@article {12121, title = {Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.}, journal = {The American Journal of Human Genetics}, volume = {108}, year = {2021}, pages = {564-582}, abstract = {

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5\%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained <=20 variants in the credible sets that jointly account for 99\% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

}, keywords = {Africa, African Americans, Blacks, Body Height, Europe, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.02.011}, author = {Graff, Mariaelisa and Justice, Anne E and Young, Kristin L and Marouli, Eirini and Zhang, Xinruo and Fine, Rebecca S and Lim, Elise and Buchanan, Victoria and Rand, Kristin and Feitosa, Mary F and Wojczynski, Mary K and Yanek, Lisa R and Shao, Yaming and Rohde, Rebecca and Adeyemo, Adebowale A and Aldrich, Melinda C and Matthew A. Allison and Ambrosone, Christine B and Ambs, Stefan and Amos, Christopher and Donna K Arnett and Atwood, Larry and Bandera, Elisa V and Traci M Bartz and Becker, Diane M and Berndt, Sonja I and Bernstein, Leslie and Bielak, Lawrence F and Blot, William J and Erwin P Bottinger and Bowden, Donald W and Bradfield, Jonathan P and Brody, Jennifer A and Broeckel, Ulrich and Burke, Gregory and Brian E Cade and Cai, Qiuyin and Caporaso, Neil and Carlson, Chris and John Carpten and Casey, Graham and Chanock, Stephen J and Chen, Guanjie and Chen, Minhui and Chen, Yii-Der I and Chen, Wei-Min and Chesi, Alessandra and Chiang, Charleston W K and Chu, Lisa and Coetzee, Gerry A and Conti, David V and Cooper, Richard S and Cushman, Mary and Ellen W Demerath and Deming, Sandra L and Dimitrov, Latchezar and Ding, Jingzhong and Diver, W Ryan and Duan, Qing and Michele K Evans and Falusi, Adeyinka G and Jessica Faul and Myriam Fornage and Caroline S Fox and Freedman, Barry I and Garcia, Melissa and Gillanders, Elizabeth M and Phyllis J Goodman and Gottesman, Omri and Grant, Struan F A and Guo, Xiuqing and Hakonarson, Hakon and Haritunians, Talin and Tamara B Harris and Harris, Curtis C and Henderson, Brian E and Hennis, Anselm and Dena G Hernandez and Hirschhorn, Joel N and McNeill, Lorna Haughton and Howard, Timothy D and Howard, Barbara and Hsing, Ann W and Hsu, Yu-Han H and Hu, Jennifer J and Huff, Chad D and Huo, Dezheng and Ingles, Sue A and Irvin, Marguerite R and John, Esther M and Johnson, Karen C and Jordan, Joanne M and Kabagambe, Edmond K and Kang, Sun J and Sharon L R Kardia and Keating, Brendan J and Rick A Kittles and Eric A Klein and Kolb, Suzanne and Kolonel, Laurence N and Charles Kooperberg and Kuller, Lewis and Kutlar, Abdullah and Leslie A Lange and Langefeld, Carl D and Loic Le Marchand and Leonard, Hampton and Lettre, Guillaume and Levin, Albert M and Li, Yun and Li, Jin and Liu, Yongmei and Liu, Youfang and Liu, Simin and Kurt Lohman and Lotay, Vaneet and Lu, Yingchang and Maixner, William and JoAnn E Manson and McKnight, Barbara and Meng, Yan and Monda, Keri L and Monroe, Kris and Moore, Jason H and Thomas H Mosley and Mudgal, Poorva and Murphy, Adam B and Nadukuru, Rajiv and Michael A Nalls and Nathanson, Katherine L and Nayak, Uma and N{\textquoteright}Diaye, Amidou and Nemesure, Barbara and Neslund-Dudas, Christine and Neuhouser, Marian L and Nyante, Sarah and Ochs-Balcom, Heather and Ogundiran, Temidayo O and Ogunniyi, Adesola and Ojengbede, Oladosu and Okut, Hayrettin and Olopade, Olufunmilayo I and Olshan, Andrew and Padhukasahasram, Badri and Palmer, Julie and Palmer, Cameron D and Palmer, Nicholette D and George J Papanicolaou and Patel, Sanjay R and Pettaway, Curtis A and Peyser, Patricia A and Press, Michael F and Rao, D C and Rasmussen-Torvik, Laura J and Redline, Susan and Reiner, Alex P and Rhie, Suhn K and Rodriguez-Gil, Jorge L and Charles N Rotimi and Rotter, Jerome I and Ruiz-Narvaez, Edward A and Rybicki, Benjamin A and Babatunde Salako and Sale, Michele M and Sanderson, Maureen and Eric E Schadt and Schreiner, Pamela J and Schurmann, Claudia and Schwartz, Ann G and Daniel Shriner and Signorello, Lisa B and Andrew B Singleton and David S Siscovick and Smith, Jennifer A and Smith, Shad and Elizabeth K Speliotes and Spitz, Margaret and Stanford, Janet L and Stevens, Victoria L and Stram, Alex and Strom, Sara S and Sucheston, Lara and Yan V Sun and Tajuddin, Salman M and Taylor, Herman and Taylor, Kira and Bamidele O Tayo and Michael J Thun and Tucker, Margaret A and Vaidya, Dhananjay and Van Den Berg, David J and Vedantam, Sailaja and Vitolins, Mara and Wang, Zhaoming and Erin B Ware and Wassertheil-Smoller, Sylvia and David R Weir and Wiencke, John K and Williams, Scott M and L Keoki Williams and Wilson, James G and Witte, John S and Wrensch, Margaret and Wu, Xifeng and Yao, Jie and Zakai, Neil and Zanetti, Krista and Zemel, Babette S and Zhao, Wei and Jing Hua Zhao and Zheng, Wei and Zhi, Degui and Zhou, Jie and Zhu, Xiaofeng and Ziegler, Regina G and Zmuda, Joe and Alan B Zonderman and Psaty, Bruce M and Ingrid B Borecki and Cupples, L Adrienne and Liu, Ching-Ti and Christopher A Haiman and Ruth J F Loos and Ng, Maggie C Y and Kari E North} } @article {12140, title = {Combined linkage and association analysis identifies rare and low frequency variants for blood pressure at 1q31.}, journal = {European Journal of Human Genetics}, volume = {27}, year = {2019}, pages = {269-277}, abstract = {

High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and is more prevalent in African Americans as compared to other US groups. Although large, population-based genome-wide association studies (GWAS) have identified over 300 common polymorphisms modulating inter-individual BP variation, largely in European ancestry subjects, most of them do not localize to regions previously identified through family-based linkage studies. This discrepancy has remained unexplained despite the statistical power differences between current GWAS and prior linkage studies. To address this issue, we performed genome-wide linkage analysis of BP traits in African-American families from the Family Blood Pressure Program (FBPP) and genotyped on the Illumina Human Exome BeadChip v1.1. We identified a genomic region on chromosome 1q31 with LOD score 3.8 for pulse pressure (PP), a region we previously implicated in DBP studies of European ancestry families. Although no reported GWAS variants map to this region, combined linkage and association analysis of PP identified 81 rare and low frequency exonic variants accounting for the linkage evidence. Replication analysis in eight independent African ancestry cohorts (N = 16,968) supports this specific association with PP (P = 0.0509). Additional association and network analyses identified multiple potential candidate genes in this region expressed in multiple tissues and with a strong biological support for a role in BP. In conclusion, multiple genes and rare variants on 1q31 contribute to PP variation. Beyond producing new insights into PP, we demonstrate how family-based linkage and association studies can implicate specific rare and low frequency variants for complex traits.

}, keywords = {African Americans, Chromosomes, Human, Pair 1, Gene Frequency, Genome-Wide Association Study, Humans, Hypertension, Linkage Disequilibrium, Polymorphism, Single Nucleotide}, issn = {1476-5438}, doi = {10.1038/s41431-018-0277-1}, author = {Wang, Heming and Nandakumar, Priyanka and Tekola-Ayele, Fasil and Bamidele O Tayo and Erin B Ware and Gu, C Charles and Lu, Yingchang and Yao, Jie and Zhao, Wei and Smith, Jennifer A and Hellwege, Jacklyn N and Guo, Xiuqing and Edwards, Todd L and Ruth J F Loos and Donna K Arnett and Myriam Fornage and Charles N Rotimi and Sharon L R Kardia and Cooper, Richard S and Rao, D C and Georg B Ehret and Chakravarti, Aravinda and Zhu, Xiaofeng} } @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 {12136, title = {Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium.}, journal = {PLoS Genetics}, volume = {13}, year = {2017}, pages = {e1006719}, abstract = {

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5{\texttimes}10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5\%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained <= 20 variants in the credible sets that jointly account for 99\% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

}, keywords = {Adiposity, Anthropometry, Blacks, Body Mass Index, Chromosome Mapping, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Obesity, Polymorphism, Single Nucleotide, Serine Endopeptidases, Transcription Factor 7-Like 2 Protein, Waist-Hip Ratio, Whites}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006719}, author = {Ng, Maggie C Y and Graff, Mariaelisa and Lu, Yingchang and Justice, Anne E and Mudgal, Poorva and Liu, Ching-Ti and Young, Kristin and Yanek, Lisa R and Feitosa, Mary F and Wojczynski, Mary K and Rand, Kristin and Brody, Jennifer A and Brian E Cade and Dimitrov, Latchezar and Duan, Qing and Guo, Xiuqing and Leslie A Lange and Michael A Nalls and Okut, Hayrettin and Tajuddin, Salman M and Bamidele O Tayo and Vedantam, Sailaja and Bradfield, Jonathan P and Chen, Guanjie and Chen, Wei-Min and Chesi, Alessandra and Irvin, Marguerite R and Padhukasahasram, Badri and Smith, Jennifer A and Zheng, Wei and Matthew A. Allison and Ambrosone, Christine B and Bandera, Elisa V and Traci M Bartz and Berndt, Sonja I and Bernstein, Leslie and Blot, William J and Erwin P Bottinger and John Carpten and Chanock, Stephen J and Chen, Yii-Der Ida and Conti, David V and Cooper, Richard S and Myriam Fornage and Freedman, Barry I and Garcia, Melissa and Phyllis J Goodman and Hsu, Yu-Han H and Hu, Jennifer and Huff, Chad D and Ingles, Sue A and John, Esther M and Rick A Kittles and Eric A Klein and Li, Jin and McKnight, Barbara and Nayak, Uma and Nemesure, Barbara and Ogunniyi, Adesola and Olshan, Andrew and Press, Michael F and Rohde, Rebecca and Rybicki, Benjamin A and Babatunde Salako and Sanderson, Maureen and Shao, Yaming and David S Siscovick and Stanford, Janet L and Stevens, Victoria L and Stram, Alex and Strom, Sara S and Vaidya, Dhananjay and Witte, John S and Yao, Jie and Zhu, Xiaofeng and Ziegler, Regina G and Alan B Zonderman and Adeyemo, Adebowale and Ambs, Stefan and Cushman, Mary and Jessica Faul and Hakonarson, Hakon and Levin, Albert M and Nathanson, Katherine L and Erin B Ware and David R Weir and Zhao, Wei and Zhi, Degui and Donna K Arnett and Grant, Struan F A and Sharon L R Kardia and Oloapde, Olufunmilayo I and Rao, D C and Charles N Rotimi and Sale, Michele M and L Keoki Williams and Zemel, Babette S and Becker, Diane M and Ingrid B Borecki and Michele K Evans and Tamara B Harris and Hirschhorn, Joel N and Li, Yun and Patel, Sanjay R and Psaty, Bruce M and Rotter, Jerome I and Wilson, James G and Bowden, Donald W and Cupples, L Adrienne and Christopher A Haiman and Ruth J F Loos and Kari E North} } @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 {12120, title = {Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.}, journal = {PLoS Genetics}, volume = {13}, year = {2017}, pages = {e1006728}, abstract = {

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25{\texttimes}10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

}, keywords = {African Americans, Animals, Basic Helix-Loop-Helix Transcription Factors, Blood pressure, Cadherins, Case-Control Studies, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Membrane Proteins, Mice, Multifactorial Inheritance, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006728}, author = {Liang, Jingjing and Le, Thu H and Digna R Velez Edwards and Bamidele O Tayo and Gaulton, Kyle J and Smith, Jennifer A and Lu, Yingchang and Jensen, Richard A and Chen, Guanjie and Yanek, Lisa R and Schwander, Karen and Tajuddin, Salman M and Sofer, Tamar and Kim, Wonji and Kayima, James and McKenzie, Colin A and Fox, Ervin and Michael A Nalls and Young, J Hunter and Yan V Sun and Lane, Jacqueline M and Cechova, Sylvia and Zhou, Jie and Tang, Hua and Myriam Fornage and Musani, Solomon K and Wang, Heming and Lee, Juyoung and Adeyemo, Adebowale and Dreisbach, Albert W and Forrester, Terrence and Chu, Pei-Lun and Anne Cappola and Michele K Evans and Alanna C Morrison and Martin, Lisa W and Kerri Wiggins and Hui, Qin and Zhao, Wei and Jackson, Rebecca D and Erin B Ware and Jessica Faul and Reiner, Alex P and Bray, Michael and Denny, Joshua C and Thomas H Mosley and Walter R Palmas and Guo, Xiuqing and George J Papanicolaou and Alan Penman and Polak, Joseph F and Kenneth Rice and Taylor, Ken D and Boerwinkle, Eric and Erwin P Bottinger and Liu, Kiang and Neil Risch and Hunt, Steven C and Charles Kooperberg and Alan B Zonderman and Laurie, Cathy C and Becker, Diane M and Cai, Jianwen and Ruth J F Loos and Psaty, Bruce M and David R Weir and Sharon L R Kardia and Donna K Arnett and Won, Sungho and Edwards, Todd L and Redline, Susan and Cooper, Richard S and Rao, D C and Rotter, Jerome I and Charles N Rotimi and Levy, Daniel and Chakravarti, Aravinda and Zhu, Xiaofeng and Franceschini, Nora} } @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 {8885, title = {Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 Oct}, pages = {1162-70}, abstract = {

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

}, issn = {1546-1718}, doi = {10.1038/ng.3660}, author = {Liu, Chunyu and Kraja, Aldi T and Jennifer A Smith and Brody, Jennifer A and Franceschini, Nora and Joshua C. Bis and Kenneth Rice and Alanna C Morrison and Lu, Yingchang and Weiss, Stefan and Guo, Xiuqing and Walter R Palmas and Martin, Lisa W and Yii-Der I Chen and Surendran, Praveen and Drenos, Fotios and Cook, James P and Auer, Paul L and Chu, Audrey Y and Giri, Ayush and Wei Zhao and Jakobsdottir, Johanna and Lin, Li-An and Stafford, Jeanette M and Amin, Najaf and Mei, Hao and Yao, Jie and Voorman, Arend and Larson, Martin G and Grove, Megan L and Albert Vernon Smith and Hwang, Shih-Jen and Chen, Han and Huan, Tianxiao and Kosova, Gulum and Stitziel, Nathan O and Kathiresan, Sekar and Nilesh J Samani and Schunkert, Heribert and Deloukas, Panos and Li, Man and Fuchsberger, Christian and Pattaro, Cristian and Gorski, Mathias and Charles Kooperberg and George J Papanicolaou and Rossouw, Jacques E and Jessica Faul and Sharon L R Kardia and Bouchard, Claude and Raffel, Leslie J and Andr{\'e} G Uitterlinden and Franco, Oscar H and Ramachandran S Vasan and O{\textquoteright}Donnell, Christopher J and Kent D Taylor and Liu, Kiang and Erwin P Bottinger and Gottesman, Omri and Daw, E Warwick and Giulianini, Franco and Ganesh, Santhi and Salfati, Elias and Tamara B Harris and Lenore J Launer and D{\"o}rr, Marcus and Felix, Stephan B and Rettig, Rainer and V{\"o}lzke, Henry and Eric S Kim and Lee, Wen-Jane and Lee, I-Te and Sheu, Wayne H-H and Tsosie, Krystal S and Digna R Velez Edwards and Yongmei Liu and Correa, Adolfo and David R Weir and V{\"o}lker, Uwe and Ridker, Paul M and Boerwinkle, Eric and Gudnason, Vilmundur and Reiner, Alexander P and Cornelia M van Duijn and Ingrid B Borecki and Edwards, Todd L and Chakravarti, Aravinda and Rotter, Jerome I and Psaty, Bruce M and Ruth J F Loos and Myriam Fornage and Georg B Ehret and Newton-Cheh, Christopher and Levy, Daniel and Daniel I Chasman} } @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 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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} }