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Genetic studies of body mass index yield new insights for obesity biology
Locke, Adam E; Kahali, Bratati; Berndt, Sonja I; Justice, Anne E; Pers, Tune H; Day, Felix R; Powell, Corey; Vedantam, Sailaja; Buchkovich, Martin L; Yang, Jian; Croteau-Chonka, Damien C; Esko, Tonu; Fall, Tove; Ferreira, Teresa; Gustafsson, Stefan; Kutalik, Zoltan; Luan, Jian'an; Magi, Reedik; Randall, Joshua C; Winkler, Thomas W; Wood, Andrew R; Workalemahu, Tsegaselassie; Faul, Jessica D; Smith, Jennifer A; Zhao, Jing Hua; Zhao, Wei; Chen, Jin; Fehrmann, Rudolf; Hedman, Asa K; Karjalainen, Juha; Schmidt, Ellen M; Absher, Devin; Amin, Najaf; Anderson, Denise; Beekman, Marian; Bolton, Jennifer L; Bragg-Gresham, Jennifer L; Buyske, Steven; Demirkan, Ayse; Deng, Guohong; Ehret, Georg B; Feenstra, Bjarke; Feitosa, Mary F; Fischer, Krista; Goel, Anuj; Gong, Jian; Jackson, Anne U; Kanoni, Stavroula; Kleber, Marcus E; Kristiansson, Kati; Lim, Unhee; Lotay, Vaneet; Mangino, Massimo; Leach, Irene Mateo; Medina-Gomez, Carolina; Medland, Sarah E; Nalls, Michael A; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Peters, Marjolein J; Prokopenko, Inga; Shungin, Dmitry; Stancakova, Alena; Strawbridge, Rona J; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; van der Laan, Sander W; van Setten, Jessica; Van Vliet-Ostaptchouk, Jana V; Wang, Zhaoming; Yengo, Loic; Zhang, Weihua; Isaacs, Aaron; Albrecht, Eva; Arnlov, Johan; Arscott, Gillian M; Attwood, Antony P; Bandinelli, Stefania; Barrett, Amy; Bas, Isabelita N; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Blagieva, Roza; Bluher, Matthias; Bohringer, Stefan; Bonnycastle, Lori L; Bottcher, Yvonne; Boyd, Heather A; Bruinenberg, Marcel; Caspersen, Ida H; Chen, Yii-Der Ida; Clarke, Robert; Daw, E Warwick; de Craen, Anton J M; Delgado, Graciela; Dimitriou, Maria; Doney, Alex S F; Eklund, Niina; Estrada, Karol; Eury, Elodie; Folkersen, Lasse; Fraser, Ross M; Garcia, Melissa E; Geller, Frank; Giedraitis, Vilmantas; Gigante, Bruna; Go, Alan S; Golay, Alain; Goodall, Alison H; Gordon, Scott D; Gorski, Mathias; Grabe, Hans-Jorgen; Grallert, Harald; Grammer, Tanja B; Grassler, Jurgen; Gronberg, Henrik; Groves, Christopher J; Gusto, Gaelle; Haessler, Jeffrey; Hall, Per; Haller, Toomas; Hallmans, Goran; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heard-Costa, Nancy L; Helmer, Quinta; Hengstenberg, Christian; Holmen, Oddgeir; Hottenga, Jouke-Jan; James, Alan L; Jeff, Janina M; Johansson, Asa; Jolley, Jennifer; Juliusdottir, Thorhildur; Kinnunen, Leena; Koenig, Wolfgang; Koskenvuo, Markku; Kratzer, Wolfgang; Laitinen, Jaana; Lamina, Claudia; Leander, Karin; Lee, Nanette R; Lichtner, Peter; Lind, Lars; Lindstrom, Jaana; Lo, Ken Sin; Lobbens, Stephane; Lorbeer, Roberto; Lu, Yingchang; Mach, Francois; Magnusson, Patrik K E; Mahajan, Anubha; McArdle, Wendy L; McLachlan, Stela; Menni, Cristina; Merger, Sigrun; Mihailov, Evelin; Milani, Lili; Moayyeri, Alireza; Monda, Keri L; Morken, Mario A; Mulas, Antonella; Muller, Gabriele; Muller-Nurasyid, Martina; Musk, Arthur W; Nagaraja, Ramaiah; Nothen, Markus M; Nolte, Ilja M; Pilz, Stefan; Rayner, Nigel W; Renstrom, Frida; Rettig, Rainer; Ried, Janina S; Ripke, Stephan; Robertson, Neil R; Rose, Lynda M; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Schumacher, Fredrick R; Scott, William R; Seufferlein, Thomas; Shi, Jianxin; Smith, Albert Vernon; Smolonska, Joanna; Stanton, Alice V; Steinthorsdottir, Valgerdur; Stirrups, Kathleen; Stringham, Heather M; Sundstrom, Johan; Swertz, Morris A; Swift, Amy J; Syvanen, Ann-Christine; Tan, Sian-Tsung; Tayo, Bamidele O; Thorand, Barbara; Thorleifsson, Gudmar; Tyrer, Jonathan P; Uh, Hae-Won; Vandenput, Liesbeth; Verhulst, Frank C; Vermeulen, Sita H; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Warren, Helen R; Waterworth, Dawn; Weedon, Michael N; Wilkens, Lynne R; Willenborg, Christina; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Wright, Alan F; Zhang, Qunyuan; Brennan, Eoin P; Choi, Murim; Dastani, Zari; Drong, Alexander W; Eriksson, Per; Franco-Cereceda, Anders; Gadin, Jesper R; Gharavi, Ali G; Goddard, Michael E; Handsaker, Robert E; Huang, Jinyan; Karpe, Fredrik; Kathiresan, Sekar; Keildson, Sarah; Kiryluk, Krzysztof; Kubo, Michiaki; Lee, Jong-Young; Liang, Liming; Lifton, Richard P; Ma, Baoshan; McCarroll, Steven A; McKnight, Amy J; Min, Josine L; Moffatt, Miriam F; Montgomery, Grant W; Murabito, Joanne M; Nicholson, George; Nyholt, Dale R; Okada, Yukinori; Perry, John R B; Dorajoo, Rajkumar; Reinmaa, Eva; Salem, Rany M; Sandholm, Niina; Scott, Robert A; Stolk, Lisette; Takahashi, Atsushi; Tanaka, Toshihiro; van 't Hooft, Ferdinand M; Vinkhuyzen, Anna A E; Westra, Harm-Jan; Zheng, Wei; Zondervan, Krina T; Heath, Andrew C; Arveiler, Dominique; Bakker, Stephan J L; Beilby, John; Bergman, Richard N; Blangero, John; Bovet, Pascal; Campbell, Harry; Caulfield, Mark J; Cesana, Giancarlo; Chakravarti, Aravinda; Chasman, Daniel I; Chines, Peter S; Collins, Francis S; Crawford, Dana C; Cupples, L Adrienne; Cusi, Daniele; Danesh, John; de Faire, Ulf; den Ruijter, Hester M; Dominiczak, Anna F; Erbel, Raimund; Erdmann, Jeanette; Eriksson, Johan G; Farrall, Martin; Felix, Stephan B; Ferrannini, Ele; Ferrieres, Jean; Ford, Ian; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Gansevoort, Ron T; Gejman, Pablo V; Gieger, Christian; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Hall, Alistair S; Harris, Tamara B; Hattersley, Andrew T; Hicks, Andrew A; Hindorff, Lucia A; Hingorani, Aroon D; Hofman, Albert; Homuth, Georg; Hovingh, G Kees; Humphries, Steve E; Hunt, Steven C; Hypponen, Elina; Illig, Thomas; Jacobs, Kevin B; Jarvelin, Marjo-Riitta; Jockel, Karl-Heinz; Johansen, Berit; Jousilahti, Pekka; Jukema, J Wouter; Jula, Antti M; Kaprio, Jaakko; Kastelein, John J P; Keinanen-Kiukaanniemi, Sirkka M; Kiemeney, Lambertus A; Knekt, Paul; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Marchand, Loic Le; Lehtimaki, Terho; Lyssenko, Valeriya; Mannisto, Satu; Marette, Andre; Matise, Tara C; McKenzie, Colin A; McKnight, Barbara; Moll, Frans L; Morris, Andrew D; Morris, Andrew P; Murray, Jeffrey C; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Madden, Pamela A F; Pasterkamp, Gerard; Peden, John F; Peters, Annette; Postma, Dirkje S; Pramstaller, Peter P; Price, Jackie F; Qi, Lu; Raitakari, Olli T; Rankinen, Tuomo; Rao, D C; Rice, Treva K; Ridker, Paul M; Rioux, John D; Ritchie, Marylyn D; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schunkert, Heribert; Schwarz, Peter E H; Sever, Peter; Shuldiner, Alan R; Sinisalo, Juha; Stolk, Ronald P; Strauch, Konstantin; Tonjes, Anke; Tregouet, David-Alexandre; Tremblay, Angelo; Tremoli, Elena; Virtamo, Jarmo; Vohl, Marie-Claude; Volker, Uwe; Waeber, Gerard; Willemsen, Gonneke; Witteman, Jacqueline C; Zillikens, M Carola; Adair, Linda S; Amouyel, Philippe; Asselbergs, Folkert W; Assimes, Themistocles L; Bochud, Murielle; Boehm, Bernhard O; Boerwinkle, Eric; Bornstein, Stefan R; Bottinger, Erwin P; Bouchard, Claude; Cauchi, Stephane; Chambers, John C; Chanock, Stephen J; Cooper, Richard S; de Bakker, Paul I W; Dedoussis, George; Ferrucci, Luigi; Franks, Paul W; Froguel, Philippe; Groop, Leif C; Haiman, Christopher A; Hamsten, Anders; Hui, Jennie; Hunter, David J; Hveem, Kristian; Kaplan, Robert C; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; Martin, Nicholas G; Marz, Winfried; Melbye, Mads; Metspalu, Andres; Moebus, Susanne; Munroe, Patricia B; Njolstad, Inger; Oostra, Ben A; Palmer, Colin N A; Pedersen, Nancy L; Perola, Markus; Perusse, Louis; Peters, Ulrike; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Rivadeneira, Fernando; Saaristo, Timo E; Saleheen, Danish; Sattar, Naveed; Schadt, Eric E; Schlessinger, David; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Thorsteinsdottir, Unnur; Stumvoll, Michael; Tuomilehto, Jaakko; Uitterlinden, Andre G; Uusitupa, Matti; van der Harst, Pim; Walker, Mark; Wallaschofski, Henri; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wichmann, H-Erich; Wilson, James F; Zanen, Pieter; Borecki, Ingrid B; Deloukas, Panos; Fox, Caroline S; Heid, Iris M; O'Connell, Jeffrey R; Strachan, David P; Stefansson, Kari; van Duijn, Cornelia M; Abecasis, Goncalo R; Franke, Lude; Frayling, Timothy M; McCarthy, Mark I; Visscher, Peter M; Scherag, Andre; Willer, Cristen J; Boehnke, Michael; Mohlke, Karen L; Lindgren, Cecilia M; Beckmann, Jacques S; Barroso, Ines; North, Kari E; Ingelsson, Erik; Hirschhorn, Joel N; Loos, Ruth J F; Speliotes, Elizabeth K
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 x 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 approximately 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.
PMCID:4382211
PMID: 25673413
ISSN: 1476-4687
CID: 2746772
New genetic loci link adipose and insulin biology to body fat distribution
Shungin, Dmitry; Winkler, Thomas W; Croteau-Chonka, Damien C; Ferreira, Teresa; Locke, Adam E; Magi, Reedik; Strawbridge, Rona J; Pers, Tune H; Fischer, Krista; Justice, Anne E; Workalemahu, Tsegaselassie; Wu, Joseph M W; Buchkovich, Martin L; Heard-Costa, Nancy L; Roman, Tamara S; Drong, Alexander W; Song, Ci; Gustafsson, Stefan; Day, Felix R; Esko, Tonu; Fall, Tove; Kutalik, Zoltan; Luan, Jian'an; Randall, Joshua C; Scherag, Andre; Vedantam, Sailaja; Wood, Andrew R; Chen, Jin; Fehrmann, Rudolf; Karjalainen, Juha; Kahali, Bratati; Liu, Ching-Ti; Schmidt, Ellen M; Absher, Devin; Amin, Najaf; Anderson, Denise; Beekman, Marian; Bragg-Gresham, Jennifer L; Buyske, Steven; Demirkan, Ayse; Ehret, Georg B; Feitosa, Mary F; Goel, Anuj; Jackson, Anne U; Johnson, Toby; Kleber, Marcus E; Kristiansson, Kati; Mangino, Massimo; Leach, Irene Mateo; Medina-Gomez, Carolina; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Peters, Marjolein J; Prokopenko, Inga; Stancakova, Alena; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Van Vliet-Ostaptchouk, Jana V; Yengo, Loic; Zhang, Weihua; Albrecht, Eva; Arnlov, Johan; Arscott, Gillian M; Bandinelli, Stefania; Barrett, Amy; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Bluher, Matthias; Bohringer, Stefan; Bonnet, Fabrice; Bottcher, Yvonne; Bruinenberg, Marcel; Carba, Delia B; Caspersen, Ida H; Clarke, Robert; Daw, E Warwick; Deelen, Joris; Deelman, Ewa; Delgado, Graciela; Doney, Alex Sf; Eklund, Niina; Erdos, Michael R; Estrada, Karol; Eury, Elodie; Friedrich, Nele; Garcia, Melissa E; Giedraitis, Vilmantas; Gigante, Bruna; Go, Alan S; Golay, Alain; Grallert, Harald; Grammer, Tanja B; Grassler, Jurgen; Grewal, Jagvir; Groves, Christopher J; Haller, Toomas; Hallmans, Goran; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heikkila, Kauko; Herzig, Karl-Heinz; Helmer, Quinta; Hillege, Hans L; Holmen, Oddgeir; Hunt, Steven C; Isaacs, Aaron; Ittermann, Till; James, Alan L; Johansson, Ingegerd; Juliusdottir, Thorhildur; Kalafati, Ioanna-Panagiota; Kinnunen, Leena; Koenig, Wolfgang; Kooner, Ishminder K; Kratzer, Wolfgang; Lamina, Claudia; Leander, Karin; Lee, Nanette R; Lichtner, Peter; Lind, Lars; Lindstrom, Jaana; Lobbens, Stephane; Lorentzon, Mattias; Mach, Francois; Magnusson, Patrik Ke; Mahajan, Anubha; McArdle, Wendy L; Menni, Cristina; Merger, Sigrun; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Moayyeri, Alireza; Monda, Keri L; Mooijaart, Simon P; Muhleisen, Thomas W; Mulas, Antonella; Muller, Gabriele; Muller-Nurasyid, Martina; Nagaraja, Ramaiah; Nalls, Michael A; Narisu, Narisu; Glorioso, Nicola; Nolte, Ilja M; Olden, Matthias; Rayner, Nigel W; Renstrom, Frida; Ried, Janina S; Robertson, Neil R; Rose, Lynda M; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Sennblad, Bengt; Seufferlein, Thomas; Sitlani, Colleen M; Smith, Albert Vernon; Stirrups, Kathleen; Stringham, Heather M; Sundstrom, Johan; Swertz, Morris A; Swift, Amy J; Syvanen, Ann-Christine; Tayo, Bamidele O; Thorand, Barbara; Thorleifsson, Gudmar; Tomaschitz, Andreas; Troffa, Chiara; van Oort, Floor Va; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Wennauer, Roman; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Zhang, Qunyuan; Zhao, Jing Hua; Brennan, Eoin P; Choi, Murim; Eriksson, Per; Folkersen, Lasse; Franco-Cereceda, Anders; Gharavi, Ali G; Hedman, Asa K; Hivert, Marie-France; Huang, Jinyan; Kanoni, Stavroula; Karpe, Fredrik; Keildson, Sarah; Kiryluk, Krzysztof; Liang, Liming; Lifton, Richard P; Ma, Baoshan; McKnight, Amy J; McPherson, Ruth; Metspalu, Andres; Min, Josine L; Moffatt, Miriam F; Montgomery, Grant W; Murabito, Joanne M; Nicholson, George; Nyholt, Dale R; Olsson, Christian; Perry, John Rb; Reinmaa, Eva; Salem, Rany M; Sandholm, Niina; Schadt, Eric E; Scott, Robert A; Stolk, Lisette; Vallejo, Edgar E; Westra, Harm-Jan; Zondervan, Krina T; Amouyel, Philippe; Arveiler, Dominique; Bakker, Stephan Jl; Beilby, John; Bergman, Richard N; Blangero, John; Brown, Morris J; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chines, Peter S; Claudi-Boehm, Simone; Collins, Francis S; Crawford, Dana C; Danesh, John; de Faire, Ulf; de Geus, Eco Jc; Dorr, Marcus; Erbel, Raimund; Eriksson, Johan G; Farrall, Martin; Ferrannini, Ele; Ferrieres, Jean; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Gansevoort, Ron T; Gieger, Christian; Gudnason, Vilmundur; Haiman, Christopher A; Harris, Tamara B; Hattersley, Andrew T; Heliovaara, Markku; Hicks, Andrew A; Hingorani, Aroon D; Hoffmann, Wolfgang; Hofman, Albert; Homuth, Georg; Humphries, Steve E; Hypponen, Elina; Illig, Thomas; Jarvelin, Marjo-Riitta; Johansen, Berit; Jousilahti, Pekka; Jula, Antti M; Kaprio, Jaakko; Kee, Frank; Keinanen-Kiukaanniemi, Sirkka M; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Le Marchand, Loic; Lehtimaki, Terho; Lyssenko, Valeriya; Mannisto, Satu; Marette, Andre; Matise, Tara C; McKenzie, Colin A; McKnight, Barbara; Musk, Arthur W; Mohlenkamp, Stefan; Morris, Andrew D; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Palmer, Lyle J; Penninx, Brenda W; Peters, Annette; Pramstaller, Peter P; Raitakari, Olli T; Rankinen, Tuomo; Rao, D C; Rice, Treva K; Ridker, Paul M; Ritchie, Marylyn D; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schwarz, Peter Eh; Shuldiner, Alan R; Staessen, Jan A; Steinthorsdottir, Valgerdur; Stolk, Ronald P; Strauch, Konstantin; Tonjes, Anke; Tremblay, Angelo; Tremoli, Elena; Vohl, Marie-Claude; Volker, Uwe; Vollenweider, Peter; Wilson, James F; Witteman, Jacqueline C; Adair, Linda S; Bochud, Murielle; Boehm, Bernhard O; Bornstein, Stefan R; Bouchard, Claude; Cauchi, Stephane; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Cooper, Richard S; Dedoussis, George; Ferrucci, Luigi; Froguel, Philippe; Grabe, Hans-Jorgen; Hamsten, Anders; Hui, Jennie; Hveem, Kristian; Jockel, Karl-Heinz; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; Marz, Winfried; Munroe, Patricia B; Njolstad, Inger; Oostra, Ben A; Palmer, Colin Na; Pedersen, Nancy L; Perola, Markus; Perusse, Louis; Peters, Ulrike; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Rivadeneira, Fernando; Saaristo, Timo E; Saleheen, Danish; Sinisalo, Juha; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Stefansson, Kari; Stumvoll, Michael; Tuomilehto, Jaakko; Uitterlinden, Andre G; Uusitupa, Matti; van der Harst, Pim; Veronesi, Giovanni; Walker, Mark; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Abecasis, Goncalo R; Assimes, Themistocles L; Berndt, Sonja I; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Franke, Lude; Frayling, Timothy M; Groop, Leif C; Hunter, David J; Kaplan, Robert C; O'Connell, Jeffrey R; Qi, Lu; Schlessinger, David; Strachan, David P; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Willer, Cristen J; Visscher, Peter M; Yang, Jian; Hirschhorn, Joel N; Zillikens, M Carola; McCarthy, Mark I; Speliotes, Elizabeth K; North, Kari E; Fox, Caroline S; Barroso, Ines; Franks, Paul W; Ingelsson, Erik; Heid, Iris M; Loos, Ruth Jf; Cupples, L Adrienne; Morris, Andrew P; Lindgren, Cecilia M; Mohlke, Karen L
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
PMCID:4338562
PMID: 25673412
ISSN: 1476-4687
CID: 2746782
Population variation in total genetic risk of Hirschsprung disease from common RET, SEMA3 and NRG1 susceptibility polymorphisms
Kapoor, Ashish; Jiang, Qian; Chatterjee, Sumantra; Chakraborty, Prakash; Sosa, Maria X; Berrios, Courtney; Chakravarti, Aravinda
The risk of Hirschsprung disease (HSCR) is approximately 15/100 000 live births per newborn but has been reported to show significant inter-individual variation from the effects of seven common susceptibility alleles at the RET, SEMA3 and NRG1 loci. We show, by analyses of these variants in 997 samples from 376 HSCR families of European ancestry, that significant genetic risk can only be detected at RET (rs2435357 and rs2506030) and at SEMA3 (rs11766001), but not at NRG1. RET rs2435357 also showed significant frequency differences by gender, segment length of aganglionosis and familiality. Further, in combination, disease risk varied >30-fold between individuals with none and up to 6 susceptibility alleles. Thus, these polymorphisms can be used to stratify the newborn population into distinct phenotypic classes with defined risks to understand HSCR etiology.
PMCID:4406299
PMID: 25666438
ISSN: 1460-2083
CID: 2746792
The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities
Chong, Jessica X; Buckingham, Kati J; Jhangiani, Shalini N; Boehm, Corinne; Sobreira, Nara; Smith, Joshua D; Harrell, Tanya M; McMillin, Margaret J; Wiszniewski, Wojciech; Gambin, Tomasz; Coban Akdemir, Zeynep H; Doheny, Kimberly; Scott, Alan F; Avramopoulos, Dimitri; Chakravarti, Aravinda; Hoover-Fong, Julie; Mathews, Debra; Witmer, P Dane; Ling, Hua; Hetrick, Kurt; Watkins, Lee; Patterson, Karynne E; Reinier, Frederic; Blue, Elizabeth; Muzny, Donna; Kircher, Martin; Bilguvar, Kaya; Lopez-Giraldez, Francesc; Sutton, V Reid; Tabor, Holly K; Leal, Suzanne M; Gunel, Murat; Mane, Shrikant; Gibbs, Richard A; Boerwinkle, Eric; Hamosh, Ada; Shendure, Jay; Lupski, James R; Lifton, Richard P; Valle, David; Nickerson, Deborah A; Bamshad, Michael J
Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying approximately 50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.
PMCID:4573249
PMID: 26166479
ISSN: 1537-6605
CID: 1675052
The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function
Wang, Ya-Juan; Tayo, Bamidele O; Bandyopadhyay, Anupam; Wang, Heming; Feng, Tao; Franceschini, Nora; Tang, Hua; Gao, Jianmin; Sung, Yun Ju; Elston, Robert C; Williams, Scott M; Cooper, Richard S; Mu, Ting-Wei; Zhu, Xiaofeng; Fox, Ervin; Zhang, Zhaogong; Edwards, Todd L; Nalls, Michael A; Sung, Yun Ju; Sun, Yan V; Gottesman, Omri; Adeyemo, Adebawole; Johnson, Andrew D; Young, J Hunter; Rice, Ken; Duan, Qing; Chen, Fang; Li, Yun; Tang, Hua; Fornage, Myriam; Keene, Keith L; Andrews, Jeanette S; Smith, Jennifer A; Faul, Jessica D; Guangfa, Zhang; Murray, Sarah S; Musani, Solomon K; Srinivasan, Sathanur; Edwards, Digna R Velez; Wang, Heming; Becker, Lewis C; Broeckel, Ulrich; Carty, Cara; Chasman, Daniel I; Chen, Wei-Min; Chen, Guanjie; Chen, Wei; Ding, Jingzhong; Dreisbach, Albert W; Evans, Michele K; Guo, Xiuqing; Garcia, Melissa E; Jensen, Rich; Keller, Margaux F; Lettre, Guillaume; Lotay, Vaneet; Martin, Lisa W; Moore, Jason H; Morrison, Alanna C; Mosley, Thomas H; Ogunniyi, Adesola; Palmas, Walter; Papanicolaou, George; Penman, Alan; Polak, Joseph F; Ridker, Paul M; Salako, Babatunde; Singleton, Andrew B; Shriner, Daniel; Taylor, Kent D; Vasan, Ramachandran; Wiggins, Kerri; Yanek, Lisa R; Zhao, Wei; Zonderman, Alan B; Becker, Diane M; Berenson, Gerald; Boerwinkle, Eric; Bottinger, Erwin; Cushman, Mary; Eaton, Charles; Nyberg, Fredrik; Heiss, Gerardo; Hirschhron, Joel N; Howard, Virginia J; Lanktree, Matthew B; Liu, Kiang; Liu, Yongmei; Loos, Ruth; Margolis, Karen; Psaty, Bruce M; Schork, Nicholas J; Weir, David R; Rotimi, Charles N; Sale, Michele M; Harris, Tamara; Kardia, Sharon L R; Hunt, Steven C; Arnett, Donna; Redline, Susan; Risch, Neil; Rao, D C; Rotter, Jerome I; Chakravarti, Aravinda; Reiner, Alex P; Levy, Daniel; Keating, Brendan J; Zhu, Xiaofeng
High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)-rs2272996-in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P=0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD) as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT) vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism.
PMCID:4169380
PMID: 25233454
ISSN: 1553-7404
CID: 5479472
Trans-ethnic meta-analysis of white blood cell phenotypes
Keller, Margaux F; Reiner, Alexander P; Okada, Yukinori; van Rooij, Frank J A; Johnson, Andrew D; Chen, Ming-Huei; Smith, Albert V; Morris, Andrew P; Tanaka, Toshiko; Ferrucci, Luigi; Zonderman, Alan B; Lettre, Guillaume; Harris, Tamara; Garcia, Melissa; Bandinelli, Stefania; Qayyum, Rehan; Yanek, Lisa R; Becker, Diane M; Becker, Lewis C; Kooperberg, Charles; Keating, Brendan; Reis, Jared; Tang, Hua; Boerwinkle, Eric; Kamatani, Yoichiro; Matsuda, Koichi; Kamatani, Naoyuki; Nakamura, Yusuke; Kubo, Michiaki; Liu, Simin; Dehghan, Abbas; Felix, Janine F; Hofman, Albert; Uitterlinden, Andre G; van Duijn, Cornelia M; Franco, Oscar H; Longo, Dan L; Singleton, Andrew B; Psaty, Bruce M; Evans, Michelle K; Cupples, L Adrienne; Rotter, Jerome I; O'Donnell, Christopher J; Takahashi, Atsushi; Wilson, James G; Ganesh, Santhi K; Nalls, Mike A; [Chakravarti, Aravinda]
White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.
PMCID:4245044
PMID: 25096241
ISSN: 1460-2083
CID: 3988842
Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences
Colonna, Vincenza; Ayub, Qasim; Chen, Yuan; Pagani, Luca; Luisi, Pierre; Pybus, Marc; Garrison, Erik; Xue, Yali; Tyler-Smith, Chris; Abecasis, Goncalo R; Auton, Adam; Brooks, Lisa D; DePristo, Mark A; Durbin, Richard M; Handsaker, Robert E; Kang, Hyun Min; Marth, Gabor T; McVean, Gil A; [Chakravarti, Aravinda]
BACKGROUND:Population differentiation has proved to be effective for identifying loci under geographically localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes. RESULTS:We demonstrate that while sites with low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively. CONCLUSIONS:We identify known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research.
PMCID:4197830
PMID: 24980144
ISSN: 1474-760x
CID: 3988812
Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel
Delaneau, Olivier; Marchini, Jonathan; [Chakravarti, Aravinda]
A major use of the 1000 Genomes Project (1000 GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000 GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants.
PMCID:4338501
PMID: 25653097
ISSN: 2041-1723
CID: 3988822
Human variation : a genetic perspective on diversity, race, and medicine
Chakravarti, Aravinda
Cold Spring Harbor NY : CSH Press, 2014
Extent: viii, 131 p. ; 26 cm
ISBN: 1936113252
CID: 3974432
Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations
Scharpf, Robert B; Mireles, Lynn; Yang, Qiong; Kottgen, Anna; Ruczinski, Ingo; Susztak, Katalin; Halper-Stromberg, Eitan; Tin, Adrienne; Cristiano, Stephen; Chakravarti, Aravinda; Boerwinkle, Eric; Fox, Caroline S; Coresh, Josef; Linda Kao, Wen Hong
BACKGROUND: Hyperuricemia is associated with multiple diseases, including gout, cardiovascular disease, and renal disease. Serum urate is highly heritable, yet association studies of single nucleotide polymorphisms (SNPs) and serum uric acid explain a small fraction of the heritability. Whether copy number polymorphisms (CNPs) contribute to uric acid levels is unknown. RESULTS: We assessed copy number on a genome-wide scale among 8,411 individuals of European ancestry (EA) who participated in the Atherosclerosis Risk in Communities (ARIC) study. CNPs upstream of the urate transporter SLC2A9 on chromosome 4p16.1 are associated with uric acid (chi2df2=3545, p=3.19x10-23). Effect sizes, expressed as the percentage change in uric acid per deleted copy, are most pronounced among women (3.974.935.87 [ 2.55097.5 denoting percentiles], p=4.57x10-23) and independent of previously reported SNPs in SLC2A9 as assessed by SNP and CNP regression models and the phasing SNP and CNP haplotypes (chi2df2=3190,p=7.23x10-08). Our finding is replicated in the Framingham Heart Study (FHS), where the effect size estimated from 4,089 women is comparable to ARIC in direction and magnitude (1.414.707.88, p=5.46x10-03). CONCLUSIONS: This is the first study to characterize CNPs in ARIC and the first genome-wide analysis of CNPs and uric acid. Our findings suggests a novel, non-coding regulatory mechanism for SLC2A9-mediated modulation of serum uric acid, and detail a bioinformatic approach for assessing the contribution of CNPs to heritable traits in large population-based studies where technical sources of variation are substantial.
PMCID:4118309
PMID: 25007794
ISSN: 1471-2156
CID: 2746852
