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1.  Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity 
Diabetes  2014;63(6):2158-2171.
Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
doi:10.2337/db13-0949
PMCID: PMC4030103  PMID: 24296717
2.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, 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, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
3.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, 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, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
4.  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, Zoltán | Luan, Jian’an | Mägi, 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, Åsa 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 | Stančáková, 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, Loïc | Zhang, Weihua | Isaacs, Aaron | Albrecht, Eva | Ärnlöv, Johan | Arscott, Gillian M. | Attwood, Antony P. | Bandinelli, Stefania | Barrett, Amy | Bas, Isabelita N. | Bellis, Claire | Bennett, Amanda J. | Berne, Christian | Blagieva, Roza | Blüher, Matthias | Böhringer, Stefan | Bonnycastle, Lori L. | Böttcher, 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-Jörgen | Grallert, Harald | Grammer, Tanja B. | Gräßler, Jürgen | Grönberg, Henrik | Groves, Christopher J. | Gusto, Gaëlle | 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, Åsa | 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 | Lindström, Jaana | Lo, Ken Sin | Lobbens, Stéphane | Lorbeer, Roberto | Lu, Yingchang | Mach, François | 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 | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W. | Nagaraja, Ramaiah | Nöthen, 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. | Sundström, Johan | Swertz, Morris A. | Swift, Amy J. | Syvänen, 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 | Gådin, 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 | Ferrières, 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. | Hyppönen, Elina | Illig, Thomas | Jacobs, Kevin B. | Jarvelin, Marjo-Riitta | Jöckel, 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 | Lehtimäki, Terho | Lyssenko, Valeriya | Männistö, Satu | Marette, André | 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 | Tönjes, Anke | Trégouët, David-Alexandre | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Völker, Uwe | Waeber, Gérard | 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, Stéphane | 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. | März, Winfried | Melbye, Mads | Metspalu, Andres | Moebus, Susanne | Munroe, Patricia B. | Njølstad, Inger | Oostra, Ben A. | Palmer, Colin N. A. | Pedersen, Nancy L. | Perola, Markus | Pérusse, 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, André 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, Gonçalo R. | Franke, Lude | Frayling, Timothy M. | McCarthy, Mark I. | Visscher, Peter M. | Scherag, André | Willer, Cristen J. | Boehnke, Michael | Mohlke, Karen L. | Lindgren, Cecilia M. | Beckmann, Jacques S. | Barroso, Inês | North, Kari E. | Ingelsson, Erik | Hirschhorn, Joel N. | Loos, Ruth J. F. | Speliotes, Elizabeth K.
Nature  2015;518(7538):197-206.
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 × 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.
doi:10.1038/nature14177
PMCID: PMC4382211  PMID: 25673413
5.  Association of Ketone Body Levels With Hyperglycemia and Type 2 Diabetes in 9,398 Finnish Men 
Diabetes  2013;62(10):3618-3626.
We investigated the association of the levels of ketone bodies (KBs) with hyperglycemia and with 62 genetic risk variants regulating glucose levels or type 2 diabetes in the population-based Metabolic Syndrome in Men (METSIM) study, including 9,398 Finnish men without diabetes or newly diagnosed type 2 diabetes. Increasing fasting and 2-h plasma glucose levels were associated with elevated levels of acetoacetate (AcAc) and β-hydroxybutyrate (BHB). AcAc and BHB predicted an increase in the glucose area under the curve in an oral glucose tolerance test, and AcAc predicted the conversion to type 2 diabetes in a 5-year follow-up of the METSIM cohort. Impaired insulin secretion, but not insulin resistance, explained these findings. Of the 62 single nucleotide polymorphisms associated with the risk of type 2 diabetes or hyperglycemia, the glucose-increasing C allele of GCKR significantly associated with elevated levels of fasting BHB levels. Adipose tissue mRNA expression levels of genes involved in ketolysis were significantly associated with insulin sensitivity (Matsuda index). In conclusion, high levels of KBs predicted subsequent worsening of hyperglycemia, and a common variant of GCKR was significantly associated with BHB levels.
doi:10.2337/db12-1363
PMCID: PMC3781437  PMID: 23557707
6.  Hyperglycemia and a Common Variant of GCKR Are Associated With the Levels of Eight Amino Acids in 9,369 Finnish Men 
Diabetes  2012;61(7):1895-1902.
We investigated the association of glycemia and 43 genetic risk variants for hyperglycemia/type 2 diabetes with amino acid levels in the population-based Metabolic Syndrome in Men (METSIM) Study, including 9,369 nondiabetic or newly diagnosed type 2 diabetic Finnish men. Plasma levels of eight amino acids were measured with proton nuclear magnetic resonance spectroscopy. Increasing fasting and 2-h plasma glucose levels were associated with increasing levels of several amino acids and decreasing levels of histidine and glutamine. Alanine, leucine, isoleucine, tyrosine, and glutamine predicted incident type 2 diabetes in a 4.7-year follow-up of the METSIM Study, and their effects were largely mediated by insulin resistance (except for glutamine). We also found significant correlations between insulin sensitivity (Matsuda insulin sensitivity index) and mRNA expression of genes regulating amino acid degradation in 200 subcutaneous adipose tissue samples. Only 1 of 43 risk single nucleotide polymorphisms for type 2 diabetes or hyperglycemia, the glucose-increasing major C allele of rs780094 of GCKR, was significantly associated with decreased levels of alanine and isoleucine and elevated levels of glutamine. In conclusion, the levels of branched-chain, aromatic amino acids and alanine increased and the levels of glutamine and histidine decreased with increasing glycemia, reflecting, at least in part, insulin resistance. Only one single nucleotide polymorphism regulating hyperglycemia was significantly associated with amino acid levels.
doi:10.2337/db11-1378
PMCID: PMC3379649  PMID: 22553379
7.  No Interactions Between Previously Associated 2-Hour Glucose Gene Variants and Physical Activity or BMI on 2-Hour Glucose Levels 
Scott, Robert A. | Chu, Audrey Y. | Grarup, Niels | Manning, Alisa K. | Hivert, Marie-France | Shungin, Dmitry | Tönjes, Anke | Yesupriya, Ajay | Barnes, Daniel | Bouatia-Naji, Nabila | Glazer, Nicole L. | Jackson, Anne U. | Kutalik, Zoltán | Lagou, Vasiliki | Marek, Diana | Rasmussen-Torvik, Laura J. | Stringham, Heather M. | Tanaka, Toshiko | Aadahl, Mette | Arking, Dan E. | Bergmann, Sven | Boerwinkle, Eric | Bonnycastle, Lori L. | Bornstein, Stefan R. | Brunner, Eric | Bumpstead, Suzannah J. | Brage, Soren | Carlson, Olga D. | Chen, Han | Chen, Yii-Der Ida | Chines, Peter S. | Collins, Francis S. | Couper, David J. | Dennison, Elaine M. | Dowling, Nicole F. | Egan, Josephine S. | Ekelund, Ulf | Erdos, Michael R. | Forouhi, Nita G. | Fox, Caroline S. | Goodarzi, Mark O. | Grässler, Jürgen | Gustafsson, Stefan | Hallmans, Göran | Hansen, Torben | Hingorani, Aroon | Holloway, John W. | Hu, Frank B. | Isomaa, Bo | Jameson, Karen A. | Johansson, Ingegerd | Jonsson, Anna | Jørgensen, Torben | Kivimaki, Mika | Kovacs, Peter | Kumari, Meena | Kuusisto, Johanna | Laakso, Markku | Lecoeur, Cécile | Lévy-Marchal, Claire | Li, Guo | Loos, Ruth J.F. | Lyssenko, Valeri | Marmot, Michael | Marques-Vidal, Pedro | Morken, Mario A. | Müller, Gabriele | North, Kari E. | Pankow, James S. | Payne, Felicity | Prokopenko, Inga | Psaty, Bruce M. | Renström, Frida | Rice, Ken | Rotter, Jerome I. | Rybin, Denis | Sandholt, Camilla H. | Sayer, Avan A. | Shrader, Peter | Schwarz, Peter E.H. | Siscovick, David S. | Stančáková, Alena | Stumvoll, Michael | Teslovich, Tanya M. | Waeber, Gérard | Williams, Gordon H. | Witte, Daniel R. | Wood, Andrew R. | Xie, Weijia | Boehnke, Michael | Cooper, Cyrus | Ferrucci, Luigi | Froguel, Philippe | Groop, Leif | Kao, W.H. Linda | Vollenweider, Peter | Walker, Mark | Watanabe, Richard M. | Pedersen, Oluf | Meigs, James B. | Ingelsson, Erik | Barroso, Inês | Florez, Jose C. | Franks, Paul W. | Dupuis, Josée | Wareham, Nicholas J. | Langenberg, Claudia
Diabetes  2012;61(5):1291-1296.
Gene–lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13–0.31], P = 1.63 × 10−6). All SNPs were associated with 2-h glucose (β = 0.06–0.12 mmol/allele, P ≤ 1.53 × 10−7), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene–lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.
doi:10.2337/db11-0973
PMCID: PMC3331745  PMID: 22415877
8.  A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance 
Manning, Alisa K. | Hivert, Marie-France | Scott, Robert A. | Grimsby, Jonna L. | Bouatia-Naji, Nabila | Chen, Han | Rybin, Denis | Liu, Ching-Ti | Bielak, Lawrence F. | Prokopenko, Inga | Amin, Najaf | Barnes, Daniel | Cadby, Gemma | Hottenga, Jouke-Jan | Ingelsson, Erik | Jackson, Anne U. | Johnson, Toby | Kanoni, Stavroula | Ladenvall, Claes | Lagou, Vasiliki | Lahti, Jari | Lecoeur, Cecile | Liu, Yongmei | Martinez-Larrad, Maria Teresa | Montasser, May E. | Navarro, Pau | Perry, John R. B. | Rasmussen-Torvik, Laura J. | Salo, Perttu | Sattar, Naveed | Shungin, Dmitry | Strawbridge, Rona J. | Tanaka, Toshiko | van Duijn, Cornelia M. | An, Ping | de Andrade, Mariza | Andrews, Jeanette S. | Aspelund, Thor | Atalay, Mustafa | Aulchenko, Yurii | Balkau, Beverley | Bandinelli, Stefania | Beckmann, Jacques S. | Beilby, John P. | Bellis, Claire | Bergman, Richard N. | Blangero, John | Boban, Mladen | Boehnke, Michael | Boerwinkle, Eric | Bonnycastle, Lori L. | Boomsma, Dorret I. | Borecki, Ingrid B. | Böttcher, Yvonne | Bouchard, Claude | Brunner, Eric | Budimir, Danijela | Campbell, Harry | Carlson, Olga | Chines, Peter S. | Clarke, Robert | Collins, Francis S. | Corbatón-Anchuelo, Arturo | Couper, David | de Faire, Ulf | Dedoussis, George V | Deloukas, Panos | Dimitriou, Maria | Egan, Josephine M | Eiriksdottir, Gudny | Erdos, Michael R. | Eriksson, Johan G. | Eury, Elodie | Ferrucci, Luigi | Ford, Ian | Forouhi, Nita G. | Fox, Caroline S | Franzosi, Maria Grazia | Franks, Paul W | Frayling, Timothy M | Froguel, Philippe | Galan, Pilar | de Geus, Eco | Gigante, Bruna | Glazer, Nicole L. | Goel, Anuj | Groop, Leif | Gudnason, Vilmundur | Hallmans, Göran | Hamsten, Anders | Hansson, Ola | Harris, Tamara B. | Hayward, Caroline | Heath, Simon | Hercberg, Serge | Hicks, Andrew A. | Hingorani, Aroon | Hofman, Albert | Hui, Jennie | Hung, Joseph | Jarvelin, Marjo Riitta | Jhun, Min A. | Johnson, Paul C.D. | Jukema, J Wouter | Jula, Antti | Kao, W.H. | Kaprio, Jaakko | Kardia, Sharon L. R. | Keinanen-Kiukaanniemi, Sirkka | Kivimaki, Mika | Kolcic, Ivana | Kovacs, Peter | Kumari, Meena | Kuusisto, Johanna | Kyvik, Kirsten Ohm | Laakso, Markku | Lakka, Timo | Lannfelt, Lars | Lathrop, G Mark | Launer, Lenore J. | Leander, Karin | Li, Guo | Lind, Lars | Lindstrom, Jaana | Lobbens, Stéphane | Loos, Ruth J. F. | Luan, Jian’an | Lyssenko, Valeriya | Mägi, Reedik | Magnusson, Patrik K. E. | Marmot, Michael | Meneton, Pierre | Mohlke, Karen L. | Mooser, Vincent | Morken, Mario A. | Miljkovic, Iva | Narisu, Narisu | O’Connell, Jeff | Ong, Ken K. | Oostra, Ben A. | Palmer, Lyle J. | Palotie, Aarno | Pankow, James S. | Peden, John F. | Pedersen, Nancy L. | Pehlic, Marina | Peltonen, Leena | Penninx, Brenda | Pericic, Marijana | Perola, Markus | Perusse, Louis | Peyser, Patricia A | Polasek, Ozren | Pramstaller, Peter P. | Province, Michael A. | Räikkönen, Katri | Rauramaa, Rainer | Rehnberg, Emil | Rice, Ken | Rotter, Jerome I. | Rudan, Igor | Ruokonen, Aimo | Saaristo, Timo | Sabater-Lleal, Maria | Salomaa, Veikko | Savage, David B. | Saxena, Richa | Schwarz, Peter | Seedorf, Udo | Sennblad, Bengt | Serrano-Rios, Manuel | Shuldiner, Alan R. | Sijbrands, Eric J.G. | Siscovick, David S. | Smit, Johannes H. | Small, Kerrin S. | Smith, Nicholas L. | Smith, Albert Vernon | Stančáková, Alena | Stirrups, Kathleen | Stumvoll, Michael | Sun, Yan V. | Swift, Amy J. | Tönjes, Anke | Tuomilehto, Jaakko | Trompet, Stella | Uitterlinden, Andre G. | Uusitupa, Matti | Vikström, Max | Vitart, Veronique | Vohl, Marie-Claude | Voight, Benjamin F. | Vollenweider, Peter | Waeber, Gerard | Waterworth, Dawn M | Watkins, Hugh | Wheeler, Eleanor | Widen, Elisabeth | Wild, Sarah H. | Willems, Sara M. | Willemsen, Gonneke | Wilson, James F. | Witteman, Jacqueline C.M. | Wright, Alan F. | Yaghootkar, Hanieh | Zelenika, Diana | Zemunik, Tatijana | Zgaga, Lina | Wareham, Nicholas J. | McCarthy, Mark I. | Barroso, Ines | Watanabe, Richard M. | Florez, Jose C. | Dupuis, Josée | Meigs, James B. | Langenberg, Claudia
Nature genetics  2012;44(6):659-669.
Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction, but contributed little to our understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways may be uncovered by accounting for differences in body mass index (BMI) and potential interaction between BMI and genetic variants. We applied a novel joint meta-analytical approach to test associations with fasting insulin (FI) and glucose (FG) on a genome-wide scale. We present six previously unknown FI loci at P<5×10−8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496non-diabetic individuals. Risk variants were associated with higher triglyceride and lower HDL cholesterol levels, suggestive of a role for these FI loci in insulin resistance pathways. The localization of these additional loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
doi:10.1038/ng.2274
PMCID: PMC3613127  PMID: 22581228
9.  Effects of 34 Risk Loci for Type 2 Diabetes or Hyperglycemia on Lipoprotein Subclasses and Their Composition in 6,580 Nondiabetic Finnish Men 
Diabetes  2011;60(5):1608-1616.
OBJECTIVE
We investigated the effects of 34 genetic risk variants for hyperglycemia/type 2 diabetes on lipoprotein subclasses and particle composition in a large population-based cohort.
RESEARCH DESIGN AND METHODS
The study included 6,580 nondiabetic Finnish men from the population-based Metabolic Syndrome in Men (METSIM) study (aged 57 ± 7 years; BMI 26.8 ± 3.7 kg/m2). Genotyping of 34 single nucleotide polymorphism (SNPs) for hyperglycemia/type 2 diabetes was performed. Proton nuclear magnetic resonance spectroscopy was used to measure particle concentrations of 14 lipoprotein subclasses and their composition in native serum samples.
RESULTS
The glucose-increasing allele of rs780094 in GCKR was significantly associated with low concentrations of VLDL particles (independently of their size) and small LDL and was nominally associated with low concentrations of intermediate-density lipoprotein, all LDL subclasses, and high concentrations of very large and large HDL particles. The glucose-increasing allele of rs174550 in FADS1 was significantly associated with high concentrations of very large and large HDL particles and nominally associated with low concentrations of all VLDL particles. SNPs rs10923931 in NOTCH2 and rs757210 in HNF1B genes showed nominal or significant associations with several lipoprotein traits. The genetic risk score of 34 SNPs was not associated with any of the lipoprotein subclasses.
CONCLUSIONS
Four of the 34 risk loci for type 2 diabetes or hyperglycemia (GCKR, FADS1, NOTCH2, and HNF1B) were significantly associated with lipoprotein traits. A GCKR variant predominantly affected the concentration of VLDL, and the FADS1 variant affected very large and large HDL particles. Only a limited number of risk loci for hyperglycemia/type 2 diabetes significantly affect lipoprotein metabolism.
doi:10.2337/db10-1655
PMCID: PMC3292337  PMID: 21421807
10.  Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes 
Defining the genetic contribution of rare variants to common diseases is a major basic and clinical science challenge that could offer new insights into disease etiology and provide potential for directed gene- and pathway-based prevention and treatment. Common and rare nonsynonymous variants in the GCKR gene are associated with alterations in metabolic traits, most notably serum triglyceride levels. GCKR encodes glucokinase regulatory protein (GKRP), a predominantly nuclear protein that inhibits hepatic glucokinase (GCK) and plays a critical role in glucose homeostasis. The mode of action of rare GCKR variants remains unexplored. We identified 19 nonsynonymous GCKR variants among 800 individuals from the ClinSeq medical sequencing project. Excluding the previously described common missense variant p.Pro446Leu, all variants were rare in the cohort. Accordingly, we functionally characterized all variants to evaluate their potential phenotypic effects. Defects were observed for the majority of the rare variants after assessment of cellular localization, ability to interact with GCK, and kinetic activity of the encoded proteins. Comparing the individuals with functional rare variants to those without such variants showed associations with lipid phenotypes. Our findings suggest that, while nonsynonymous GCKR variants, excluding p.Pro446Leu, are rare in individuals of mixed European descent, the majority do affect protein function. In sum, this study utilizes computational, cell biological, and biochemical methods to present a model for interpreting the clinical significance of rare genetic variants in common disease.
doi:10.1172/JCI46425
PMCID: PMC3248284  PMID: 22182842
11.  Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans 
Diabetes  2010;59(5):1266-1275.
OBJECTIVE
Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action.
RESEARCH DESIGN AND METHODS
We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084).
RESULTS
The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction.
CONCLUSIONS
Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
doi:10.2337/db09-1568
PMCID: PMC2857908  PMID: 20185807
12.  Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution 
Heid, Iris M. | Jackson, Anne U. | Randall, Joshua C. | Winkler, Thomas W. | Qi, Lu | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Zillikens, M. Carola | Speliotes, Elizabeth K. | Mägi, Reedik | Workalemahu, Tsegaselassie | White, Charles C. | Bouatia-Naji, Nabila | Harris, Tamara B. | Berndt, Sonja I. | Ingelsson, Erik | Willer, Cristen J. | Weedon, Michael N. | Luan, Jian'an | Vedantam, Sailaja | Esko, Tõnu | Kilpeläinen, Tuomas O. | Kutalik, Zoltán | Li, Shengxu | Monda, Keri L. | Dixon, Anna L. | Holmes, Christopher C. | Kaplan, Lee M. | Liang, Liming | Min, Josine L. | Moffatt, Miriam F. | Molony, Cliona | Nicholson, George | Schadt, Eric E. | Zondervan, Krina T. | Feitosa, Mary F. | Ferreira, Teresa | Allen, Hana Lango | Weyant, Robert J. | Wheeler, Eleanor | Wood, Andrew R. | Estrada, Karol | Goddard, Michael E. | Lettre, Guillaume | Mangino, Massimo | Nyholt, Dale R. | Purcell, Shaun | Vernon Smith, Albert | Visscher, Peter M. | Yang, Jian | McCaroll, Steven A. | Nemesh, James | Voight, Benjamin F. | Absher, Devin | Amin, Najaf | Aspelund, Thor | Coin, Lachlan | Glazer, Nicole L. | Hayward, Caroline | Heard-Costa, Nancy L. | Hottenga, Jouke-Jan | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kapur, Karen | Ketkar, Shamika | Knowles, Joshua W. | Kraft, Peter | Kraja, Aldi T. | Lamina, Claudia | Leitzmann, Michael F. | McKnight, Barbara | Morris, Andrew P. | Ong, Ken K. | Perry, John R.B. | Peters, Marjolein J. | Polasek, Ozren | Prokopenko, Inga | Rayner, Nigel W. | Ripatti, Samuli | Rivadeneira, Fernando | Robertson, Neil R. | Sanna, Serena | Sovio, Ulla | Surakka, Ida | Teumer, Alexander | van Wingerden, Sophie | Vitart, Veronique | Zhao, Jing Hua | Cavalcanti-Proença, Christine | Chines, Peter S. | Fisher, Eva | Kulzer, Jennifer R. | Lecoeur, Cecile | Narisu, Narisu | Sandholt, Camilla | Scott, Laura J. | Silander, Kaisa | Stark, Klaus | Tammesoo, Mari-Liis | Teslovich, Tanya M. | John Timpson, Nicholas | Watanabe, Richard M. | Welch, Ryan | Chasman, Daniel I. | Cooper, Matthew N. | Jansson, John-Olov | Kettunen, Johannes | Lawrence, Robert W. | Pellikka, Niina | Perola, Markus | Vandenput, Liesbeth | Alavere, Helene | Almgren, Peter | Atwood, Larry D. | Bennett, Amanda J. | Biffar, Reiner | Bonnycastle, Lori L. | Bornstein, Stefan R. | Buchanan, Thomas A. | Campbell, Harry | Day, Ian N.M. | Dei, Mariano | Dörr, Marcus | Elliott, Paul | Erdos, Michael R. | Eriksson, Johan G. | Freimer, Nelson B. | Fu, Mao | Gaget, Stefan | Geus, Eco J.C. | Gjesing, Anette P. | Grallert, Harald | Gräßler, Jürgen | Groves, Christopher J. | Guiducci, Candace | Hartikainen, Anna-Liisa | Hassanali, Neelam | Havulinna, Aki S. | Herzig, Karl-Heinz | Hicks, Andrew A. | Hui, Jennie | Igl, Wilmar | Jousilahti, Pekka | Jula, Antti | Kajantie, Eero | Kinnunen, Leena | Kolcic, Ivana | Koskinen, Seppo | Kovacs, Peter | Kroemer, Heyo K. | Krzelj, Vjekoslav | Kuusisto, Johanna | Kvaloy, Kirsti | Laitinen, Jaana | Lantieri, Olivier | Lathrop, G. Mark | Lokki, Marja-Liisa | Luben, Robert N. | Ludwig, Barbara | McArdle, Wendy L. | McCarthy, Anne | Morken, Mario A. | Nelis, Mari | Neville, Matt J. | Paré, Guillaume | Parker, Alex N. | Peden, John F. | Pichler, Irene | Pietiläinen, Kirsi H. | Platou, Carl G.P. | Pouta, Anneli | Ridderstråle, Martin | Samani, Nilesh J. | Saramies, Jouko | Sinisalo, Juha | Smit, Jan H. | Strawbridge, Rona J. | Stringham, Heather M. | Swift, Amy J. | Teder-Laving, Maris | Thomson, Brian | Usala, Gianluca | van Meurs, Joyce B.J. | van Ommen, Gert-Jan | Vatin, Vincent | Volpato, Claudia B. | Wallaschofski, Henri | Walters, G. Bragi | Widen, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Witte, Daniel R. | Zgaga, Lina | Zitting, Paavo | Beilby, John P. | James, Alan L. | Kähönen, Mika | Lehtimäki, Terho | Nieminen, Markku S. | Ohlsson, Claes | Palmer, Lyle J. | Raitakari, Olli | Ridker, Paul M. | Stumvoll, Michael | Tönjes, Anke | Viikari, Jorma | Balkau, Beverley | Ben-Shlomo, Yoav | Bergman, Richard N. | Boeing, Heiner | Smith, George Davey | Ebrahim, Shah | Froguel, Philippe | Hansen, Torben | Hengstenberg, Christian | Hveem, Kristian | Isomaa, Bo | Jørgensen, Torben | Karpe, Fredrik | Khaw, Kay-Tee | Laakso, Markku | Lawlor, Debbie A. | Marre, Michel | Meitinger, Thomas | Metspalu, Andres | Midthjell, Kristian | Pedersen, Oluf | Salomaa, Veikko | Schwarz, Peter E.H. | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Valle, Timo T. | Wareham, Nicholas J. | Arnold, Alice M. | Beckmann, Jacques S. | Bergmann, Sven | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Collins, Francis S. | Eiriksdottir, Gudny | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Hattersley, Andrew T. | Hofman, Albert | Hu, Frank B. | Illig, Thomas | Iribarren, Carlos | Jarvelin, Marjo-Riitta | Kao, W.H. Linda | Kaprio, Jaakko | Launer, Lenore J. | Munroe, Patricia B. | Oostra, Ben | Penninx, Brenda W. | Pramstaller, Peter P. | Psaty, Bruce M. | Quertermous, Thomas | Rissanen, Aila | Rudan, Igor | Shuldiner, Alan R. | Soranzo, Nicole | Spector, Timothy D. | Syvanen, Ann-Christine | Uda, Manuela | Uitterlinden, André | Völzke, Henry | Vollenweider, Peter | Wilson, James F. | Witteman, Jacqueline C. | Wright, Alan F. | Abecasis, Gonçalo R. | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Frayling, Timothy M. | Groop, Leif C. | Haritunians, Talin | Hunter, David J. | Kaplan, Robert C. | North, Kari E. | O'Connell, Jeffrey R. | Peltonen, Leena | Schlessinger, David | Strachan, David P. | Hirschhorn, Joel N. | Assimes, Themistocles L. | Wichmann, H.-Erich | Thorsteinsdottir, Unnur | van Duijn, Cornelia M. | Stefansson, Kari | Cupples, L. Adrienne | Loos, Ruth J.F. | Barroso, Inês | McCarthy, Mark I. | Fox, Caroline S. | Mohlke, Karen L. | Lindgren, Cecilia M.
Nature genetics  2010;42(11):949-960.
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body-mass-index (up to 77,167 participants), following up 16 loci in an additional 29 studies (up to 113,636 subjects). We identified 13 novel loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1, and CPEB4 (P 1.9 × 10−9 to 1.8 × 10−40), and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex-difference 1.9 × 10−3 to 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution, independent of overall adiposity, and reveal powerful gene-by-sex interactions.
doi:10.1038/ng.685
PMCID: PMC3000924  PMID: 20935629
genome-wide association; waist-hip-ratio; body fat distribution; central obesity; meta-analysis; genetics; visceral adipose tissue; metabolism; body composition; Expression Quantitative Trait Loci; sex difference
13.  Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution 
Heid, Iris M | Jackson, Anne U | Randall, Joshua C | Winkler, Thomas W | Qi, Lu | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Zillikens, M Carola | Speliotes, Elizabeth K | Mägi, Reedik | Workalemahu, Tsegaselassie | White, Charles C | Bouatia-Naji, Nabila | Harris, Tamara B | Berndt, Sonja I | Ingelsson, Erik | Willer, Cristen J | Weedon, Michael N | Luan, Jian’An | Vedantam, Sailaja | Esko, Tõnu | Kilpeläinen, Tuomas O | Kutalik, Zoltán | Li, Shengxu | Monda, Keri L | Dixon, Anna L | Holmes, Christopher C | Kaplan, Lee M | Liang, Liming | Min, Josine L | Moffatt, Miriam F | Molony, Cliona | Nicholson, George | Schadt, Eric E | Zondervan, Krina T | Feitosa, Mary F | Ferreira, Teresa | Allen, Hana Lango | Weyant, Robert J | Wheeler, Eleanor | Wood, Andrew R | Estrada, Karol | Goddard, Michael E | Lettre, Guillaume | Mangino, Massimo | Nyholt, Dale R | Purcell, Shaun | Smith, Albert Vernon | Visscher, Peter M | Yang, Jian | McCarroll, Steven A | Nemesh, James | Voight, Benjamin F | Absher, Devin | Amin, Najaf | Aspelund, Thor | Coin, Lachlan | Glazer, Nicole L | Hayward, Caroline | Heard-costa, Nancy L | Hottenga, Jouke-Jan | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kapur, Karen | Ketkar, Shamika | Knowles, Joshua W | Kraft, Peter | Kraja, Aldi T | Lamina, Claudia | Leitzmann, Michael F | McKnight, Barbara | Morris, Andrew P | Ong, Ken K | Perry, John R B | Peters, Marjolein J | Polasek, Ozren | Prokopenko, Inga | Rayner, Nigel W | Ripatti, Samuli | Rivadeneira, Fernando | Robertson, Neil R | Sanna, Serena | Sovio, Ulla | Surakka, Ida | Teumer, Alexander | van Wingerden, Sophie | Vitart, Veronique | Zhao, Jing Hua | Cavalcanti-Proença, Christine | Chines, Peter S | Fisher, Eva | Kulzer, Jennifer R | Lecoeur, Cecile | Narisu, Narisu | Sandholt, Camilla | Scott, Laura J | Silander, Kaisa | Stark, Klaus | Tammesoo, Mari-Liis | Teslovich, Tanya M | Timpson, Nicholas John | Watanabe, Richard M | Welch, Ryan | Chasman, Daniel I | Cooper, Matthew N | Jansson, John-Olov | Kettunen, Johannes | Lawrence, Robert W | Pellikka, Niina | Perola, Markus | Vandenput, Liesbeth | Alavere, Helene | Almgren, Peter | Atwood, Larry D | Bennett, Amanda J | Biffar, Reiner | Bonnycastle, Lori L | Bornstein, Stefan R | Buchanan, Thomas A | Campbell, Harry | Day, Ian N M | Dei, Mariano | Dörr, Marcus | Elliott, Paul | Erdos, Michael R | Eriksson, Johan G | Freimer, Nelson B | Fu, Mao | Gaget, Stefan | Geus, Eco J C | Gjesing, Anette P | Grallert, Harald | Gräßler, Jürgen | Groves, Christopher J | Guiducci, Candace | Hartikainen, Anna-Liisa | Hassanali, Neelam | Havulinna, Aki S | Herzig, Karl-Heinz | Hicks, Andrew A | Hui, Jennie | Igl, Wilmar | Jousilahti, Pekka | Jula, Antti | Kajantie, Eero | Kinnunen, Leena | Kolcic, Ivana | Koskinen, Seppo | Kovacs, Peter | Kroemer, Heyo K | Krzelj, Vjekoslav | Kuusisto, Johanna | Kvaloy, Kirsti | Laitinen, Jaana | Lantieri, Olivier | Lathrop, G Mark | Lokki, Marja-Liisa | Luben, Robert N | Ludwig, Barbara | McArdle, Wendy L | McCarthy, Anne | Morken, Mario A | Nelis, Mari | Neville, Matt J | Paré, Guillaume | Parker, Alex N | Peden, John F | Pichler, Irene | Pietiläinen, Kirsi H | Platou, Carl G P | Pouta, Anneli | Ridderstråle, Martin | Samani, Nilesh J | Saramies, Jouko | Sinisalo, Juha | Smit, Jan H | Strawbridge, Rona J | Stringham, Heather M | Swift, Amy J | Teder-Laving, Maris | Thomson, Brian | Usala, Gianluca | van Meurs, Joyce B J | van Ommen, Gert-Jan | Vatin, Vincent | Volpato, Claudia B | Wallaschofski, Henri | Walters, G Bragi | Widen, Elisabeth | Wild, Sarah H | Willemsen, Gonneke | Witte, Daniel R | Zgaga, Lina | Zitting, Paavo | Beilby, John P | James, Alan L | Kähönen, Mika | Lehtimäki, Terho | Nieminen, Markku S | Ohlsson, Claes | Palmer, Lyle J | Raitakari, Olli | Ridker, Paul M | Stumvoll, Michael | Tönjes, Anke | Viikari, Jorma | Balkau, Beverley | Ben-Shlomo, Yoav | Bergman, Richard N | Boeing, Heiner | Smith, George Davey | Ebrahim, Shah | Froguel, Philippe | Hansen, Torben | Hengstenberg, Christian | Hveem, Kristian | Isomaa, Bo | Jørgensen, Torben | Karpe, Fredrik | Khaw, Kay-Tee | Laakso, Markku | Lawlor, Debbie A | Marre, Michel | Meitinger, Thomas | Metspalu, Andres | Midthjell, Kristian | Pedersen, Oluf | Salomaa, Veikko | Schwarz, Peter E H | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Valle, Timo T | Wareham, Nicholas J | Arnold, Alice M | Beckmann, Jacques S | Bergmann, Sven | Boerwinkle, Eric | Boomsma, Dorret I | Caulfield, Mark J | Collins, Francis S | Eiriksdottir, Gudny | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Hattersley, Andrew T | Hofman, Albert | Hu, Frank B | Illig, Thomas | Iribarren, Carlos | Jarvelin, Marjo-Riitta | Kao, W H Linda | Kaprio, Jaakko | Launer, Lenore J | Munroe, Patricia B | Oostra, Ben | Penninx, Brenda W | Pramstaller, Peter P | Psaty, Bruce M | Quertermous, Thomas | Rissanen, Aila | Rudan, Igor | Shuldiner, Alan R | Soranzo, Nicole | Spector, Timothy D | Syvanen, Ann-Christine | Uda, Manuela | Uitterlinden, André | Völzke, Henry | Vollenweider, Peter | Wilson, James F | Witteman, Jacqueline C | Wright, Alan F | Abecasis, Gonçalo R | Boehnke, Michael | Borecki, Ingrid B | Deloukas, Panos | Frayling, Timothy M | Groop, Leif C | Haritunians, Talin | Hunter, David J | Kaplan, Robert C | North, Kari E | O’connell, Jeffrey R | Peltonen, Leena | Schlessinger, David | Strachan, David P | Hirschhorn, Joel N | Assimes, Themistocles L | Wichmann, H-Erich | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Stefansson, Kari | Cupples, L Adrienne | Loos, Ruth J F | Barroso, Inês | McCarthy, Mark I | Fox, Caroline S | Mohlke, Karen L | Lindgren, Cecilia M
Nature genetics  2010;42(11):949-960.
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
doi:10.1038/ng.685
PMCID: PMC3000924  PMID: 20935629
14.  Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index 
Speliotes, Elizabeth K. | Willer, Cristen J. | Berndt, Sonja I. | Monda, Keri L. | Thorleifsson, Gudmar | Jackson, Anne U. | Allen, Hana Lango | Lindgren, Cecilia M. | Luan, Jian’an | Mägi, Reedik | Randall, Joshua C. | Vedantam, Sailaja | Winkler, Thomas W. | Qi, Lu | Workalemahu, Tsegaselassie | Heid, Iris M. | Steinthorsdottir, Valgerdur | Stringham, Heather M. | Weedon, Michael N. | Wheeler, Eleanor | Wood, Andrew R. | Ferreira, Teresa | Weyant, Robert J. | Segré, Ayellet V. | Estrada, Karol | Liang, Liming | Nemesh, James | Park, Ju-Hyun | Gustafsson, Stefan | Kilpeläinen, Tuomas O. | Yang, Jian | Bouatia-Naji, Nabila | Esko, Tõnu | Feitosa, Mary F. | Kutalik, Zoltán | Mangino, Massimo | Raychaudhuri, Soumya | Scherag, Andre | Smith, Albert Vernon | Welch, Ryan | Zhao, Jing Hua | Aben, Katja K. | Absher, Devin M. | Amin, Najaf | Dixon, Anna L. | Fisher, Eva | Glazer, Nicole L. | Goddard, Michael E. | Heard-Costa, Nancy L. | Hoesel, Volker | Hottenga, Jouke-Jan | Johansson, Åsa | Johnson, Toby | Ketkar, Shamika | Lamina, Claudia | Li, Shengxu | Moffatt, Miriam F. | Myers, Richard H. | Narisu, Narisu | Perry, John R.B. | Peters, Marjolein J. | Preuss, Michael | Ripatti, Samuli | Rivadeneira, Fernando | Sandholt, Camilla | Scott, Laura J. | Timpson, Nicholas J. | Tyrer, Jonathan P. | van Wingerden, Sophie | Watanabe, Richard M. | White, Charles C. | Wiklund, Fredrik | Barlassina, Christina | Chasman, Daniel I. | Cooper, Matthew N. | Jansson, John-Olov | Lawrence, Robert W. | Pellikka, Niina | Prokopenko, Inga | Shi, Jianxin | Thiering, Elisabeth | Alavere, Helene | Alibrandi, Maria T. S. | Almgren, Peter | Arnold, Alice M. | Aspelund, Thor | Atwood, Larry D. | Balkau, Beverley | Balmforth, Anthony J. | Bennett, Amanda J. | Ben-Shlomo, Yoav | Bergman, Richard N. | Bergmann, Sven | Biebermann, Heike | Blakemore, Alexandra I.F. | Boes, Tanja | Bonnycastle, Lori L. | Bornstein, Stefan R. | Brown, Morris J. | Buchanan, Thomas A. | Busonero, Fabio | Campbell, Harry | Cappuccio, Francesco P. | Cavalcanti-Proença, Christine | Chen, Yii-Der Ida | Chen, Chih-Mei | Chines, Peter S. | Clarke, Robert | Coin, Lachlan | Connell, John | Day, Ian N.M. | Heijer, Martin den | Duan, Jubao | Ebrahim, Shah | Elliott, Paul | Elosua, Roberto | Eiriksdottir, Gudny | Erdos, Michael R. | Eriksson, Johan G. | Facheris, Maurizio F. | Felix, Stephan B. | Fischer-Posovszky, Pamela | Folsom, Aaron R. | Friedrich, Nele | Freimer, Nelson B. | Fu, Mao | Gaget, Stefan | Gejman, Pablo V. | Geus, Eco J.C. | Gieger, Christian | Gjesing, Anette P. | Goel, Anuj | Goyette, Philippe | Grallert, Harald | Gräßler, Jürgen | Greenawalt, Danielle M. | Groves, Christopher J. | Gudnason, Vilmundur | Guiducci, Candace | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hall, Alistair S. | Havulinna, Aki S. | Hayward, Caroline | Heath, Andrew C. | Hengstenberg, Christian | Hicks, Andrew A. | Hinney, Anke | Hofman, Albert | Homuth, Georg | Hui, Jennie | Igl, Wilmar | Iribarren, Carlos | Isomaa, Bo | Jacobs, Kevin B. | Jarick, Ivonne | Jewell, Elizabeth | John, Ulrich | Jørgensen, Torben | Jousilahti, Pekka | Jula, Antti | Kaakinen, Marika | Kajantie, Eero | Kaplan, Lee M. | Kathiresan, Sekar | Kettunen, Johannes | Kinnunen, Leena | Knowles, Joshua W. | Kolcic, Ivana | König, Inke R. | Koskinen, Seppo | Kovacs, Peter | Kuusisto, Johanna | Kraft, Peter | Kvaløy, Kirsti | Laitinen, Jaana | Lantieri, Olivier | Lanzani, Chiara | Launer, Lenore J. | Lecoeur, Cecile | Lehtimäki, Terho | Lettre, Guillaume | Liu, Jianjun | Lokki, Marja-Liisa | Lorentzon, Mattias | Luben, Robert N. | Ludwig, Barbara | Manunta, Paolo | Marek, Diana | Marre, Michel | Martin, Nicholas G. | McArdle, Wendy L. | McCarthy, Anne | McKnight, Barbara | Meitinger, Thomas | Melander, Olle | Meyre, David | Midthjell, Kristian | Montgomery, Grant W. | Morken, Mario A. | Morris, Andrew P. | Mulic, Rosanda | Ngwa, Julius S. | Nelis, Mari | Neville, Matt J. | Nyholt, Dale R. | O’Donnell, Christopher J. | O’Rahilly, Stephen | Ong, Ken K. | Oostra, Ben | Paré, Guillaume | Parker, Alex N. | Perola, Markus | Pichler, Irene | Pietiläinen, Kirsi H. | Platou, Carl G.P. | Polasek, Ozren | Pouta, Anneli | Rafelt, Suzanne | Raitakari, Olli | Rayner, Nigel W. | Ridderstråle, Martin | Rief, Winfried | Ruokonen, Aimo | Robertson, Neil R. | Rzehak, Peter | Salomaa, Veikko | Sanders, Alan R. | Sandhu, Manjinder S. | Sanna, Serena | Saramies, Jouko | Savolainen, Markku J. | Scherag, Susann | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Silander, Kaisa | Sinisalo, Juha | Siscovick, David S. | Smit, Jan H. | Soranzo, Nicole | Sovio, Ulla | Stephens, Jonathan | Surakka, Ida | Swift, Amy J. | Tammesoo, Mari-Liis | Tardif, Jean-Claude | Teder-Laving, Maris | Teslovich, Tanya M. | Thompson, John R. | Thomson, Brian | Tönjes, Anke | Tuomi, Tiinamaija | van Meurs, Joyce B.J. | van Ommen, Gert-Jan | Vatin, Vincent | Viikari, Jorma | Visvikis-Siest, Sophie | Vitart, Veronique | Vogel, Carla I. G. | Voight, Benjamin F. | Waite, Lindsay L. | Wallaschofski, Henri | Walters, G. Bragi | Widen, Elisabeth | Wiegand, Susanna | Wild, Sarah H. | Willemsen, Gonneke | Witte, Daniel R. | Witteman, Jacqueline C. | Xu, Jianfeng | Zhang, Qunyuan | Zgaga, Lina | Ziegler, Andreas | Zitting, Paavo | Beilby, John P. | Farooqi, I. Sadaf | Hebebrand, Johannes | Huikuri, Heikki V. | James, Alan L. | Kähönen, Mika | Levinson, Douglas F. | Macciardi, Fabio | Nieminen, Markku S. | Ohlsson, Claes | Palmer, Lyle J. | Ridker, Paul M. | Stumvoll, Michael | Beckmann, Jacques S. | Boeing, Heiner | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Collins, Francis S. | Cupples, L. Adrienne | Smith, George Davey | Erdmann, Jeanette | Froguel, Philippe | Grönberg, Henrik | Gyllensten, Ulf | Hall, Per | Hansen, Torben | Harris, Tamara B. | Hattersley, Andrew T. | Hayes, Richard B. | Heinrich, Joachim | Hu, Frank B. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Kaprio, Jaakko | Karpe, Fredrik | Khaw, Kay-Tee | Kiemeney, Lambertus A. | Krude, Heiko | Laakso, Markku | Lawlor, Debbie A. | Metspalu, Andres | Munroe, Patricia B. | Ouwehand, Willem H. | Pedersen, Oluf | Penninx, Brenda W. | Peters, Annette | Pramstaller, Peter P. | Quertermous, Thomas | Reinehr, Thomas | Rissanen, Aila | Rudan, Igor | Samani, Nilesh J. | Schwarz, Peter E.H. | Shuldiner, Alan R. | Spector, Timothy D. | Tuomilehto, Jaakko | Uda, Manuela | Uitterlinden, André | Valle, Timo T. | Wabitsch, Martin | Waeber, Gérard | Wareham, Nicholas J. | Watkins, Hugh | Wilson, James F. | Wright, Alan F. | Zillikens, M. Carola | Chatterjee, Nilanjan | McCarroll, Steven A. | Purcell, Shaun | Schadt, Eric E. | Visscher, Peter M. | Assimes, Themistocles L. | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Groop, Leif C. | Haritunians, Talin | Hunter, David J. | Kaplan, Robert C. | Mohlke, Karen L. | O’Connell, Jeffrey R. | Peltonen, Leena | Schlessinger, David | Strachan, David P. | van Duijn, Cornelia M. | Wichmann, H.-Erich | Frayling, Timothy M. | Thorsteinsdottir, Unnur | Abecasis, Gonçalo R. | Barroso, Inês | Boehnke, Michael | Stefansson, Kari | North, Kari E. | McCarthy, Mark I. | Hirschhorn, Joel N. | Ingelsson, Erik | Loos, Ruth J.F.
Nature genetics  2010;42(11):937-948.
Obesity is globally prevalent and highly heritable, but the underlying genetic factors remain largely elusive. To identify genetic loci for obesity-susceptibility, we examined associations between body mass index (BMI) and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity-susceptibility loci and identified 18 new loci associated with BMI (P<5×10−8), one of which includes a copy number variant near GPRC5B. Some loci (MC4R, POMC, SH2B1, BDNF) map near key hypothalamic regulators of energy balance, and one is near GIPR, an incretin receptor. Furthermore, genes in other newly-associated loci may provide novel insights into human body weight regulation.
doi:10.1038/ng.686
PMCID: PMC3014648  PMID: 20935630
15.  Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis 
Voight, Benjamin F | Scott, Laura J | Steinthorsdottir, Valgerdur | Morris, Andrew P | Dina, Christian | Welch, Ryan P | Zeggini, Eleftheria | Huth, Cornelia | Aulchenko, Yurii S | Thorleifsson, Gudmar | McCulloch, Laura J | Ferreira, Teresa | Grallert, Harald | Amin, Najaf | Wu, Guanming | Willer, Cristen J | Raychaudhuri, Soumya | McCarroll, Steve A | Langenberg, Claudia | Hofmann, Oliver M | Dupuis, Josée | Qi, Lu | Segrè, Ayellet V | van Hoek, Mandy | Navarro, Pau | Ardlie, Kristin | Balkau, Beverley | Benediktsson, Rafn | Bennett, Amanda J | Blagieva, Roza | Boerwinkle, Eric | Bonnycastle, Lori L | Boström, Kristina Bengtsson | Bravenboer, Bert | Bumpstead, Suzannah | Burtt, Noisël P | Charpentier, Guillaume | Chines, Peter S | Cornelis, Marilyn | Couper, David J | Crawford, Gabe | Doney, Alex S F | Elliott, Katherine S | Elliott, Amanda L | Erdos, Michael R | Fox, Caroline S | Franklin, Christopher S | Ganser, Martha | Gieger, Christian | Grarup, Niels | Green, Todd | Griffin, Simon | Groves, Christopher J | Guiducci, Candace | Hadjadj, Samy | Hassanali, Neelam | Herder, Christian | Isomaa, Bo | Jackson, Anne U | Johnson, Paul R V | Jørgensen, Torben | Kao, Wen H L | Klopp, Norman | Kong, Augustine | Kraft, Peter | Kuusisto, Johanna | Lauritzen, Torsten | Li, Man | Lieverse, Aloysius | Lindgren, Cecilia M | Lyssenko, Valeriya | Marre, Michel | Meitinger, Thomas | Midthjell, Kristian | Morken, Mario A | Narisu, Narisu | Nilsson, Peter | Owen, Katharine R | Payne, Felicity | Perry, John R B | Petersen, Ann-Kristin | Platou, Carl | Proença, Christine | Prokopenko, Inga | Rathmann, Wolfgang | Rayner, N William | Robertson, Neil R | Rocheleau, Ghislain | Roden, Michael | Sampson, Michael J | Saxena, Richa | Shields, Beverley M | Shrader, Peter | Sigurdsson, Gunnar | Sparsø, Thomas | Strassburger, Klaus | Stringham, Heather M | Sun, Qi | Swift, Amy J | Thorand, Barbara | Tichet, Jean | Tuomi, Tiinamaija | van Dam, Rob M | van Haeften, Timon W | van Herpt, Thijs | van Vliet-Ostaptchouk, Jana V | Walters, G Bragi | Weedon, Michael N | Wijmenga, Cisca | Witteman, Jacqueline | Bergman, Richard N | Cauchi, Stephane | Collins, Francis S | Gloyn, Anna L | Gyllensten, Ulf | Hansen, Torben | Hide, Winston A | Hitman, Graham A | Hofman, Albert | Hunter, David J | Hveem, Kristian | Laakso, Markku | Mohlke, Karen L | Morris, Andrew D | Palmer, Colin N A | Pramstaller, Peter P | Rudan, Igor | Sijbrands, Eric | Stein, Lincoln D | Tuomilehto, Jaakko | Uitterlinden, Andre | Walker, Mark | Wareham, Nicholas J | Watanabe, Richard M | Abecasis, Gonçalo R | Boehm, Bernhard O | Campbell, Harry | Daly, Mark J | Hattersley, Andrew T | Hu, Frank B | Meigs, James B | Pankow, James S | Pedersen, Oluf | Wichmann, H-Erich | Barroso, Inês | Florez, Jose C | Frayling, Timothy M | Groop, Leif | Sladek, Rob | Thorsteinsdottir, Unnur | Wilson, James F | Illig, Thomas | Froguel, Philippe | van Duijn, Cornelia M | Stefansson, Kari | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2010;42(7):579-589.
By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combinedP < 5 × 10−8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
doi:10.1038/ng.609
PMCID: PMC3080658  PMID: 20581827
16.  Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study 
Fox, Ervin R. | Young, J. Hunter | Li, Yali | Dreisbach, Albert W. | Keating, Brendan J. | Musani, Solomon K. | Liu, Kiang | Morrison, Alanna C. | Ganesh, Santhi | Kutlar, Abdullah | Ramachandran, Vasan S. | Polak, Josef F. | Fabsitz, Richard R. | Dries, Daniel L. | Farlow, Deborah N. | Redline, Susan | Adeyemo, Adebowale | Hirschorn, Joel N. | Sun, Yan V. | Wyatt, Sharon B. | Penman, Alan D. | Palmas, Walter | Rotter, Jerome I. | Townsend, Raymond R. | Doumatey, Ayo P. | Tayo, Bamidele O. | Mosley, Thomas H. | Lyon, Helen N. | Kang, Sun J. | Rotimi, Charles N. | Cooper, Richard S. | Franceschini, Nora | Curb, J. David | Martin, Lisa W. | Eaton, Charles B. | Kardia, Sharon L.R. | Taylor, Herman A. | Caulfield, Mark J. | Ehret, Georg B. | Johnson, Toby | Chakravarti, Aravinda | Zhu, Xiaofeng | Levy, Daniel | Munroe, Patricia B. | Rice, Kenneth M. | Bochud, Murielle | Johnson, Andrew D. | Chasman, Daniel I. | Smith, Albert V. | Tobin, Martin D. | Verwoert, Germaine C. | Hwang, Shih-Jen | Pihur, Vasyl | Vollenweider, Peter | O'Reilly, Paul F. | Amin, Najaf | Bragg-Gresham, Jennifer L. | Teumer, Alexander | Glazer, Nicole L. | Launer, Lenore | Zhao, Jing Hua | Aulchenko, Yurii | Heath, Simon | Sõber, Siim | Parsa, Afshin | Luan, Jian'an | Arora, Pankaj | Dehghan, Abbas | Zhang, Feng | Lucas, Gavin | Hicks, Andrew A. | Jackson, Anne U. | Peden, John F. | Tanaka, Toshiko | Wild, Sarah H. | Rudan, Igor | Igl, Wilmar | Milaneschi, Yuri | Parker, Alex N. | Fava, Cristiano | Chambers, John C. | Kumari, Meena | JinGo, Min | van der Harst, Pim | Kao, Wen Hong Linda | Sjögren, Marketa | Vinay, D.G. | Alexander, Myriam | Tabara, Yasuharu | Shaw-Hawkins, Sue | Whincup, Peter H. | Liu, Yongmei | Shi, Gang | Kuusisto, Johanna | Seielstad, Mark | Sim, Xueling | Nguyen, Khanh-Dung Hoang | Lehtimäki, Terho | Matullo, Giuseppe | Wu, Ying | Gaunt, Tom R. | Charlotte Onland-Moret, N. | Cooper, Matthew N. | Platou, Carl G.P. | Org, Elin | Hardy, Rebecca | Dahgam, Santosh | Palmen, Jutta | Vitart, Veronique | Braund, Peter S. | Kuznetsova, Tatiana | Uiterwaal, Cuno S.P.M. | Campbell, Harry | Ludwig, Barbara | Tomaszewski, Maciej | Tzoulaki, Ioanna | Palmer, Nicholette D. | Aspelund, Thor | Garcia, Melissa | Chang, Yen-Pei C. | O'Connell, Jeffrey R. | Steinle, Nanette I. | Grobbee, Diederick E. | Arking, Dan E. | Hernandez, Dena | Najjar, Samer | McArdle, Wendy L. | Hadley, David | Brown, Morris J. | Connell, John M. | Hingorani, Aroon D. | Day, Ian N.M. | Lawlor, Debbie A. | Beilby, John P. | Lawrence, Robert W. | Clarke, Robert | Collins, Rory | Hopewell, Jemma C. | Ongen, Halit | Bis, Joshua C. | Kähönen, Mika | Viikari, Jorma | Adair, Linda S. | Lee, Nanette R. | Chen, Ming-Huei | Olden, Matthias | Pattaro, Cristian | Hoffman Bolton, Judith A. | Köttgen, Anna | Bergmann, Sven | Mooser, Vincent | Chaturvedi, Nish | Frayling, Timothy M. | Islam, Muhammad | Jafar, Tazeen H. | Erdmann, Jeanette | Kulkarni, Smita R. | Bornstein, Stefan R. | Grässler, Jürgen | Groop, Leif | Voight, Benjamin F. | Kettunen, Johannes | Howard, Philip | Taylor, Andrew | Guarrera, Simonetta | Ricceri, Fulvio | Emilsson, Valur | Plump, Andrew | Barroso, Inês | Khaw, Kay-Tee | Weder, Alan B. | Hunt, Steven C. | Bergman, Richard N. | Collins, Francis S. | Bonnycastle, Lori L. | Scott, Laura J. | Stringham, Heather M. | Peltonen, Leena | Perola, Markus | Vartiainen, Erkki | Brand, Stefan-Martin | Staessen, Jan A. | Wang, Thomas J. | Burton, Paul R. | SolerArtigas, Maria | Dong, Yanbin | Snieder, Harold | Wang, Xiaoling | Zhu, Haidong | Lohman, Kurt K. | Rudock, Megan E. | Heckbert, Susan R. | Smith, Nicholas L. | Wiggins, Kerri L. | Shriner, Daniel | Veldre, Gudrun | Viigimaa, Margus | Kinra, Sanjay | Prabhakaran, Dorairajan | Tripathy, Vikal | Langefeld, Carl D. | Rosengren, Annika | Thelle, Dag S. | MariaCorsi, Anna | Singleton, Andrew | Forrester, Terrence | Hilton, Gina | McKenzie, Colin A. | Salako, Tunde | Iwai, Naoharu | Kita, Yoshikuni | Ogihara, Toshio | Ohkubo, Takayoshi | Okamura, Tomonori | Ueshima, Hirotsugu | Umemura, Satoshi | Eyheramendy, Susana | Meitinger, Thomas | Wichmann, H.-Erich | Cho, Yoon Shin | Kim, Hyung-Lae | Lee, Jong-Young | Scott, James | Sehmi, Joban S. | Zhang, Weihua | Hedblad, Bo | Nilsson, Peter | Smith, George Davey | Wong, Andrew | Narisu, Narisu | Stančáková, Alena | Raffel, Leslie J. | Yao, Jie | Kathiresan, Sekar | O'Donnell, Chris | Schwartz, Steven M. | Arfan Ikram, M. | Longstreth, Will T. | Seshadri, Sudha | Shrine, Nick R.G. | Wain, Louise V. | Morken, Mario A. | Swift, Amy J. | Laitinen, Jaana | Prokopenko, Inga | Zitting, Paavo | Cooper, Jackie A. | Humphries, Steve E. | Danesh, John | Rasheed, Asif | Goel, Anuj | Hamsten, Anders | Watkins, Hugh | Bakker, Stephan J.L. | van Gilst, Wiek H. | Janipalli, Charles S. | Radha Mani, K. | Yajnik, Chittaranjan S. | Hofman, Albert | Mattace-Raso, Francesco U.S. | Oostra, Ben A. | Demirkan, Ayse | Isaacs, Aaron | Rivadeneira, Fernando | Lakatta, Edward G. | Orru, Marco | Scuteri, Angelo | Ala-Korpela, Mika | Kangas, Antti J. | Lyytikäinen, Leo-Pekka | Soininen, Pasi | Tukiainen, Taru | Würz, Peter | Twee-Hee Ong, Rick | Dörr, Marcus | Kroemer, Heyo K. | Völker, Uwe | Völzke, Henry | Galan, Pilar | Hercberg, Serge | Lathrop, Mark | Zelenika, Diana | Deloukas, Panos | Mangino, Massimo | Spector, Tim D. | Zhai, Guangju | Meschia, James F. | Nalls, Michael A. | Sharma, Pankaj | Terzic, Janos | Kranthi Kumar, M.J. | Denniff, Matthew | Zukowska-Szczechowska, Ewa | Wagenknecht, Lynne E. | Fowkes, Gerald R. | Charchar, Fadi J. | Schwarz, Peter E.H. | Hayward, Caroline | Guo, Xiuqing | Bots, Michiel L. | Brand, Eva | Samani, Nilesh J. | Polasek, Ozren | Talmud, Philippa J. | Nyberg, Fredrik | Kuh, Diana | Laan, Maris | Hveem, Kristian | Palmer, Lyle J. | van der Schouw, Yvonne T. | Casas, Juan P. | Mohlke, Karen L. | Vineis, Paolo | Raitakari, Olli | Wong, Tien Y. | Shyong Tai, E. | Laakso, Markku | Rao, Dabeeru C. | Harris, Tamara B. | Morris, Richard W. | Dominiczak, Anna F. | Kivimaki, Mika | Marmot, Michael G. | Miki, Tetsuro | Saleheen, Danish | Chandak, Giriraj R. | Coresh, Josef | Navis, Gerjan | Salomaa, Veikko | Han, Bok-Ghee | Kooner, Jaspal S. | Melander, Olle | Ridker, Paul M. | Bandinelli, Stefania | Gyllensten, Ulf B. | Wright, Alan F. | Wilson, James F. | Ferrucci, Luigi | Farrall, Martin | Tuomilehto, Jaakko | Pramstaller, Peter P. | Elosua, Roberto | Soranzo, Nicole | Sijbrands, Eric J.G. | Altshuler, David | Loos, Ruth J.F. | Shuldiner, Alan R. | Gieger, Christian | Meneton, Pierre | Uitterlinden, Andre G. | Wareham, Nicholas J. | Gudnason, Vilmundur | Rettig, Rainer | Uda, Manuela | Strachan, David P. | Witteman, Jacqueline C.M. | Hartikainen, Anna-Liisa | Beckmann, Jacques S. | Boerwinkle, Eric | Boehnke, Michael | Larson, Martin G. | Järvelin, Marjo-Riitta | Psaty, Bruce M. | Abecasis, Gonçalo R. | Elliott, Paul | van Duijn , Cornelia M. | Newton-Cheh, Christopher
Human Molecular Genetics  2011;20(11):2273-2284.
The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
doi:10.1093/hmg/ddr092
PMCID: PMC3090190  PMID: 21378095
17.  New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk 
Dupuis, Josée | Langenberg, Claudia | Prokopenko, Inga | Saxena, Richa | Soranzo, Nicole | Jackson, Anne U | Wheeler, Eleanor | Glazer, Nicole L | Bouatia-Naji, Nabila | Gloyn, Anna L | Lindgren, Cecilia M | Mägi, Reedik | Morris, Andrew P | Randall, Joshua | Johnson, Toby | Elliott, Paul | Rybin, Denis | Thorleifsson, Gudmar | Steinthorsdottir, Valgerdur | Henneman, Peter | Grallert, Harald | Dehghan, Abbas | Hottenga, Jouke Jan | Franklin, Christopher S | Navarro, Pau | Song, Kijoung | Goel, Anuj | Perry, John R B | Egan, Josephine M | Lajunen, Taina | Grarup, Niels | Sparsø, Thomas | Doney, Alex | Voight, Benjamin F | Stringham, Heather M | Li, Man | Kanoni, Stavroula | Shrader, Peter | Cavalcanti-Proença, Christine | Kumari, Meena | Qi, Lu | Timpson, Nicholas J | Gieger, Christian | Zabena, Carina | Rocheleau, Ghislain | Ingelsson, Erik | An, Ping | O’Connell, Jeffrey | Luan, Jian'an | Elliott, Amanda | McCarroll, Steven A | Payne, Felicity | Roccasecca, Rosa Maria | Pattou, François | Sethupathy, Praveen | Ardlie, Kristin | Ariyurek, Yavuz | Balkau, Beverley | Barter, Philip | Beilby, John P | Ben-Shlomo, Yoav | Benediktsson, Rafn | Bennett, Amanda J | Bergmann, Sven | Bochud, Murielle | Boerwinkle, Eric | Bonnefond, Amélie | Bonnycastle, Lori L | Borch-Johnsen, Knut | Böttcher, Yvonne | Brunner, Eric | Bumpstead, Suzannah J | Charpentier, Guillaume | Chen, Yii-Der Ida | Chines, Peter | Clarke, Robert | Coin, Lachlan J M | Cooper, Matthew N | Cornelis, Marilyn | Crawford, Gabe | Crisponi, Laura | Day, Ian N M | de Geus, Eco | Delplanque, Jerome | Dina, Christian | Erdos, Michael R | Fedson, Annette C | Fischer-Rosinsky, Antje | Forouhi, Nita G | Fox, Caroline S | Frants, Rune | Franzosi, Maria Grazia | Galan, Pilar | Goodarzi, Mark O | Graessler, Jürgen | Groves, Christopher J | Grundy, Scott | Gwilliam, Rhian | Gyllensten, Ulf | Hadjadj, Samy | Hallmans, Göran | Hammond, Naomi | Han, Xijing | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hayward, Caroline | Heath, Simon C | Hercberg, Serge | Herder, Christian | Hicks, Andrew A | Hillman, David R | Hingorani, Aroon D | Hofman, Albert | Hui, Jennie | Hung, Joe | Isomaa, Bo | Johnson, Paul R V | Jørgensen, Torben | Jula, Antti | Kaakinen, Marika | Kaprio, Jaakko | Kesaniemi, Y Antero | Kivimaki, Mika | Knight, Beatrice | Koskinen, Seppo | Kovacs, Peter | Kyvik, Kirsten Ohm | Lathrop, G Mark | Lawlor, Debbie A | Le Bacquer, Olivier | Lecoeur, Cécile | Li, Yun | Lyssenko, Valeriya | Mahley, Robert | Mangino, Massimo | Manning, Alisa K | Martínez-Larrad, María Teresa | McAteer, Jarred B | McCulloch, Laura J | McPherson, Ruth | Meisinger, Christa | Melzer, David | Meyre, David | Mitchell, Braxton D | Morken, Mario A | Mukherjee, Sutapa | Naitza, Silvia | Narisu, Narisu | Neville, Matthew J | Oostra, Ben A | Orrù, Marco | Pakyz, Ruth | Palmer, Colin N A | Paolisso, Giuseppe | Pattaro, Cristian | Pearson, Daniel | Peden, John F | Pedersen, Nancy L. | Perola, Markus | Pfeiffer, Andreas F H | Pichler, Irene | Polasek, Ozren | Posthuma, Danielle | Potter, Simon C | Pouta, Anneli | Province, Michael A | Psaty, Bruce M | Rathmann, Wolfgang | Rayner, Nigel W | Rice, Kenneth | Ripatti, Samuli | Rivadeneira, Fernando | Roden, Michael | Rolandsson, Olov | Sandbaek, Annelli | Sandhu, Manjinder | Sanna, Serena | Sayer, Avan Aihie | Scheet, Paul | Scott, Laura J | Seedorf, Udo | Sharp, Stephen J | Shields, Beverley | Sigurðsson, Gunnar | Sijbrands, Erik J G | Silveira, Angela | Simpson, Laila | Singleton, Andrew | Smith, Nicholas L | Sovio, Ulla | Swift, Amy | Syddall, Holly | Syvänen, Ann-Christine | Tanaka, Toshiko | Thorand, Barbara | Tichet, Jean | Tönjes, Anke | Tuomi, Tiinamaija | Uitterlinden, André G | van Dijk, Ko Willems | van Hoek, Mandy | Varma, Dhiraj | Visvikis-Siest, Sophie | Vitart, Veronique | Vogelzangs, Nicole | Waeber, Gérard | Wagner, Peter J | Walley, Andrew | Walters, G Bragi | Ward, Kim L | Watkins, Hugh | Weedon, Michael N | Wild, Sarah H | Willemsen, Gonneke | Witteman, Jaqueline C M | Yarnell, John W G | Zeggini, Eleftheria | Zelenika, Diana | Zethelius, Björn | Zhai, Guangju | Zhao, Jing Hua | Zillikens, M Carola | Borecki, Ingrid B | Loos, Ruth J F | Meneton, Pierre | Magnusson, Patrik K E | Nathan, David M | Williams, Gordon H | Hattersley, Andrew T | Silander, Kaisa | Salomaa, Veikko | Smith, George Davey | Bornstein, Stefan R | Schwarz, Peter | Spranger, Joachim | Karpe, Fredrik | Shuldiner, Alan R | Cooper, Cyrus | Dedoussis, George V | Serrano-Ríos, Manuel | Morris, Andrew D | Lind, Lars | Palmer, Lyle J | Hu, Frank B. | Franks, Paul W | Ebrahim, Shah | Marmot, Michael | Kao, W H Linda | Pankow, James S | Sampson, Michael J | Kuusisto, Johanna | Laakso, Markku | Hansen, Torben | Pedersen, Oluf | Pramstaller, Peter Paul | Wichmann, H Erich | Illig, Thomas | Rudan, Igor | Wright, Alan F | Stumvoll, Michael | Campbell, Harry | Wilson, James F | Hamsten, Anders | Bergman, Richard N | Buchanan, Thomas A | Collins, Francis S | Mohlke, Karen L | Tuomilehto, Jaakko | Valle, Timo T | Altshuler, David | Rotter, Jerome I | Siscovick, David S | Penninx, Brenda W J H | Boomsma, Dorret | Deloukas, Panos | Spector, Timothy D | Frayling, Timothy M | Ferrucci, Luigi | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari | van Duijn, Cornelia M | Aulchenko, Yurii S | Cao, Antonio | Scuteri, Angelo | Schlessinger, David | Uda, Manuela | Ruokonen, Aimo | Jarvelin, Marjo-Riitta | Waterworth, Dawn M | Vollenweider, Peter | Peltonen, Leena | Mooser, Vincent | Abecasis, Goncalo R | Wareham, Nicholas J | Sladek, Robert | Froguel, Philippe | Watanabe, Richard M | Meigs, James B | Groop, Leif | Boehnke, Michael | McCarthy, Mark I | Florez, Jose C | Barroso, Inês
Nature genetics  2010;42(2):105-116.
Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.
doi:10.1038/ng.520
PMCID: PMC3018764  PMID: 20081858
18.  Eight blood pressure loci identified by genome-wide association study of 34,433 people of European ancestry 
Newton-Cheh, Christopher | Johnson, Toby | Gateva, Vesela | Tobin, Martin D | Bochud, Murielle | Coin, Lachlan | Najjar, Samer S | Zhao, Jing Hua | Heath, Simon C | Eyheramendy, Susana | Papadakis, Konstantinos | Voight, Benjamin F | Scott, Laura J | Zhang, Feng | Farrall, Martin | Tanaka, Toshiko | Wallace, Chris | Chambers, John C | Khaw, Kay-Tee | Nilsson, Peter | van der Harst, Pim | Polidoro, Silvia | Grobbee, Diederick E | Onland-Moret, N Charlotte | Bots, Michiel L | Wain, Louise V | Elliott, Katherine S | Teumer, Alexander | Luan, Jian’an | Lucas, Gavin | Kuusisto, Johanna | Burton, Paul R | Hadley, David | McArdle, Wendy L | Brown, Morris | Dominiczak, Anna | Newhouse, Stephen J | Samani, Nilesh J | Webster, John | Zeggini, Eleftheria | Beckmann, Jacques S | Bergmann, Sven | Lim, Noha | Song, Kijoung | Vollenweider, Peter | Waeber, Gerard | Waterworth, Dawn M | Yuan, Xin | Groop, Leif | Orho-Melander, Marju | Allione, Alessandra | Di Gregorio, Alessandra | Guarrera, Simonetta | Panico, Salvatore | Ricceri, Fulvio | Romanazzi, Valeria | Sacerdote, Carlotta | Vineis, Paolo | Barroso, Inês | Sandhu, Manjinder S | Luben, Robert N | Crawford, Gabriel J. | Jousilahti, Pekka | Perola, Markus | Boehnke, Michael | Bonnycastle, Lori L | Collins, Francis S | Jackson, Anne U | Mohlke, Karen L | Stringham, Heather M | Valle, Timo T | Willer, Cristen J | Bergman, Richard N | Morken, Mario A | Döring, Angela | Gieger, Christian | Illig, Thomas | Meitinger, Thomas | Org, Elin | Pfeufer, Arne | Wichmann, H Erich | Kathiresan, Sekar | Marrugat, Jaume | O’Donnell, Christopher J | Schwartz, Stephen M | Siscovick, David S | Subirana, Isaac | Freimer, Nelson B | Hartikainen, Anna-Liisa | McCarthy, Mark I | O’Reilly, Paul F | Peltonen, Leena | Pouta, Anneli | de Jong, Paul E | Snieder, Harold | van Gilst, Wiek H | Clarke, Robert | Goel, Anuj | Hamsten, Anders | Peden, John F | Seedorf, Udo | Syvänen, Ann-Christine | Tognoni, Giovanni | Lakatta, Edward G | Sanna, Serena | Scheet, Paul | Schlessinger, David | Scuteri, Angelo | Dörr, Marcus | Ernst, Florian | Felix, Stephan B | Homuth, Georg | Lorbeer, Roberto | Reffelmann, Thorsten | Rettig, Rainer | Völker, Uwe | Galan, Pilar | Gut, Ivo G | Hercberg, Serge | Lathrop, G Mark | Zeleneka, Diana | Deloukas, Panos | Soranzo, Nicole | Williams, Frances M | Zhai, Guangju | Salomaa, Veikko | Laakso, Markku | Elosua, Roberto | Forouhi, Nita G | Völzke, Henry | Uiterwaal, Cuno S | van der Schouw, Yvonne T | Numans, Mattijs E | Matullo, Giuseppe | Navis, Gerjan | Berglund, Göran | Bingham, Sheila A | Kooner, Jaspal S | Paterson, Andrew D | Connell, John M | Bandinelli, Stefania | Ferrucci, Luigi | Watkins, Hugh | Spector, Tim D | Tuomilehto, Jaakko | Altshuler, David | Strachan, David P | Laan, Maris | Meneton, Pierre | Wareham, Nicholas J | Uda, Manuela | Jarvelin, Marjo-Riitta | Mooser, Vincent | Melander, Olle | Loos, Ruth JF | Elliott, Paul | Abecasis, Goncalo R | Caulfield, Mark | Munroe, Patricia B
Nature genetics  2009;41(6):666-676.
Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5m genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N≤71,225 European ancestry, N=12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N=29,136). We identified association between systolic or diastolic blood pressure and common variants in 8 regions near the CYP17A1 (P=7×10−24), CYP1A2 (P=1×10−23), FGF5 (P=1×10−21), SH2B3 (P=3×10−18), MTHFR (P=2×10−13), c10orf107 (P=1×10−9), ZNF652 (P=5×10−9) and PLCD3 (P=1×10−8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
doi:10.1038/ng.361
PMCID: PMC2891673  PMID: 19430483
19.  Heritable Individual-Specific and Allele-Specific Chromatin Signatures in Humans 
Science (New York, N.Y.)  2010;328(5975):235-239.
The extent to which variation in chromatin structure and transcription factor binding may influence gene expression, and thus underlie or contribute to variation in phenotype, is unknown. To address this question, we cataloged both individual-to-individual variation and differences between homologous chromosomes within the same individual (allele-specific variation) in chromatin structure and transcription factor binding in lymphoblastoid cells derived from individuals of geographically diverse ancestry. Ten percent of active chromatin sites were individual-specific; a similar proportion were allele-specific. Both individual-specific and allele-specific sites were commonly transmitted from parent to child, which suggests that they are heritable features of the human genome. Our study shows that heritable chromatin status and transcription factor binding differ as a result of genetic variation and may underlie phenotypic variation in humans.
doi:10.1126/science.1184655
PMCID: PMC2929018  PMID: 20299549
20.  Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge 
Saxena, Richa | Hivert, Marie-France | Langenberg, Claudia | Tanaka, Toshiko | Pankow, James S | Vollenweider, Peter | Lyssenko, Valeriya | Bouatia-Naji, Nabila | Dupuis, Josée | Jackson, Anne U | Kao, W H Linda | Li, Man | Glazer, Nicole L | Manning, Alisa K | Luan, Jian’an | Stringham, Heather M | Prokopenko, Inga | Johnson, Toby | Grarup, Niels | Boesgaard, Trine W | Lecoeur, Cécile | Shrader, Peter | O’Connell, Jeffrey | Ingelsson, Erik | Couper, David J | Rice, Kenneth | Song, Kijoung | Andreasen, Camilla H | Dina, Christian | Köttgen, Anna | Le Bacquer, Olivier | Pattou, François | Taneera, Jalal | Steinthorsdottir, Valgerdur | Rybin, Denis | Ardlie, Kristin | Sampson, Michael | Qi, Lu | van Hoek, Mandy | Weedon, Michael N | Aulchenko, Yurii S | Voight, Benjamin F | Grallert, Harald | Balkau, Beverley | Bergman, Richard N | Bielinski, Suzette J | Bonnefond, Amelie | Bonnycastle, Lori L | Borch-Johnsen, Knut | Böttcher, Yvonne | Brunner, Eric | Buchanan, Thomas A | Bumpstead, Suzannah J | Cavalcanti-Proença, Christine | Charpentier, Guillaume | Chen, Yii-Der Ida | Chines, Peter S | Collins, Francis S | Cornelis, Marilyn | Crawford, Gabriel J | Delplanque, Jerome | Doney, Alex | Egan, Josephine M | Erdos, Michael R | Firmann, Mathieu | Forouhi, Nita G | Fox, Caroline S | Goodarzi, Mark O | Graessler, Jürgen | Hingorani, Aroon | Isomaa, Bo | Jørgensen, Torben | Kivimaki, Mika | Kovacs, Peter | Krohn, Knut | Kumari, Meena | Lauritzen, Torsten | Lévy-Marchal, Claire | Mayor, Vladimir | McAteer, Jarred B | Meyre, David | Mitchell, Braxton D | Mohlke, Karen L | Morken, Mario A | Narisu, Narisu | Palmer, Colin N A | Pakyz, Ruth | Pascoe, Laura | Payne, Felicity | Pearson, Daniel | Rathmann, Wolfgang | Sandbaek, Annelli | Sayer, Avan Aihie | Scott, Laura J | Sharp, Stephen J | Sijbrands, Eric | Singleton, Andrew | Siscovick, David S | Smith, Nicholas L | Sparsø, Thomas | Swift, Amy J | Syddall, Holly | Thorleifsson, Gudmar | Tönjes, Anke | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Valle, Timo T | Waeber, Gérard | Walley, Andrew | Waterworth, Dawn M | Zeggini, Eleftheria | Zhao, Jing Hua | Illig, Thomas | Wichmann, H Erich | Wilson, James F | van Duijn, Cornelia | Hu, Frank B | Morris, Andrew D | Frayling, Timothy M | Hattersley, Andrew T | Thorsteinsdottir, Unnur | Stefansson, Kari | Nilsson, Peter | Syvänen, Ann-Christine | Shuldiner, Alan R | Walker, Mark | Bornstein, Stefan R | Schwarz, Peter | Williams, Gordon H | Nathan, David M | Kuusisto, Johanna | Laakso, Markku | Cooper, Cyrus | Marmot, Michael | Ferrucci, Luigi | Mooser, Vincent | Stumvoll, Michael | Loos, Ruth J F | Altshuler, David | Psaty, Bruce M | Rotter, Jerome I | Boerwinkle, Eric | Hansen, Torben | Pedersen, Oluf | Florez, Jose C | McCarthy, Mark I | Boehnke, Michael | Barroso, Inês | Sladek, Robert | Froguel, Philippe | Meigs, James B | Groop, Leif | Wareham, Nicholas J | Watanabe, Richard M
Nature genetics  2010;42(2):142-148.
Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18).
doi:10.1038/ng.521
PMCID: PMC2922003  PMID: 20081857