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1.  A Systems Genetics Approach Identifies CXCL14, ITGAX, and LPCAT2 as Novel Aggressive Prostate Cancer Susceptibility Genes 
PLoS Genetics  2014;10(11):e1004809.
Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n = 228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will facilitate the identification of novel germline factors driving aggressive disease susceptibility and allow for new insights into these deadly forms of prostate cancer.
Author Summary
Prostate cancer is a remarkably common disease, and in 2014 it is estimated that it will account for 27% of new cancer cases in men in the US. However, less than 13% those diagnosed will succumb to prostate cancer, with most men dying from unrelated causes. The tests used to identify men at risk of fatal prostate cancer are inaccurate, which leads to overtreatment, unnecessary patient suffering, and represents a significant public health burden. Many studies have shown that hereditary genetic variation significantly alters susceptibility to fatal prostate cancer, although the identities of genes responsible for this are mostly unknown. Here, we used a mouse model of prostate cancer to identify such genes. We introduced hereditary genetic variation into this mouse model through breeding, and used a genetic mapping technique to identify 35 genes associated with aggressive disease. The levels of three of these genes were consistently abnormal in human prostate cancers with a more aggressive disease course. Additionally, hereditary differences in these same three genes were associated with markers of fatal prostate cancer in men. This approach has given us unique insights into how hereditary variation influences fatal forms of prostate cancer.
doi:10.1371/journal.pgen.1004809
PMCID: PMC4238980  PMID: 25411967
2.  Autosomal Dominant Diabetes Arising From a Wolfram Syndrome 1 Mutation 
Diabetes  2013;62(11):3943-3950.
We used an unbiased genome-wide approach to identify exonic variants segregating with diabetes in a multigenerational Finnish family. At least eight members of this family presented with diabetes with age of diagnosis ranging from 18 to 51 years and a pattern suggesting autosomal dominant inheritance. We sequenced the exomes of four affected members of this family and performed follow-up genotyping of additional affected and unaffected family members. We uncovered a novel nonsynonymous variant (p.Trp314Arg) in the Wolfram syndrome 1 (WFS1) gene that segregates completely with the diabetic phenotype. Multipoint parametric linkage analysis with 13 members of this family identified a single linkage signal with maximum logarithm of odds score 3.01 at 4p16.2-p16.1, corresponding to a region harboring the WFS1 locus. Functional studies demonstrate a role for this variant in endoplasmic reticulum stress, which is consistent with the β-cell failure phenotype seen in mutation carriers. This represents the first compelling report of a mutation in WFS1 associated with dominantly inherited nonsyndromic adult-onset diabetes.
doi:10.2337/db13-0571
PMCID: PMC3806620  PMID: 23903355
3.  Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders 
den Hoed, Marcel | Eijgelsheim, Mark | Esko, Tõnu | Brundel, Bianca J J M | Peal, David S | Evans, David M | Nolte, Ilja M | Segrè, Ayellet V | Holm, Hilma | Handsaker, Robert E | Westra, Harm-Jan | Johnson, Toby | Isaacs, Aaron | Yang, Jian | Lundby, Alicia | Zhao, Jing Hua | Kim, Young Jin | Go, Min Jin | Almgren, Peter | Bochud, Murielle | Boucher, Gabrielle | Cornelis, Marilyn C | Gudbjartsson, Daniel | Hadley, David | Van Der Harst, Pim | Hayward, Caroline | Heijer, Martin Den | Igl, Wilmar | Jackson, Anne U | Kutalik, Zoltán | Luan, Jian’an | Kemp, John P | Kristiansson, Kati | Ladenvall, Claes | Lorentzon, Mattias | Montasser, May E | Njajou, Omer T | O’Reilly, Paul F | Padmanabhan, Sandosh | Pourcain, Beate St. | Rankinen, Tuomo | Salo, Perttu | Tanaka, Toshiko | Timpson, Nicholas J | Vitart, Veronique | Waite, Lindsay | Wheeler, William | Zhang, Weihua | Draisma, Harmen H M | Feitosa, Mary F | Kerr, Kathleen F | Lind, Penelope A | Mihailov, Evelin | Onland-Moret, N Charlotte | Song, Ci | Weedon, Michael N | Xie, Weijia | Yengo, Loic | Absher, Devin | Albert, Christine M | Alonso, Alvaro | Arking, Dan E | de Bakker, Paul I W | Balkau, Beverley | Barlassina, Cristina | Benaglio, Paola | Bis, Joshua C | Bouatia-Naji, Nabila | Brage, Søren | Chanock, Stephen J | Chines, Peter S | Chung, Mina | Darbar, Dawood | Dina, Christian | Dörr, Marcus | Elliott, Paul | Felix, Stephan B | Fischer, Krista | Fuchsberger, Christian | de Geus, Eco J C | Goyette, Philippe | Gudnason, Vilmundur | Harris, Tamara B | Hartikainen, Anna-liisa | Havulinna, Aki S | Heckbert, Susan R | Hicks, Andrew A | Hofman, Albert | Holewijn, Suzanne | Hoogstra-Berends, Femke | Hottenga, Jouke-Jan | Jensen, Majken K | Johansson, Åsa | Junttila, Juhani | Kääb, Stefan | Kanon, Bart | Ketkar, Shamika | Khaw, Kay-Tee | Knowles, Joshua W | Kooner, Angrad S | Kors, Jan A | Kumari, Meena | Milani, Lili | Laiho, Päivi | Lakatta, Edward G | Langenberg, Claudia | Leusink, Maarten | Liu, Yongmei | Luben, Robert N | Lunetta, Kathryn L | Lynch, Stacey N | Markus, Marcello R P | Marques-Vidal, Pedro | Leach, Irene Mateo | McArdle, Wendy L | McCarroll, Steven A | Medland, Sarah E | Miller, Kathryn A | Montgomery, Grant W | Morrison, Alanna C | Müller-Nurasyid, Martina | Navarro, Pau | Nelis, Mari | O’Connell, Jeffrey R | O’Donnell, Christopher J | Ong, Ken K | Newman, Anne B | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P | Psaty, Bruce M | Rao, Dabeeru C | Ring, Susan M | Rossin, Elizabeth J | Rudan, Diana | Sanna, Serena | Scott, Robert A | Sehmi, Jaban S | Sharp, Stephen | Shin, Jordan T | Singleton, Andrew B | Smith, Albert V | Soranzo, Nicole | Spector, Tim D | Stewart, Chip | Stringham, Heather M | Tarasov, Kirill V | Uitterlinden, André G | Vandenput, Liesbeth | Hwang, Shih-Jen | Whitfield, John B | Wijmenga, Cisca | Wild, Sarah H | Willemsen, Gonneke | Wilson, James F | Witteman, Jacqueline C M | Wong, Andrew | Wong, Quenna | Jamshidi, Yalda | Zitting, Paavo | Boer, Jolanda M A | Boomsma, Dorret I | Borecki, Ingrid B | Van Duijn, Cornelia M | Ekelund, Ulf | Forouhi, Nita G | Froguel, Philippe | Hingorani, Aroon | Ingelsson, Erik | Kivimaki, Mika | Kronmal, Richard A | Kuh, Diana | Lind, Lars | Martin, Nicholas G | Oostra, Ben A | Pedersen, Nancy L | Quertermous, Thomas | Rotter, Jerome I | van der Schouw, Yvonne T | Verschuren, W M Monique | Walker, Mark | Albanes, Demetrius | Arnar, David O | Assimes, Themistocles L | Bandinelli, Stefania | Boehnke, Michael | de Boer, Rudolf A | Bouchard, Claude | Caulfield, W L Mark | Chambers, John C | Curhan, Gary | Cusi, Daniele | Eriksson, Johan | Ferrucci, Luigi | van Gilst, Wiek H | Glorioso, Nicola | de Graaf, Jacqueline | Groop, Leif | Gyllensten, Ulf | Hsueh, Wen-Chi | Hu, Frank B | Huikuri, Heikki V | Hunter, David J | Iribarren, Carlos | Isomaa, Bo | Jarvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kiemeney, Lambertus A | van der Klauw, Melanie M | Kooner, Jaspal S | Kraft, Peter | Iacoviello, Licia | Lehtimäki, Terho | Lokki, Marja-Liisa L | Mitchell, Braxton D | Navis, Gerjan | Nieminen, Markku S | Ohlsson, Claes | Poulter, Neil R | Qi, Lu | Raitakari, Olli T | Rimm, Eric B | Rioux, John D | Rizzi, Federica | Rudan, Igor | Salomaa, Veikko | Sever, Peter S | Shields, Denis C | Shuldiner, Alan R | Sinisalo, Juha | Stanton, Alice V | Stolk, Ronald P | Strachan, David P | Tardif, Jean-Claude | Thorsteinsdottir, Unnur | Tuomilehto, Jaako | van Veldhuisen, Dirk J | Virtamo, Jarmo | Viikari, Jorma | Vollenweider, Peter | Waeber, Gérard | Widen, Elisabeth | Cho, Yoon Shin | Olsen, Jesper V | Visscher, Peter M | Willer, Cristen | Franke, Lude | Erdmann, Jeanette | Thompson, John R | Pfeufer, Arne | Sotoodehnia, Nona | Newton-Cheh, Christopher | Ellinor, Patrick T | Stricker, Bruno H Ch | Metspalu, Andres | Perola, Markus | Beckmann, Jacques S | Smith, George Davey | Stefansson, Kari | Wareham, Nicholas J | Munroe, Patricia B | Sibon, Ody C M | Milan, David J | Snieder, Harold | Samani, Nilesh J | Loos, Ruth J F
Nature genetics  2013;45(6):621-631.
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
doi:10.1038/ng.2610
PMCID: PMC3696959  PMID: 23583979
4.  Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture 
Berndt, Sonja I. | Gustafsson, Stefan | Mägi, Reedik | Ganna, Andrea | Wheeler, Eleanor | Feitosa, Mary F. | Justice, Anne E. | Monda, Keri L. | Croteau-Chonka, Damien C. | Day, Felix R. | Esko, Tõnu | Fall, Tove | Ferreira, Teresa | Gentilini, Davide | Jackson, Anne U. | Luan, Jian’an | Randall, Joshua C. | Vedantam, Sailaja | Willer, Cristen J. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Hu, Yi-Juan | Lee, Sang Hong | Liang, Liming | Lin, Dan-Yu | Min, Josine L. | Neale, Benjamin M. | Thorleifsson, Gudmar | Yang, Jian | Albrecht, Eva | Amin, Najaf | Bragg-Gresham, Jennifer L. | Cadby, Gemma | den Heijer, Martin | Eklund, Niina | Fischer, Krista | Goel, Anuj | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jarick, Ivonne | Johansson, Åsa | Johnson, Toby | Kanoni, Stavroula | Kleber, Marcus E. | König, Inke R. | Kristiansson, Kati | Kutalik, Zoltán | Lamina, Claudia | Lecoeur, Cecile | Li, Guo | Mangino, Massimo | McArdle, Wendy L. | Medina-Gomez, Carolina | Müller-Nurasyid, Martina | Ngwa, Julius S. | Nolte, Ilja M. | Paternoster, Lavinia | Pechlivanis, Sonali | Perola, Markus | Peters, Marjolein J. | Preuss, Michael | Rose, Lynda M. | Shi, Jianxin | Shungin, Dmitry | Smith, Albert Vernon | Strawbridge, Rona J. | Surakka, Ida | Teumer, Alexander | Trip, Mieke D. | Tyrer, Jonathan | Van Vliet-Ostaptchouk, Jana V. | Vandenput, Liesbeth | Waite, Lindsay L. | Zhao, Jing Hua | Absher, Devin | Asselbergs, Folkert W. | Atalay, Mustafa | Attwood, Antony P. | Balmforth, Anthony J. | Basart, Hanneke | Beilby, John | Bonnycastle, Lori L. | Brambilla, Paolo | Bruinenberg, Marcel | Campbell, Harry | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Connell, John M. | Cookson, William | de Faire, Ulf | de Vegt, Femmie | Dei, Mariano | Dimitriou, Maria | Edkins, Sarah | Estrada, Karol | Evans, David M. | Farrall, Martin | Ferrario, Marco M. | Ferrières, Jean | Franke, Lude | Frau, Francesca | Gejman, Pablo V. | Grallert, Harald | Grönberg, Henrik | Gudnason, Vilmundur | Hall, Alistair S. | Hall, Per | Hartikainen, Anna-Liisa | Hayward, Caroline | Heard-Costa, Nancy L. | Heath, Andrew C. | Hebebrand, Johannes | Homuth, Georg | Hu, Frank B. | Hunt, Sarah E. | Hyppönen, Elina | Iribarren, Carlos | Jacobs, Kevin B. | Jansson, John-Olov | Jula, Antti | Kähönen, Mika | Kathiresan, Sekar | Kee, Frank | Khaw, Kay-Tee | Kivimaki, Mika | Koenig, Wolfgang | Kraja, Aldi T. | Kumari, Meena | Kuulasmaa, Kari | Kuusisto, Johanna | Laitinen, Jaana H. | Lakka, Timo A. | Langenberg, Claudia | Launer, Lenore J. | Lind, Lars | Lindström, Jaana | Liu, Jianjun | Liuzzi, Antonio | Lokki, Marja-Liisa | Lorentzon, Mattias | Madden, Pamela A. | Magnusson, Patrik K. | Manunta, Paolo | Marek, Diana | März, Winfried | Mateo Leach, Irene | McKnight, Barbara | Medland, Sarah E. | Mihailov, Evelin | Milani, Lili | Montgomery, Grant W. | Mooser, Vincent | Mühleisen, Thomas W. | Munroe, Patricia B. | Musk, Arthur W. | Narisu, Narisu | Navis, Gerjan | Nicholson, George | Nohr, Ellen A. | Ong, Ken K. | Oostra, Ben A. | Palmer, Colin N.A. | Palotie, Aarno | Peden, John F. | Pedersen, Nancy | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P. | Prokopenko, Inga | Pütter, Carolin | Radhakrishnan, Aparna | Raitakari, Olli | Rendon, Augusto | Rivadeneira, Fernando | Rudan, Igor | Saaristo, Timo E. | Sambrook, Jennifer G. | Sanders, Alan R. | Sanna, Serena | Saramies, Jouko | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Shin, So-Youn | Signorini, Stefano | Sinisalo, Juha | Skrobek, Boris | Soranzo, Nicole | Stančáková, Alena | Stark, Klaus | Stephens, Jonathan C. | Stirrups, Kathleen | Stolk, Ronald P. | Stumvoll, Michael | Swift, Amy J. | Theodoraki, Eirini V. | Thorand, Barbara | Tregouet, David-Alexandre | Tremoli, Elena | Van der Klauw, Melanie M. | van Meurs, Joyce B.J. | Vermeulen, Sita H. | Viikari, Jorma | Virtamo, Jarmo | Vitart, Veronique | Waeber, Gérard | Wang, Zhaoming | Widén, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Witteman, Jacqueline C.M. | Wolffenbuttel, Bruce H.R. | Wong, Andrew | Wright, Alan F. | Zillikens, M. Carola | Amouyel, Philippe | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Cupples, L. Adrienne | Cusi, Daniele | Dedoussis, George V. | Erdmann, Jeanette | Eriksson, Johan G. | Franks, Paul W. | Froguel, Philippe | Gieger, Christian | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hengstenberg, Christian | Hicks, Andrew A. | Hingorani, Aroon | Hinney, Anke | Hofman, Albert | Hovingh, Kees G. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Kuh, Diana | Laakso, Markku | Lehtimäki, Terho | Levinson, Douglas F. | Martin, Nicholas G. | Metspalu, Andres | Morris, Andrew D. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Ouwehand, Willem H. | Palmer, Lyle J. | Penninx, Brenda | Power, Chris | Province, Michael A. | Psaty, Bruce M. | Qi, Lu | Rauramaa, Rainer | Ridker, Paul M. | Ripatti, Samuli | Salomaa, Veikko | Samani, Nilesh J. | Snieder, Harold | Sørensen, Thorkild I.A. | Spector, Timothy D. | Stefansson, Kari | Tönjes, Anke | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Vollenweider, Peter | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Wichmann, H.-Erich | Wilson, James F. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Frayling, Timothy | Groop, Leif C. | Haritunian, Talin | Heid, Iris M. | Hunter, David | Kaplan, Robert C. | Karpe, Fredrik | Moffatt, Miriam | Mohlke, Karen L. | O’Connell, Jeffrey R. | Pawitan, Yudi | Schadt, Eric E. | Schlessinger, David | Steinthorsdottir, Valgerdur | Strachan, David P. | Thorsteinsdottir, Unnur | van Duijn, Cornelia M. | Visscher, Peter M. | Di Blasio, Anna Maria | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Morris, Andrew P. | Meyre, David | Scherag, André | McCarthy, Mark I. | Speliotes, Elizabeth K. | North, Kari E. | Loos, Ruth J.F. | Ingelsson, Erik
Nature genetics  2013;45(5):501-512.
Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups.
doi:10.1038/ng.2606
PMCID: PMC3973018  PMID: 23563607
5.  Exome array analysis identifies novel loci and low-frequency variants for insulin processing and secretion 
Nature genetics  2012;45(2):197-201.
Insulin secretion plays a critical role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci contributing to insulin processing and secretion1,2; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5% to 5%) and rare (MAF<0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 non-diabetic Finnish males. We identified low-frequency coding variants associated with fasting proinsulin levels at the SGSM2 and MADD GWAS loci and three novel genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1, and PAM. We also demonstrate that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs nearby and megabases (Mb) away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits.
doi:10.1038/ng.2507
PMCID: PMC3727235  PMID: 23263489
6.  Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits 
Randall, Joshua C. | Winkler, Thomas W. | Kutalik, Zoltán | Berndt, Sonja I. | Jackson, Anne U. | Monda, Keri L. | Kilpeläinen, Tuomas O. | Esko, Tõnu | Mägi, Reedik | Li, Shengxu | Workalemahu, Tsegaselassie | Feitosa, Mary F. | Croteau-Chonka, Damien C. | Day, Felix R. | Fall, Tove | Ferreira, Teresa | Gustafsson, Stefan | Locke, Adam E. | Mathieson, Iain | Scherag, Andre | Vedantam, Sailaja | Wood, Andrew R. | Liang, Liming | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Dermitzakis, Emmanouil T. | Dimas, Antigone S. | Karpe, Fredrik | Min, Josine L. | Nicholson, George | Clegg, Deborah J. | Person, Thomas | Krohn, Jon P. | Bauer, Sabrina | Buechler, Christa | Eisinger, Kristina | Bonnefond, Amélie | Froguel, Philippe | Hottenga, Jouke-Jan | Prokopenko, Inga | Waite, Lindsay L. | Harris, Tamara B. | Smith, Albert Vernon | Shuldiner, Alan R. | McArdle, Wendy L. | Caulfield, Mark J. | Munroe, Patricia B. | Grönberg, Henrik | Chen, Yii-Der Ida | Li, Guo | Beckmann, Jacques S. | Johnson, Toby | Thorsteinsdottir, Unnur | Teder-Laving, Maris | Khaw, Kay-Tee | Wareham, Nicholas J. | Zhao, Jing Hua | Amin, Najaf | Oostra, Ben A. | Kraja, Aldi T. | Province, Michael A. | Cupples, L. Adrienne | Heard-Costa, Nancy L. | Kaprio, Jaakko | Ripatti, Samuli | Surakka, Ida | Collins, Francis S. | Saramies, Jouko | Tuomilehto, Jaakko | Jula, Antti | Salomaa, Veikko | Erdmann, Jeanette | Hengstenberg, Christian | Loley, Christina | Schunkert, Heribert | Lamina, Claudia | Wichmann, H. Erich | Albrecht, Eva | Gieger, Christian | Hicks, Andrew A. | Johansson, Åsa | Pramstaller, Peter P. | Kathiresan, Sekar | Speliotes, Elizabeth K. | Penninx, Brenda | Hartikainen, Anna-Liisa | Jarvelin, Marjo-Riitta | Gyllensten, Ulf | Boomsma, Dorret I. | Campbell, Harry | Wilson, James F. | Chanock, Stephen J. | Farrall, Martin | Goel, Anuj | Medina-Gomez, Carolina | Rivadeneira, Fernando | Estrada, Karol | Uitterlinden, André G. | Hofman, Albert | Zillikens, M. Carola | den Heijer, Martin | Kiemeney, Lambertus A. | Maschio, Andrea | Hall, Per | Tyrer, Jonathan | Teumer, Alexander | Völzke, Henry | Kovacs, Peter | Tönjes, Anke | Mangino, Massimo | Spector, Tim D. | Hayward, Caroline | Rudan, Igor | Hall, Alistair S. | Samani, Nilesh J. | Attwood, Antony Paul | Sambrook, Jennifer G. | Hung, Joseph | Palmer, Lyle J. | Lokki, Marja-Liisa | Sinisalo, Juha | Boucher, Gabrielle | Huikuri, Heikki | Lorentzon, Mattias | Ohlsson, Claes | Eklund, Niina | Eriksson, Johan G. | Barlassina, Cristina | Rivolta, Carlo | Nolte, Ilja M. | Snieder, Harold | Van der Klauw, Melanie M. | Van Vliet-Ostaptchouk, Jana V. | Gejman, Pablo V. | Shi, Jianxin | Jacobs, Kevin B. | Wang, Zhaoming | Bakker, Stephan J. L. | Mateo Leach, Irene | Navis, Gerjan | van der Harst, Pim | Martin, Nicholas G. | Medland, Sarah E. | Montgomery, Grant W. | Yang, Jian | Chasman, Daniel I. | Ridker, Paul M. | Rose, Lynda M. | Lehtimäki, Terho | Raitakari, Olli | Absher, Devin | Iribarren, Carlos | Basart, Hanneke | Hovingh, Kees G. | Hyppönen, Elina | Power, Chris | Anderson, Denise | Beilby, John P. | Hui, Jennie | Jolley, Jennifer | Sager, Hendrik | Bornstein, Stefan R. | Schwarz, Peter E. H. | Kristiansson, Kati | Perola, Markus | Lindström, Jaana | Swift, Amy J. | Uusitupa, Matti | Atalay, Mustafa | Lakka, Timo A. | Rauramaa, Rainer | Bolton, Jennifer L. | Fowkes, Gerry | Fraser, Ross M. | Price, Jackie F. | Fischer, Krista | KrjutÅ¡kov, Kaarel | Metspalu, Andres | Mihailov, Evelin | Langenberg, Claudia | Luan, Jian'an | Ong, Ken K. | Chines, Peter S. | Keinanen-Kiukaanniemi, Sirkka M. | Saaristo, Timo E. | Edkins, Sarah | Franks, Paul W. | Hallmans, Göran | Shungin, Dmitry | Morris, Andrew David | Palmer, Colin N. A. | Erbel, Raimund | Moebus, Susanne | Nöthen, Markus M. | Pechlivanis, Sonali | Hveem, Kristian | Narisu, Narisu | Hamsten, Anders | Humphries, Steve E. | Strawbridge, Rona J. | Tremoli, Elena | Grallert, Harald | Thorand, Barbara | Illig, Thomas | Koenig, Wolfgang | Müller-Nurasyid, Martina | Peters, Annette | Boehm, Bernhard O. | Kleber, Marcus E. | März, Winfried | Winkelmann, Bernhard R. | Kuusisto, Johanna | Laakso, Markku | Arveiler, Dominique | Cesana, Giancarlo | Kuulasmaa, Kari | Virtamo, Jarmo | Yarnell, John W. G. | Kuh, Diana | Wong, Andrew | Lind, Lars | de Faire, Ulf | Gigante, Bruna | Magnusson, Patrik K. E. | Pedersen, Nancy L. | Dedoussis, George | Dimitriou, Maria | Kolovou, Genovefa | Kanoni, Stavroula | Stirrups, Kathleen | Bonnycastle, Lori L. | Njølstad, Inger | Wilsgaard, Tom | Ganna, Andrea | Rehnberg, Emil | Hingorani, Aroon | Kivimaki, Mika | Kumari, Meena | Assimes, Themistocles L. | Barroso, Inês | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Frayling, Timothy | Groop, Leif C. | Haritunians, Talin | Hunter, David | Ingelsson, Erik | Kaplan, Robert | Mohlke, Karen L. | O'Connell, Jeffrey R. | Schlessinger, David | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Abecasis, Gonçalo R. | McCarthy, Mark I. | Hirschhorn, Joel N. | Qi, Lu | Loos, Ruth J. F. | Lindgren, Cecilia M. | North, Kari E. | Heid, Iris M.
PLoS Genetics  2013;9(6):e1003500.
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10−8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
Author Summary
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
doi:10.1371/journal.pgen.1003500
PMCID: PMC3674993  PMID: 23754948
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.  Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways 
Scott, Robert A | Lagou, Vasiliki | Welch, Ryan P | Wheeler, Eleanor | Montasser, May E | Luan, Jian’an | Mägi, Reedik | Strawbridge, Rona J | Rehnberg, Emil | Gustafsson, Stefan | Kanoni, Stavroula | Rasmussen-Torvik, Laura J | Yengo, Loïc | Lecoeur, Cecile | Shungin, Dmitry | Sanna, Serena | Sidore, Carlo | Johnson, Paul C D | Jukema, J Wouter | Johnson, Toby | Mahajan, Anubha | Verweij, Niek | Thorleifsson, Gudmar | Hottenga, Jouke-Jan | Shah, Sonia | Smith, Albert V | Sennblad, Bengt | Gieger, Christian | Salo, Perttu | Perola, Markus | Timpson, Nicholas J | Evans, David M | Pourcain, Beate St | Wu, Ying | Andrews, Jeanette S | Hui, Jennie | Bielak, Lawrence F | Zhao, Wei | Horikoshi, Momoko | Navarro, Pau | Isaacs, Aaron | O’Connell, Jeffrey R | Stirrups, Kathleen | Vitart, Veronique | Hayward, Caroline | Esko, Tönu | Mihailov, Evelin | Fraser, Ross M | Fall, Tove | Voight, Benjamin F | Raychaudhuri, Soumya | Chen, Han | Lindgren, Cecilia M | Morris, Andrew P | Rayner, Nigel W | Robertson, Neil | Rybin, Denis | Liu, Ching-Ti | Beckmann, Jacques S | Willems, Sara M | Chines, Peter S | Jackson, Anne U | Kang, Hyun Min | Stringham, Heather M | Song, Kijoung | Tanaka, Toshiko | Peden, John F | Goel, Anuj | Hicks, Andrew A | An, Ping | Müller-Nurasyid, Martina | Franco-Cereceda, Anders | Folkersen, Lasse | Marullo, Letizia | Jansen, Hanneke | Oldehinkel, Albertine J | Bruinenberg, Marcel | Pankow, James S | North, Kari E | Forouhi, Nita G | Loos, Ruth J F | Edkins, Sarah | Varga, Tibor V | Hallmans, Göran | Oksa, Heikki | Antonella, Mulas | Nagaraja, Ramaiah | Trompet, Stella | Ford, Ian | Bakker, Stephan J L | Kong, Augustine | Kumari, Meena | Gigante, Bruna | Herder, Christian | Munroe, Patricia B | Caulfield, Mark | Antti, Jula | Mangino, Massimo | Small, Kerrin | Miljkovic, Iva | Liu, Yongmei | Atalay, Mustafa | Kiess, Wieland | James, Alan L | Rivadeneira, Fernando | Uitterlinden, Andre G | Palmer, Colin N A | Doney, Alex S F | Willemsen, Gonneke | Smit, Johannes H | Campbell, Susan | Polasek, Ozren | Bonnycastle, Lori L | Hercberg, Serge | Dimitriou, Maria | Bolton, Jennifer L | Fowkes, Gerard R | Kovacs, Peter | Lindström, Jaana | Zemunik, Tatijana | Bandinelli, Stefania | Wild, Sarah H | Basart, Hanneke V | Rathmann, Wolfgang | Grallert, Harald | Maerz, Winfried | Kleber, Marcus E | Boehm, Bernhard O | Peters, Annette | Pramstaller, Peter P | Province, Michael A | Borecki, Ingrid B | Hastie, Nicholas D | Rudan, Igor | Campbell, Harry | Watkins, Hugh | Farrall, Martin | Stumvoll, Michael | Ferrucci, Luigi | Waterworth, Dawn M | Bergman, Richard N | Collins, Francis S | Tuomilehto, Jaakko | Watanabe, Richard M | de Geus, Eco J C | Penninx, Brenda W | Hofman, Albert | Oostra, Ben A | Psaty, Bruce M | Vollenweider, Peter | Wilson, James F | Wright, Alan F | Hovingh, G Kees | Metspalu, Andres | Uusitupa, Matti | Magnusson, Patrik K E | Kyvik, Kirsten O | Kaprio, Jaakko | Price, Jackie F | Dedoussis, George V | Deloukas, Panos | Meneton, Pierre | Lind, Lars | Boehnke, Michael | Shuldiner, Alan R | van Duijn, Cornelia M | Morris, Andrew D | Toenjes, Anke | Peyser, Patricia A | Beilby, John P | Körner, Antje | Kuusisto, Johanna | Laakso, Markku | Bornstein, Stefan R | Schwarz, Peter E H | Lakka, Timo A | Rauramaa, Rainer | Adair, Linda S | Smith, George Davey | Spector, Tim D | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Gudnason, Vilmundur | Kivimaki, Mika | Hingorani, Aroon | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Boomsma, Dorret I | Stefansson, Kari | van der Harst, Pim | Dupuis, Josée | Pedersen, Nancy L | Sattar, Naveed | Harris, Tamara B | Cucca, Francesco | Ripatti, Samuli | Salomaa, Veikko | Mohlke, Karen L | Balkau, Beverley | Froguel, Philippe | Pouta, Anneli | Jarvelin, Marjo-Riitta | Wareham, Nicholas J | Bouatia-Naji, Nabila | McCarthy, Mark I | Franks, Paul W | Meigs, James B | Teslovich, Tanya M | Florez, Jose C | Langenberg, Claudia | Ingelsson, Erik | Prokopenko, Inga | Barroso, Inês
Nature genetics  2012;44(9):991-1005.
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have raised the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional follow-up of these newly discovered loci will further improve our understanding of glycemic control.
doi:10.1038/ng.2385
PMCID: PMC3433394  PMID: 22885924
10.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segrè, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian'an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John RB | Platou, Carl GP | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden89-, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
11.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segré, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian’an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John R B | Platou, Carl G P | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
12.  Use of microarray hybrid capture and next-generation sequencing to identify the anatomy of a transgene 
Nucleic Acids Research  2013;41(6):e70.
Transgenic animals are extensively used to model human disease. Typically, the transgene copy number is estimated, but the exact integration site and configuration of the foreign DNA remains uncharacterized. When transgenes have been closely examined, some unexpected configurations have been found. Here, we describe a method to recover transgene insertion sites and assess structural rearrangements of host and transgene DNA using microarray hybridization and targeted sequence capture. We used information about the transgene insertion site to develop a polymerase chain reaction genotyping assay to distinguish heterozygous from homozygous transgenic animals. Although we worked with a bacterial artificial chromosome transgenic mouse line, this method can be used to analyse the integration site and configuration of any foreign DNA in a sequenced genome.
doi:10.1093/nar/gks1463
PMCID: PMC3616733  PMID: 23314155
13.  The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits 
PLoS Genetics  2012;8(8):e1002793.
Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the “Metabochip,” a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits.
Author Summary
Recent genetic studies have identified hundreds of regions of the human genome that contribute to risk for type 2 diabetes, coronary artery disease and myocardial infarction, and to related quantitative traits such as body mass index, glucose and insulin levels, blood lipid levels, and blood pressure. These results motivate two central questions: (1) can further genetic investigation identify additional associated regions?; and (2) can more detailed genetic investigation help us identify the causal variants (or variants more strongly correlated with the causal variants) in the regions identified so far? Addressing these questions requires assaying many genetic variants in DNA samples from thousands of individuals, which is expensive and timeconsuming when done a few SNPs at a time. To facilitate these investigations, we designed the “Metabochip,” a custom genotyping array that assays variation in nearly 200,000 sites in the human genome. Here we describe the Metabochip, evaluate its performance in assaying human genetic variation, and describe solutions to methodological challenges commonly encountered in its analysis.
doi:10.1371/journal.pgen.1002793
PMCID: PMC3410907  PMID: 22876189
14.  Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects 
BMC Medical Genetics  2012;13:62.
Background
Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk.
Methods
A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.
Results
Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003–0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.
Conclusions
To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.
doi:10.1186/1471-2350-13-62
PMCID: PMC3458983  PMID: 22856873
Neural tube defects; Spina bifida; Folic acid; One-carbon metabolism; Candidate gene
15.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants 
Science (New York, N.Y.)  2007;316(5829):1341-1345.
Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.
doi:10.1126/science.1142382
PMCID: PMC3214617  PMID: 17463248
16.  Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci 
Cell metabolism  2010;12(5):443-455.
Summary
Identifying cis-regulatory elements is important to understand how human pancreatic islets modulate gene expression in physiologic or pathophysiologic (e.g., diabetic) conditions. We conducted genome-wide analysis of DNase I hypersensitive sites, histone H3 lysine methylation modifications (K4me1, K4me3, K79me2), and CCCTC factor (CTCF) binding in human islets. This identified ~18,000 putative promoters (several hundred unannotated and islet-active). Surprisingly, active promoter modifications were absent at genes encoding islet-specific hormones, suggesting a distinct regulatory mechanism. Of 34,039 distal (non-promoter) regulatory elements, 47% are islet-unique and 22% are CTCF-bound. In the 18 type 2 diabetes (T2D)-associated loci, we identified 118 putative regulatory elements and confirmed enhancer activity for 12/33 tested. Among 6 regulatory elements harboring T2D-associated variants, 2 exhibit significant allele-specific differences in activity. These findings present a global snapshot of the human islet epigenome and should provide functional context for non-coding variants emerging from genetic studies of T2D and other islet disorders.
doi:10.1016/j.cmet.2010.09.012
PMCID: PMC3026436  PMID: 21035756
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate 
Human Molecular Genetics  2009;18(24):4879-4896.
Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22–q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22–q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22–q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E − 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E − 13) and rs4460498 (P = 6.51E − 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5′ and 3′ of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies.
doi:10.1093/hmg/ddp444
PMCID: PMC2778374  PMID: 19779022
24.  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
25.  Common variants in the GDF5-BFZB region are associated with variation in human height 
Nature genetics  2008;40(2):198-203.
Identifying genetic variants that influence human height will further our understanding of skeletal growth and development. A number of rare genetic variants have been convincingly and reproducibly associated with height in Mendelian syndromes, and common variants in HMGA2 were recently found to be associated with variation in height in the general population1. Here, we report genome-wide association analyses of 6,669 individuals from Finland and Sardinia, using genotyped and imputed markers, and follow-up in an additional 28,801 individuals. We show that common variants in the osteoarthritis-associated2 GDF5-BFZB locus are responsible for variation in height (estimated additive effect of 0.44 cm, overall p<10−15). Our results suggest a link between the genetic basis of height and osteoarthritis, potentially mediated through alterations in bone growth and development.
doi:10.1038/ng.74
PMCID: PMC2914680  PMID: 18193045

Results 1-25 (33)