@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 {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 {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 {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 {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} }