visser, Jenny A and Ong, Ken K and Chang-Claude, Jenny and Joanne M Murabito and Perry, John R B and Murray, Anna} } @article {10656, title = {Common genetic variants associated with cognitive performance identified using the proxy-phenotype method.}, journal = {Proc Natl Acad Sci U S A}, volume = {111}, year = {2014}, month = {2014 Sep 23}, pages = {13790-4}, abstract = {

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.

}, keywords = {Cell Adhesion Molecules, Neuronal, Cognition, Female, Humans, Learning, Male, Memory, Multifactorial Inheritance, Nerve Tissue Proteins, Neuronal Plasticity, Octamer Transcription Factors, Polymorphism, Single Nucleotide, Synaptic Transmission}, issn = {1091-6490}, doi = {10.1073/pnas.1404623111}, author = {Cornelius A Rietveld and T{\~o}nu Esko and Gail Davies and Pers, Tune H and Turley, Patrick and Benyamin, Beben and Chabris, Christopher F and Emilsson, Valur and Andrew D Johnson and Lee, James J and Christiaan de Leeuw and Riccardo E Marioni and Sarah E Medland and Michael B Miller and Rostapshova, Olga and Sven J van der Lee and Anna A E Vinkhuyzen and Amin, Najaf and Dalton C Conley and Derringer, Jaime and Cornelia M van Duijn and Fehrmann, Rudolf and Lude L Franke and Edward L Glaeser and Narelle K Hansell and Caroline Hayward and Iacono, William G and Carla A Ibrahim-Verbaas and Vincent Jaddoe and Karjalainen, Juha and David I Laibson and Paul Lichtenstein and David C Liewald and Patrik K E Magnusson and Nicholas G Martin and McGue, Matt and McMahon, George and Nancy L Pedersen and Pinker, Steven and David J Porteous and Posthuma, Danielle and Fernando Rivadeneira and Smith, Blair H and John M Starr and Henning Tiemeier and Nicholas J Timpson and Trzaskowski, Maciej and Andr{\'e} G Uitterlinden and Verhulst, Frank C and Mary E Ward and Margaret J Wright and George Davey Smith and Ian J Deary and Johannesson, Magnus and Plomin, Robert and Peter M Visscher and Daniel J. Benjamin and Cesarini, David and Philipp D Koellinger} } @article {8620, title = {GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.}, journal = {Science}, volume = {340}, year = {2013}, month = {2013 Jun 21}, pages = {1467-71}, abstract = {

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02\%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2\% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

}, keywords = {Cognition, Educational Status, Endophenotypes, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide}, issn = {1095-9203}, doi = {10.1126/science.1235488}, author = {Cornelius A Rietveld and Sarah E Medland and Derringer, Jaime and Yang, Jian and T{\~o}nu Esko and Martin, Nicolas W and Westra, Harm-Jan and Shakhbazov, Konstantin and Abdel Abdellaoui and Agrawal, Arpana and Albrecht, Eva and Alizadeh, Behrooz Z and Amin, Najaf and Barnard, John and Baumeister, Sebastian E and Benke, Kelly S and Bielak, Lawrence F and Boatman, Jeffrey A and Patricia A. Boyle and Gail Davies and Christiaan de Leeuw and Eklund, Niina and Daniel S Evans and Rudolf Ferhmann and Fischer, Krista and Gieger, Christian and Gjessing, H{\r a}kon K and H{\"a}gg, Sara and Harris, Jennifer R and Caroline Hayward and Holzapfel, Christina and Carla A Ibrahim-Verbaas and Ingelsson, Erik and Jacobsson, Bo and Joshi, Peter K and Jugessur, Astanand and Marika A Kaakinen and Kanoni, Stavroula and Karjalainen, Juha and Kolcic, Ivana and Kristiansson, Kati and Kutalik, Zolt{\'a}n and J. Lahti and Lee, Sang H and Lin, Peng and Penelope A Lind and Yongmei Liu and Kurt Lohman and Loitfelder, Marisa and McMahon, George and Vidal, Pedro Marques and Osorio Meirelles and Lili Milani and Myhre, Ronny and Nuotio, Marja-Liisa and Christopher J Oldmeadow and Katja E Petrovic and Wouter J Peyrot and Polasek, Ozren and Quaye, Lydia and Reinmaa, Eva and Rice, John P and Rizzi, Thais S and Schmidt, Helena and Schmidt, Reinhold and Albert Vernon Smith and Jennifer A Smith and Toshiko Tanaka and Antonio Terracciano and van der Loos, Matthijs J H M and Vitart, Veronique and V{\"o}lzke, Henry and J{\"u}rgen Wellmann and Lei Yu and Wei Zhao and Allik, J{\"u}ri and John R. Attia and Bandinelli, Stefania and Bastardot, Fran{\c c}ois and Jonathan P. Beauchamp and David A Bennett and Klaus Berger and Laura Bierut and Dorret I Boomsma and B{\"u}ltmann, Ute and Campbell, Harry and Chabris, Christopher F and Cherkas, Lynn and Chung, Mina K and Francesco Cucca and de Andrade, Mariza and Philip L de Jager and De Neve, Jan-Emmanuel and Ian J Deary and George Dedoussis and Deloukas, Panos and Dimitriou, Maria and Gu{\dh}ny Eir{\'\i}ksd{\'o}ttir and Elderson, Martin F and Johan G Eriksson and Jessica Faul and Luigi Ferrucci and Melissa E Garcia and Gr{\"o}nberg, Henrik and Gu{\dh}nason, Vilmundur and Hall, Per and Harris, Juliette M and Tamara B Harris and Nicholas D Hastie and Andrew C Heath and Dena G Hernandez and Hoffmann, Wolfgang and Hofman, Adriaan and Holle, Rolf and Holliday, Elizabeth G and Jouke-Jan Hottenga and Iacono, William G and Illig, Thomas and J{\"a}rvelin, Marjo-Riitta and K{\"a}h{\"o}nen, Mika and Kaprio, Jaakko and Kirkpatrick, Robert M and Kowgier, Matthew and Latvala, Antti and Lenore J Launer and Lawlor, Debbie A and Lehtim{\"a}ki, Terho and Li, Jingmei and Paul Lichtenstein and Lichtner, Peter and David C Liewald and Pamela A F Madden and Patrik K E Magnusson and M{\"a}kinen, Tomi E and Masala, Marco and McGue, Matt and Andres Metspalu and Mielck, Andreas and Michael B Miller and Grant W Montgomery and Mukherjee, Sutapa and Nyholt, Dale R and Ben A Oostra and Palmer, Lyle J and Aarno Palotie and Brenda W J H Penninx and Markus Perola and Peyser, Patricia A and Preisig, Martin and Katri R{\"a}ikk{\"o}nen and Olli T Raitakari and Realo, Anu and Ring, Susan M and Ripatti, Samuli and Fernando Rivadeneira and Rudan, Igor and Rustichini, Aldo and Veikko Salomaa and Sarin, Antti-Pekka and Schlessinger, David and Rodney J Scott and Snieder, Harold and St Pourcain, Beate and John M Starr and Sul, Jae Hoon and Surakka, Ida and Svento, Rauli and Teumer, Alexander and Henning Tiemeier and van Rooij, Frank J A and Van Wagoner, David R and Vartiainen, Erkki and Viikari, Jorma and Vollenweider, Peter and Vonk, Judith M and Waeber, G{\'e}rard and David R Weir and Wichmann, H-Erich and Elisabeth Widen and Gonneke Willemsen and James F Wilson and Alan F Wright and Dalton C Conley and Davey-Smith, George and Lude L Franke and Groenen, Patrick J F and Hofman, Albert and Johannesson, Magnus and Sharon L R Kardia and Krueger, Robert F and David I Laibson and Nicholas G Martin and Meyer, Michelle N and Posthuma, Danielle and A. Roy Thurik and Nicholas J Timpson and Andr{\'e} G Uitterlinden and Cornelia M van Duijn and Peter M Visscher and Daniel J. Benjamin and Cesarini, David and Philipp D Koellinger} }