%0 Journal Article %J The American Journal of Human Genetics %D 2021 %T Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. %A Graff, Mariaelisa %A Justice, Anne E %A Young, Kristin L %A Marouli, Eirini %A Zhang, Xinruo %A Fine, Rebecca S %A Lim, Elise %A Buchanan, Victoria %A Rand, Kristin %A Feitosa, Mary F %A Wojczynski, Mary K %A Yanek, Lisa R %A Shao, Yaming %A Rohde, Rebecca %A Adeyemo, Adebowale A %A Aldrich, Melinda C %A Matthew A. Allison %A Ambrosone, Christine B %A Ambs, Stefan %A Amos, Christopher %A Donna K Arnett %A Atwood, Larry %A Bandera, Elisa V %A Traci M Bartz %A Becker, Diane M %A Berndt, Sonja I %A Bernstein, Leslie %A Bielak, Lawrence F %A Blot, William J %A Erwin P Bottinger %A Bowden, Donald W %A Bradfield, Jonathan P %A Brody, Jennifer A %A Broeckel, Ulrich %A Burke, Gregory %A Brian E Cade %A Cai, Qiuyin %A Caporaso, Neil %A Carlson, Chris %A John Carpten %A Casey, Graham %A Chanock, Stephen J %A Chen, Guanjie %A Chen, Minhui %A Chen, Yii-Der I %A Chen, Wei-Min %A Chesi, Alessandra %A Chiang, Charleston W K %A Chu, Lisa %A Coetzee, Gerry A %A Conti, David V %A Cooper, Richard S %A Cushman, Mary %A Ellen W Demerath %A Deming, Sandra L %A Dimitrov, Latchezar %A Ding, Jingzhong %A Diver, W Ryan %A Duan, Qing %A Michele K Evans %A Falusi, Adeyinka G %A Jessica Faul %A Myriam Fornage %A Caroline S Fox %A Freedman, Barry I %A Garcia, Melissa %A Gillanders, Elizabeth M %A Phyllis J Goodman %A Gottesman, Omri %A Grant, Struan F A %A Guo, Xiuqing %A Hakonarson, Hakon %A Haritunians, Talin %A Tamara B Harris %A Harris, Curtis C %A Henderson, Brian E %A Hennis, Anselm %A Dena G Hernandez %A Hirschhorn, Joel N %A McNeill, Lorna Haughton %A Howard, Timothy D %A Howard, Barbara %A Hsing, Ann W %A Hsu, Yu-Han H %A Hu, Jennifer J %A Huff, Chad D %A Huo, Dezheng %A Ingles, Sue A %A Irvin, Marguerite R %A John, Esther M %A Johnson, Karen C %A Jordan, Joanne M %A Kabagambe, Edmond K %A Kang, Sun J %A Sharon L R Kardia %A Keating, Brendan J %A Rick A Kittles %A Eric A Klein %A Kolb, Suzanne %A Kolonel, Laurence N %A Charles Kooperberg %A Kuller, Lewis %A Kutlar, Abdullah %A Leslie A Lange %A Langefeld, Carl D %A Loic Le Marchand %A Leonard, Hampton %A Lettre, Guillaume %A Levin, Albert M %A Li, Yun %A Li, Jin %A Liu, Yongmei %A Liu, Youfang %A Liu, Simin %A Kurt Lohman %A Lotay, Vaneet %A Lu, Yingchang %A Maixner, William %A JoAnn E Manson %A McKnight, Barbara %A Meng, Yan %A Monda, Keri L %A Monroe, Kris %A Moore, Jason H %A Thomas H Mosley %A Mudgal, Poorva %A Murphy, Adam B %A Nadukuru, Rajiv %A Michael A Nalls %A Nathanson, Katherine L %A Nayak, Uma %A N'Diaye, Amidou %A Nemesure, Barbara %A Neslund-Dudas, Christine %A Neuhouser, Marian L %A Nyante, Sarah %A Ochs-Balcom, Heather %A Ogundiran, Temidayo O %A Ogunniyi, Adesola %A Ojengbede, Oladosu %A Okut, Hayrettin %A Olopade, Olufunmilayo I %A Olshan, Andrew %A Padhukasahasram, Badri %A Palmer, Julie %A Palmer, Cameron D %A Palmer, Nicholette D %A George J Papanicolaou %A Patel, Sanjay R %A Pettaway, Curtis A %A Peyser, Patricia A %A Press, Michael F %A Rao, D C %A Rasmussen-Torvik, Laura J %A Redline, Susan %A Reiner, Alex P %A Rhie, Suhn K %A Rodriguez-Gil, Jorge L %A Charles N Rotimi %A Rotter, Jerome I %A Ruiz-Narvaez, Edward A %A Rybicki, Benjamin A %A Babatunde Salako %A Sale, Michele M %A Sanderson, Maureen %A Eric E Schadt %A Schreiner, Pamela J %A Schurmann, Claudia %A Schwartz, Ann G %A Daniel Shriner %A Signorello, Lisa B %A Andrew B Singleton %A David S Siscovick %A Smith, Jennifer A %A Smith, Shad %A Elizabeth K Speliotes %A Spitz, Margaret %A Stanford, Janet L %A Stevens, Victoria L %A Stram, Alex %A Strom, Sara S %A Sucheston, Lara %A Yan V Sun %A Tajuddin, Salman M %A Taylor, Herman %A Taylor, Kira %A Bamidele O Tayo %A Michael J Thun %A Tucker, Margaret A %A Vaidya, Dhananjay %A Van Den Berg, David J %A Vedantam, Sailaja %A Vitolins, Mara %A Wang, Zhaoming %A Erin B Ware %A Wassertheil-Smoller, Sylvia %A David R Weir %A Wiencke, John K %A Williams, Scott M %A L Keoki Williams %A Wilson, James G %A Witte, John S %A Wrensch, Margaret %A Wu, Xifeng %A Yao, Jie %A Zakai, Neil %A Zanetti, Krista %A Zemel, Babette S %A Zhao, Wei %A Jing Hua Zhao %A Zheng, Wei %A Zhi, Degui %A Zhou, Jie %A Zhu, Xiaofeng %A Ziegler, Regina G %A Zmuda, Joe %A Alan B Zonderman %A Psaty, Bruce M %A Ingrid B Borecki %A Cupples, L Adrienne %A Liu, Ching-Ti %A Christopher A Haiman %A Ruth J F Loos %A Ng, Maggie C Y %A Kari E North %K Africa %K African Americans %K Blacks %K Body Height %K Europe %K Female %K Genome-Wide Association Study %K Humans %K Male %K Polymorphism, Single Nucleotide %X
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.
%B The American Journal of Human Genetics %V 108 %P 564-582 %G eng %N 4 %R 10.1016/j.ajhg.2021.02.011 %0 Journal Article %J Nature Communications %D 2019 %T Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. %A Kilpeläinen, Tuomas O %A Bentley, Amy R %A Noordam, Raymond %A Yun Ju Sung %A Schwander, Karen %A Thomas W Winkler %A Jakupović, Hermina %A Daniel I Chasman %A Alisa Manning %A Ntalla, Ioanna %A Aschard, Hugues %A Brown, Michael R %A de Las Fuentes, Lisa %A Franceschini, Nora %A Guo, Xiuqing %A Vojinovic, Dina %A Aslibekyan, Stella %A Feitosa, Mary F %A Kho, Minjung %A Musani, Solomon K %A Melissa Richard %A Wang, Heming %A Wang, Zhe %A Traci M Bartz %A Bielak, Lawrence F %A Campbell, Archie %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Li, Changwei %A Kurt Lohman %A Marten, Jonathan %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Jin-Fang Chai %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Graff, Mariaelisa %A Sarah E Harris %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Jing Hua Zhao %A Kraja, Aldi T %A Kühnel, Brigitte %A Laguzzi, Federica %A Lyytikäinen, Leo-Pekka %A Ilja M Nolte %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Rueedi, Rico %A Heather M Stringham %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Verweij, Niek %A Erin B Ware %A Wen, Wanqing %A Li, Xiaoyin %A Yanek, Lisa R %A Amin, Najaf %A Donna K Arnett %A Boerwinkle, Eric %A Brumat, Marco %A Brian E Cade %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Concas, Maria Pina %A Connell, John %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Demirkan, Ayse %A Ding, Jingzhong %A Charles B Eaton %A Jessica Faul %A Friedlander, Yechiel %A Gabriel, Kelley P %A Ghanbari, Mohsen %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Tamara B Harris %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven C %A Ikram, M Arfan %A Jost Bruno Jonas %A Koh, Woon-Puay %A Komulainen, Pirjo %A Krieger, Jose E %A Stephen B Kritchevsky %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Lenore J Launer %A Leander, Karin %A Lemaitre, Rozenn N %A Lewis, Cora E %A Liang, Jingjing %A Liu, Jianjun %A Mägi, Reedik %A Manichaikul, Ani %A Meitinger, Thomas %A Andres Metspalu %A Milaneschi, Yuri %A Mohlke, Karen L %A Thomas H Mosley %A Murray, Alison D %A Michael A Nalls %A Nang, Ei-Ei Khaing %A Nelson, Christopher P %A Nona, Sotoodehnia %A Norris, Jill M %A Nwuba, Chiamaka Vivian %A Jeff O'Connell %A Palmer, Nicholette D %A Papanicolau, George J %A Pazoki, Raha %A Nancy L Pedersen %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A David J Porteous %A Poveda, Alaitz %A Olli T Raitakari %A Rich, Stephen S %A Neil Risch %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schreiner, Pamela J %A Scott, Robert A %A Stephen Sidney %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Sofer, Tamar %A John M Starr %A Sternfeld, Barbara %A Strauch, Konstantin %A Tang, Hua %A Kent D Taylor %A Tsai, Michael Y %A Tuomilehto, Jaakko %A André G Uitterlinden %A van der Ende, M Yldau %A van Heemst, Diana %A Voortman, Trudy %A Waldenberger, Melanie %A Wennberg, Patrik %A Wilson, Gregory %A Xiang, Yong-Bing %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Alan B Zonderman %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A de Faire, Ulf %A Ian J Deary %A Elliott, Paul %A Tõnu Esko %A Freedman, Barry I %A Froguel, Philippe %A Paolo P. Gasparini %A Gieger, Christian %A Kato, Norihiro %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Patrik K E Magnusson %A Oldehinkel, Albertine J %A Brenda W J H Penninx %A Nilesh J Samani %A Shu, Xiao-Ou %A van der Harst, Pim %A Jana V. van Vliet-Ostaptchouk %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wang, Ya X %A Wareham, Nicholas J %A David R Weir %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Michele K Evans %A Franks, Paul W %A Gudnason, Vilmundur %A Caroline Hayward %A Horta, Bernardo L %A Tanika N Kelly %A Liu, Yongmei %A Kari E North %A Pereira, Alexandre C %A Ridker, Paul M %A Tai, E Shyong %A van Dam, Rob M %A Fox, Ervin R %A Sharon L R Kardia %A Liu, Ching-Ti %A Dennis O Mook-Kanamori %A Province, Michael A %A Redline, Susan %A Cornelia M van Duijn %A Rotter, Jerome I %A Charles Kooperberg %A Gauderman, W James %A Psaty, Bruce M %A Kenneth Rice %A Munroe, Patricia B %A Myriam Fornage %A Cupples, L Adrienne %A Charles N Rotimi %A Alanna C Morrison %A Rao, Dabeeru C %A Ruth J F Loos %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Asians %K Blacks %K Brazil %K Calcium-Binding Proteins %K Cholesterol %K Cholesterol, HDL %K Cholesterol, LDL %K Exercise %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Hispanic or Latino %K Humans %K LIM-Homeodomain Proteins %K Lipid Metabolism %K Lipids %K Male %K Membrane Proteins %K Microtubule-Associated Proteins %K Middle Aged %K Muscle Proteins %K Nerve Tissue Proteins %K Transcription Factors %K Triglycerides %K Whites %K Young Adult %XMany genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
%B Nature Communications %V 10 %P 376 %G eng %N 1 %R 10.1038/s41467-018-08008-w %0 Journal Article %J Nat Genet %D 2018 %T Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. %A Turcot, Valérie %A Lu, Yingchang %A Highland, Heather M %A Schurmann, Claudia %A Justice, Anne E %A Fine, Rebecca S %A Bradfield, Jonathan P %A Tõnu Esko %A Giri, Ayush %A Graff, Mariaelisa %A Guo, Xiuqing %A Hendricks, Audrey E %A Karaderi, Tugce %A Lempradl, Adelheid %A Locke, Adam E %A Mahajan, Anubha %A Marouli, Eirini %A Sivapalaratnam, Suthesh %A Young, Kristin L %A Alfred, Tamuno %A Feitosa, Mary F %A Masca, Nicholas G D %A Alisa Manning %A Medina-Gomez, Carolina %A Mudgal, Poorva %A Ng, Maggie C Y %A Reiner, Alex P %A Vedantam, Sailaja %A Willems, Sara M %A Thomas W Winkler %A Gonçalo R Abecasis %A Aben, Katja K %A Alam, Dewan S %A Alharthi, Sameer E %A Matthew A. Allison %A Amouyel, Philippe %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Bang, Lia E %A Barroso, Inês %A Bastarache, Lisa %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Boerwinkle, Eric %A Böger, Carsten A %A Bork-Jensen, Jette %A Bots, Michiel L %A Erwin P Bottinger %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Brumat, Marco %A Burt, Amber A %A Adam S Butterworth %A Campbell, Peter T %A Cappellani, Stefania %A Carey, David J %A Catamo, Eulalia %A Caulfield, Mark J %A Chambers, John C %A Daniel I Chasman %A Yii-Der I Chen %A Chowdhury, Rajiv %A Cramer Christensen %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Jordi Corominas Galbany %A Cox, Amanda J %A Crosslin, David S %A Cuellar-Partida, Gabriel %A D'Eustacchio, Angela %A Danesh, John %A Gail Davies %A Bakker, Paul I W %A Groot, Mark C H %A Mutsert, Renée %A Ian J Deary %A George Dedoussis %A Ellen W Demerath %A Heijer, Martin %A Anneke I den Hollander %A Hester M den Ruijter %A Joe G Dennis %A Denny, Josh C %A Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dubé, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Edwards, Todd L %A Ellinghaus, David %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Farooqi, I Sadaf %A Jessica Faul %A Fauser, Sascha %A Feng, Shuang %A Ferrannini, Ele %A Ferrières, Jean %A Florez, Jose C %A Ford, Ian %A Myriam Fornage %A Franco, Oscar H %A Franke, Andre %A Franks, Paul W %A Friedrich, Nele %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Paolo P. Gasparini %A Gibson, Jane %A Giedraitis, Vilmantas %A Gjesing, Anette P %A Gordon-Larsen, Penny %A Gorski, Mathias %A Hans-Jörgen Grabe %A Grant, Struan F A %A Grarup, Niels %A Griffiths, Helen L %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Jeffrey Haessler %A Hakonarson, Hakon %A Anke R Hammerschlag %A Hansen, Torben %A Tamara B Harris %A Andrew T Hattersley %A Have, Christian T %A Caroline Hayward %A He, Liang %A Heard-Costa, Nancy L %A Andrew C Heath %A Iris M Heid %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Oddgeir L Holmen %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Huang, Paul L %A Huffman, Jennifer E %A Mohammed Arfan Ikram %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jia, Yucheng %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Sharon L R Kardia %A Karpe, Fredrik %A Kathiresan, Sekar %A Kee, Frank %A Lambertus A Kiemeney %A Eric S Kim %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Charles Kooperberg %A Korhonen, Tellervo %A Kovacs, Peter %A Kuivaniemi, Helena %A Kutalik, Zoltán %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Ethan M %A Leslie A Lange %A Langenberg, Claudia %A Eric B Larson %A Lee, Nanette R %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Keng-Hung %A Lin, Li-An %A Lin, Xu %A Lars Lind %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Yongmei Liu %A Ken Sin Lo %A Lophatananon, Artitaya %A Lotery, Andrew J %A Loukola, Anu %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Männistö, Satu %A Marenne, Gaëlle %A Mazul, Angela L %A McCarthy, Mark I %A McKean-Cowdin, Roberta %A Sarah E Medland %A Meidtner, Karina %A Lili Milani %A Mistry, Vanisha %A Mitchell, Paul %A Mohlke, Karen L %A Moilanen, Leena %A Moitry, Marie %A Grant W Montgomery %A Dennis O Mook-Kanamori %A Moore, Carmel %A Mori, Trevor A %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Michael A Nalls %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Sune Fallgaard Nielsen %A Nikus, Kjell %A Njølstad, Pål R %A Børge G Nordestgaard %A Nyholt, Dale R %A Jeff O'Connell %A O'Donoghue, Michelle L %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Palmer, Nicholette D %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Markus Perola %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Person, Thomas N %A Peters, Annette %A Petersen, Eva R B %A Peyser, Patricia A %A Pirie, Ailith %A Polasek, Ozren %A Tinca J Polderman %A Puolijoki, Hannu %A Olli T Raitakari %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Renstrom, Frida %A Rheinberger, Myriam %A Ridker, Paul M %A Rioux, John D %A Rivas, Manuel A %A Roberts, David J %A Neil R Robertson %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Veikko Salomaa %A Nilesh J Samani %A Sapkota, Yadav %A Sattar, Naveed %A Schoen, Robert E %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Svati H Shah %A Sheu, Wayne H-H %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Albert Vernon Smith %A Southam, Lorraine %A Timothy Spector %A Elizabeth K Speliotes %A John M Starr %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Kathleen E Stirrups %A Strauch, Konstantin %A Heather M Stringham %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swift, Amy J %A Tada, Hayato %A Tansey, Katherine E %A Tardif, Jean-Claude %A Kent D Taylor %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tönjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A André G Uitterlinden %A Uusitupa, Matti %A Laan, Sander W %A Duijn, Cornelia M %A Leeuwen, Nienke %A van Setten, Jessica %A Vanhala, Mauno %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Digna R Velez Edwards %A Vermeulen, Sita H %A Veronesi, Giovanni %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Völker, Uwe %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Erin B Ware %A Wareham, Nicholas J %A Warren, Helen R %A Dawn M Waterworth %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Daniel Witte %A Andrew R Wood %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Laura M Yerges-Armstrong %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Wei Zhao %A Zhou, Wei %A Krina T Zondervan %A Rotter, Jerome I %A Pospisilik, John A %A Fernando Rivadeneira %A Ingrid B Borecki %A Deloukas, Panos %A Timothy M Frayling %A Lettre, Guillaume %A Kari E North %A Lindgren, Cecilia M %A Joel N Hirschhron %A Ruth J F Loos %XGenome-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.
%B Nat Genet %V 50 %P 26-41 %8 2018 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29273807?dopt=Abstract %R 10.1038/s41588-017-0011-x %0 Journal Article %J PLoS Genetics %D 2017 %T 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. %A Ng, Maggie C Y %A Graff, Mariaelisa %A Lu, Yingchang %A Justice, Anne E %A Mudgal, Poorva %A Liu, Ching-Ti %A Young, Kristin %A Yanek, Lisa R %A Feitosa, Mary F %A Wojczynski, Mary K %A Rand, Kristin %A Brody, Jennifer A %A Brian E Cade %A Dimitrov, Latchezar %A Duan, Qing %A Guo, Xiuqing %A Leslie A Lange %A Michael A Nalls %A Okut, Hayrettin %A Tajuddin, Salman M %A Bamidele O Tayo %A Vedantam, Sailaja %A Bradfield, Jonathan P %A Chen, Guanjie %A Chen, Wei-Min %A Chesi, Alessandra %A Irvin, Marguerite R %A Padhukasahasram, Badri %A Smith, Jennifer A %A Zheng, Wei %A Matthew A. Allison %A Ambrosone, Christine B %A Bandera, Elisa V %A Traci M Bartz %A Berndt, Sonja I %A Bernstein, Leslie %A Blot, William J %A Erwin P Bottinger %A John Carpten %A Chanock, Stephen J %A Chen, Yii-Der Ida %A Conti, David V %A Cooper, Richard S %A Myriam Fornage %A Freedman, Barry I %A Garcia, Melissa %A Phyllis J Goodman %A Hsu, Yu-Han H %A Hu, Jennifer %A Huff, Chad D %A Ingles, Sue A %A John, Esther M %A Rick A Kittles %A Eric A Klein %A Li, Jin %A McKnight, Barbara %A Nayak, Uma %A Nemesure, Barbara %A Ogunniyi, Adesola %A Olshan, Andrew %A Press, Michael F %A Rohde, Rebecca %A Rybicki, Benjamin A %A Babatunde Salako %A Sanderson, Maureen %A Shao, Yaming %A David S Siscovick %A Stanford, Janet L %A Stevens, Victoria L %A Stram, Alex %A Strom, Sara S %A Vaidya, Dhananjay %A Witte, John S %A Yao, Jie %A Zhu, Xiaofeng %A Ziegler, Regina G %A Alan B Zonderman %A Adeyemo, Adebowale %A Ambs, Stefan %A Cushman, Mary %A Jessica Faul %A Hakonarson, Hakon %A Levin, Albert M %A Nathanson, Katherine L %A Erin B Ware %A David R Weir %A Zhao, Wei %A Zhi, Degui %A Donna K Arnett %A Grant, Struan F A %A Sharon L R Kardia %A Oloapde, Olufunmilayo I %A Rao, D C %A Charles N Rotimi %A Sale, Michele M %A L Keoki Williams %A Zemel, Babette S %A Becker, Diane M %A Ingrid B Borecki %A Michele K Evans %A Tamara B Harris %A Hirschhorn, Joel N %A Li, Yun %A Patel, Sanjay R %A Psaty, Bruce M %A Rotter, Jerome I %A Wilson, James G %A Bowden, Donald W %A Cupples, L Adrienne %A Christopher A Haiman %A Ruth J F Loos %A Kari E North %K Adiposity %K Anthropometry %K Blacks %K Body Mass Index %K Chromosome Mapping %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Male %K Obesity %K Polymorphism, Single Nucleotide %K Serine Endopeptidases %K Transcription Factor 7-Like 2 Protein %K Waist-Hip Ratio %K Whites %XGenome-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 < 5×10-8: 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.
%B PLoS Genetics %V 13 %P e1006719 %G eng %N 4 %R 10.1371/journal.pgen.1006719 %0 Journal Article %J Nature Communications %D 2017 %T Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. %A Joshi, Peter K %A Nicola Pirastu %A Kentistou, Katherine A %A Fischer, Krista %A Edith Hofer %A Schraut, Katharina E %A Clark, David W %A Nutile, Teresa %A Barnes, Catriona L K %A Paul Rhj Timmers %A Shen, Xia %A Gandin, Ilaria %A McDaid, Aaron F %A Hansen, Thomas Folkmann %A Gordon, Scott D %A Giulianini, Franco %A Boutin, Thibaud S %A Abdellaoui, Abdel %A Zhao, Wei %A Medina-Gomez, Carolina %A Traci M Bartz %A Trompet, Stella %A Leslie A Lange %A Raffield, Laura %A van der Spek, Ashley %A Galesloot, Tessel E %A Proitsi, Petroula %A Yanek, Lisa R %A Bielak, Lawrence F %A Payton, Antony %A Murgia, Federico %A Concas, Maria Pina %A Biino, Ginevra %A Tajuddin, Salman M %A Seppälä, Ilkka %A Amin, Najaf %A Boerwinkle, Eric %A Børglum, Anders D %A Campbell, Archie %A Ellen W Demerath %A Demuth, Ilja %A Jessica Faul %A Ford, Ian %A Gialluisi, Alessandro %A Gögele, Martin %A Graff, Mariaelisa %A Aroon Hingorani %A Jouke-Jan Hottenga %A Hougaard, David M %A Hurme, Mikko A %A Ikram, M Arfan %A Jylhä, Marja %A Kuh, Diana %A Ligthart, Lannie %A Lill, Christina M %A Lindenberger, Ulman %A Lumley, Thomas %A Mägi, Reedik %A Marques-Vidal, Pedro %A Sarah E Medland %A Lili Milani %A Nagy, Reka %A William E R Ollier %A Peyser, Patricia A %A Pramstaller, Peter P %A Ridker, Paul M %A Fernando Rivadeneira %A Ruggiero, Daniela %A Saba, Yasaman %A Schmidt, Reinhold %A Schmidt, Helena %A Slagboom, P Eline %A Smith, Blair H %A Smith, Jennifer A %A Sotoodehnia, Nona %A Steinhagen-Thiessen, Elisabeth %A van Rooij, Frank J A %A Verbeek, André L %A Vermeulen, Sita H %A Vollenweider, Peter %A Wang, Yunpeng %A Werge, Thomas %A Whitfield, John B %A Alan B Zonderman %A Lehtimäki, Terho %A Michele K Evans %A Pirastu, Mario %A Fuchsberger, Christian %A Bertram, Lars %A Pendleton, Neil %A Sharon L R Kardia %A Ciullo, Marina %A Becker, Diane M %A Wong, Andrew %A Psaty, Bruce M %A Cornelia M van Duijn %A Wilson, James G %A Jukema, J Wouter %A Lambertus A Kiemeney %A André G Uitterlinden %A Franceschini, Nora %A Kari E North %A David R Weir %A Andres Metspalu %A Dorret I Boomsma %A Caroline Hayward %A Daniel I Chasman %A Nicholas G Martin %A Sattar, Naveed %A Campbell, Harry %A Tõnu Esko %A Kutalik, Zoltán %A James F Wilson %K Alleles %K Body Mass Index %K Coronary Disease %K Education %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K HLA-DQ alpha-Chains %K HLA-DRB1 Chains %K Humans %K Insulin Resistance %K Life Style %K Lipoprotein(a) %K Lipoproteins, HDL %K Longevity %K Lung Neoplasms %K Obesity %K Polymorphism, Single Nucleotide %K Smoking %K Socioeconomic factors %XGenomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
%B Nature Communications %V 8 %P 910 %G eng %N 1 %R 10.1038/s41467-017-00934-5 %0 Journal Article %J Nature %D 2017 %T Rare and low-frequency coding variants alter human adult height. %A Marouli, Eirini %A Graff, Mariaelisa %A Medina-Gomez, Carolina %A Ken Sin Lo %A Andrew R Wood %A Kjaer, Troels R %A Fine, Rebecca S %A Lu, Yingchang %A Schurmann, Claudia %A Highland, Heather M %A Rüeger, Sina %A Thorleifsson, Gudmar %A Justice, Anne E %A Lamparter, David %A Kathleen E Stirrups %A Turcot, Valérie %A Young, Kristin L %A Thomas W Winkler %A Tõnu Esko %A Karaderi, Tugce %A Locke, Adam E %A Masca, Nicholas G D %A Ng, Maggie C Y %A Mudgal, Poorva %A Rivas, Manuel A %A Vedantam, Sailaja %A Mahajan, Anubha %A Guo, Xiuqing %A Gonçalo R Abecasis %A Aben, Katja K %A Adair, Linda S %A Alam, Dewan S %A Albrecht, Eva %A Allin, Kristine H %A Matthew A. Allison %A Amouyel, Philippe %A Appel, Emil V %A Arveiler, Dominique %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Banas, Bernhard %A Bang, Lia E %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boeing, Heiner %A Boerwinkle, Eric %A Böger, Carsten A %A Bonnycastle, Lori L %A Bork-Jensen, Jette %A Bots, Michiel L %A Erwin P Bottinger %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Burt, Amber A %A Adam S Butterworth %A Carey, David J %A Caulfield, Mark J %A Chambers, John C %A Daniel I Chasman %A Yii-Der I Chen %A Chowdhury, Rajiv %A Cramer Christensen %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Jordi Corominas Galbany %A Cox, Amanda J %A Cuellar-Partida, Gabriel %A Danesh, John %A Gail Davies %A de Bakker, Paul I W %A de Borst, Gert J %A de Denus, Simon %A de Groot, Mark C H %A de Mutsert, Renée %A Ian J Deary %A George Dedoussis %A Ellen W Demerath %A Anneke I den Hollander %A Joe G Dennis %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dunning, Alison M %A Easton, Douglas F %A Ebeling, Tapani %A Edwards, Todd L %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Jessica Faul %A Feitosa, Mary F %A Feng, Shuang %A Ferrannini, Ele %A Marco M Ferrario %A Ferrières, Jean %A Florez, Jose C %A Ford, Ian %A Myriam Fornage %A Franks, Paul W %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Paolo P. Gasparini %A Giedraitis, Vilmantas %A Giri, Ayush %A Giorgia G Girotto %A Gordon, Scott D %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grarup, Niels %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Hansen, Torben %A Kathleen Mullan Harris %A Tamara B Harris %A Andrew T Hattersley %A Caroline Hayward %A He, Liang %A Iris M Heid %A Heikkilä, Kauko %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Lynne J Hocking %A Hollensted, Mette %A Oddgeir L Holmen %A Hovingh, G Kees %A Howson, Joanna M M %A Hoyng, Carel B %A Huang, Paul L %A Hveem, Kristian %A Mohammed Arfan Ikram %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jhun, Min A %A Jia, Yucheng %A Jiang, Xuejuan %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jousilahti, Pekka %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Sharon L R Kardia %A Karpe, Fredrik %A Kee, Frank %A Keeman, Renske %A Lambertus A Kiemeney %A Kitajima, Hidetoshi %A Kluivers, Kirsten B %A Kocher, Thomas %A Komulainen, Pirjo %A Kontto, Jukka %A Kooner, Jaspal S %A Charles Kooperberg %A Kovacs, Peter %A Kriebel, Jennifer %A Kuivaniemi, Helena %A Küry, Sébastien %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lakka, Timo A %A Lange, Ethan M %A Leslie A Lange %A Langefeld, Carl D %A Langenberg, Claudia %A Eric B Larson %A Lee, I-Te %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Li-An %A Lin, Xu %A Lars Lind %A Lindström, Jaana %A Linneberg, Allan %A Liu, Yeheng %A Yongmei Liu %A Lophatananon, Artitaya %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Mackey, David A %A Pamela A F Madden %A Alisa Manning %A Männistö, Satu %A Marenne, Gaëlle %A Marten, Jonathan %A Nicholas G Martin %A Mazul, Angela L %A Meidtner, Karina %A Andres Metspalu %A Mitchell, Paul %A Mohlke, Karen L %A Dennis O Mook-Kanamori %A Morgan, Anna %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Michael A Nalls %A Nauck, Matthias %A Nelson, Christopher P %A Neville, Matt %A Sune Fallgaard Nielsen %A Nikus, Kjell %A Njølstad, Pål R %A Børge G Nordestgaard %A Ntalla, Ioanna %A Jeff O'Connell %A Oksa, Heikki %A Loes M Olde Loohuis %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Markus Perola %A Perry, James A %A Perry, John R B %A Person, Thomas N %A Pirie, Ailith %A Polasek, Ozren %A Posthuma, Danielle %A Olli T Raitakari %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Renstrom, Frida %A Ridker, Paul M %A Rioux, John D %A Neil R Robertson %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Veikko Salomaa %A Nilesh J Samani %A Sandow, Kevin %A Sapkota, Yadav %A Sattar, Naveed %A Schmidt, Marjanka K %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Svati H Shah %A Sim, Xueling %A Sivapalaratnam, Suthesh %A Small, Kerrin S %A Albert Vernon Smith %A Jennifer A Smith %A Southam, Lorraine %A Timothy Spector %A Elizabeth K Speliotes %A John M Starr %A Steinthorsdottir, Valgerdur %A Heather M Stringham %A Stumvoll, Michael %A Surendran, Praveen %A 't Hart, Leen M %A Tansey, Katherine E %A Tardif, Jean-Claude %A Kent D Taylor %A Teumer, Alexander %A Thompson, Deborah J %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tönjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A André G Uitterlinden %A Ulivi, Sheila %A van der Laan, Sander W %A Van Der Leij, Andries R %A Cornelia M van Duijn %A van Schoor, Natasja M %A van Setten, Jessica %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Digna R Velez Edwards %A Vermeulen, Sita H %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Vozzi, Diego %A Walker, Mark %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Wareham, Nicholas J %A Warren, Helen R %A Wessel, Jennifer %A Willems, Sara M %A Wilson, James G %A Daniel Witte %A Woods, Michael O %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Laura M Yerges-Armstrong %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Jing Hua Zhao %A Wei Zhao %A Wei Zhao %A Zheng, He %A Zhou, Wei %A Rotter, Jerome I %A Boehnke, Michael %A Kathiresan, Sekar %A McCarthy, Mark I %A Willer, Cristen J %A Stefansson, Kari %A Ingrid B Borecki %A Liu, Dajiang J %A Kari E North %A Heard-Costa, Nancy L %A Pers, Tune H %A Lindgren, Cecilia M %A Oxvig, Claus %A Kutalik, Zoltán %A Fernando Rivadeneira %A Ruth J F Loos %A Timothy M Frayling %A Joel N Hirschhron %A Deloukas, Panos %A Lettre, Guillaume %XHeight 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.
%B Nature %V 542 %P 186-190 %8 2017 Feb 09 %G eng %N 7640 %1 http://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract %R 10.1038/nature21039