@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 {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 {8884, title = {Directional dominance on stature and cognition in~diverse human populations.}, journal = {Nature}, volume = {523}, year = {2015}, month = {2015 Jul 23}, pages = {459-62}, abstract = {

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

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

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

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