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1.  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
2.  Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes 
Strawbridge, Rona J. | Dupuis, Josée | Prokopenko, Inga | Barker, Adam | Ahlqvist, Emma | Rybin, Denis | Petrie, John R. | Travers, Mary E. | Bouatia-Naji, Nabila | Dimas, Antigone S. | Nica, Alexandra | Wheeler, Eleanor | Chen, Han | Voight, Benjamin F. | Taneera, Jalal | Kanoni, Stavroula | Peden, John F. | Turrini, Fabiola | Gustafsson, Stefan | Zabena, Carina | Almgren, Peter | Barker, David J.P. | Barnes, Daniel | Dennison, Elaine M. | Eriksson, Johan G. | Eriksson, Per | Eury, Elodie | Folkersen, Lasse | Fox, Caroline S. | Frayling, Timothy M. | Goel, Anuj | Gu, Harvest F. | Horikoshi, Momoko | Isomaa, Bo | Jackson, Anne U. | Jameson, Karen A. | Kajantie, Eero | Kerr-Conte, Julie | Kuulasmaa, Teemu | Kuusisto, Johanna | Loos, Ruth J.F. | Luan, Jian'an | Makrilakis, Konstantinos | Manning, Alisa K. | Martínez-Larrad, María Teresa | Narisu, Narisu | Nastase Mannila, Maria | Öhrvik, John | Osmond, Clive | Pascoe, Laura | Payne, Felicity | Sayer, Avan A. | Sennblad, Bengt | Silveira, Angela | Stančáková, Alena | Stirrups, Kathy | Swift, Amy J. | Syvänen, Ann-Christine | Tuomi, Tiinamaija | van 't Hooft, Ferdinand M. | Walker, Mark | Weedon, Michael N. | Xie, Weijia | Zethelius, Björn | Ongen, Halit | Mälarstig, Anders | Hopewell, Jemma C. | Saleheen, Danish | Chambers, John | Parish, Sarah | Danesh, John | Kooner, Jaspal | Östenson, Claes-Göran | Lind, Lars | Cooper, Cyrus C. | Serrano-Ríos, Manuel | Ferrannini, Ele | Forsen, Tom J. | Clarke, Robert | Franzosi, Maria Grazia | Seedorf, Udo | Watkins, Hugh | Froguel, Philippe | Johnson, Paul | Deloukas, Panos | Collins, Francis S. | Laakso, Markku | Dermitzakis, Emmanouil T. | Boehnke, Michael | McCarthy, Mark I. | Wareham, Nicholas J. | Groop, Leif | Pattou, François | Gloyn, Anna L. | Dedoussis, George V. | Lyssenko, Valeriya | Meigs, James B. | Barroso, Inês | Watanabe, Richard M. | Ingelsson, Erik | Langenberg, Claudia | Hamsten, Anders | Florez, Jose C.
Diabetes  2011;60(10):2624-2634.
OBJECTIVE
Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.
RESEARCH DESIGN AND METHODS
We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.
RESULTS
Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.
CONCLUSIONS
We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
doi:10.2337/db11-0415
PMCID: PMC3178302  PMID: 21873549
3.  Genome-wide association and large scale follow-up identifies 16 new loci influencing lung function 
Artigas, María Soler | Loth, Daan W | Wain, Louise V | Gharib, Sina A | Obeidat, Ma’en | Tang, Wenbo | Zhai, Guangju | Zhao, Jing Hua | Smith, Albert Vernon | Huffman, Jennifer E | Albrecht, Eva | Jackson, Catherine M | Evans, David M | Cadby, Gemma | Fornage, Myriam | Manichaikul, Ani | Lopez, Lorna M | Johnson, Toby | Aldrich, Melinda C | Aspelund, Thor | Barroso, Inês | Campbell, Harry | Cassano, Patricia A | Couper, David J | Eiriksdottir, Gudny | Franceschini, Nora | Garcia, Melissa | Gieger, Christian | Gislason, Gauti Kjartan | Grkovic, Ivica | Hammond, Christopher J | Hancock, Dana B | Harris, Tamara B | Ramasamy, Adaikalavan | Heckbert, Susan R | Heliövaara, Markku | Homuth, Georg | Hysi, Pirro G | James, Alan L | Jankovic, Stipan | Joubert, Bonnie R | Karrasch, Stefan | Klopp, Norman | Koch, Beate | Kritchevsky, Stephen B | Launer, Lenore J | Liu, Yongmei | Loehr, Laura R | Lohman, Kurt | Loos, Ruth JF | Lumley, Thomas | Al Balushi, Khalid A | Ang, Wei Q | Barr, R Graham | Beilby, John | Blakey, John D | Boban, Mladen | Boraska, Vesna | Brisman, Jonas | Britton, John R | Brusselle, Guy G | Cooper, Cyrus | Curjuric, Ivan | Dahgam, Santosh | Deary, Ian J | Ebrahim, Shah | Eijgelsheim, Mark | Francks, Clyde | Gaysina, Darya | Granell, Raquel | Gu, Xiangjun | Hankinson, John L | Hardy, Rebecca | Harris, Sarah E | Henderson, John | Henry, Amanda | Hingorani, Aroon D | Hofman, Albert | Holt, Patrick G | Hui, Jennie | Hunter, Michael L | Imboden, Medea | Jameson, Karen A | Kerr, Shona M | Kolcic, Ivana | Kronenberg, Florian | Liu, Jason Z | Marchini, Jonathan | McKeever, Tricia | Morris, Andrew D | Olin, Anna-Carin | Porteous, David J | Postma, Dirkje S | Rich, Stephen S | Ring, Susan M | Rivadeneira, Fernando | Rochat, Thierry | Sayer, Avan Aihie | Sayers, Ian | Sly, Peter D | Smith, George Davey | Sood, Akshay | Starr, John M | Uitterlinden, André G | Vonk, Judith M | Wannamethee, S Goya | Whincup, Peter H | Wijmenga, Cisca | Williams, O Dale | Wong, Andrew | Mangino, Massimo | Marciante, Kristin D | McArdle, Wendy L | Meibohm, Bernd | Morrison, Alanna C | North, Kari E | Omenaas, Ernst | Palmer, Lyle J | Pietiläinen, Kirsi H | Pin, Isabelle | Polašek, Ozren | Pouta, Anneli | Psaty, Bruce M | Hartikainen, Anna-Liisa | Rantanen, Taina | Ripatti, Samuli | Rotter, Jerome I | Rudan, Igor | Rudnicka, Alicja R | Schulz, Holger | Shin, So-Youn | Spector, Tim D | Surakka, Ida | Vitart, Veronique | Völzke, Henry | Wareham, Nicholas J | Warrington, Nicole M | Wichmann, H-Erich | Wild, Sarah H | Wilk, Jemma B | Wjst, Matthias | Wright, Alan F | Zgaga, Lina | Zemunik, Tatijana | Pennell, Craig E | Nyberg, Fredrik | Kuh, Diana | Holloway, John W | Boezen, H Marike | Lawlor, Debbie A | Morris, Richard W | Probst-Hensch, Nicole | Kaprio, Jaakko | Wilson, James F | Hayward, Caroline | Kähönen, Mika | Heinrich, Joachim | Musk, Arthur W | Jarvis, Deborah L | Gläser, Sven | Järvelin, Marjo-Riitta | Stricker, Bruno H Ch | Elliott, Paul | O’Connor, George T | Strachan, David P | London, Stephanie J | Hall, Ian P | Gudnason, Vilmundur | Tobin, Martin D
Nature Genetics  2011;43(11):1082-1090.
Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD). We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
doi:10.1038/ng.941
PMCID: PMC3267376  PMID: 21946350
4.  Effect of Five Genetic Variants Associated with Lung Function on the Risk of Chronic Obstructive Lung Disease, and Their Joint Effects on Lung Function 
Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.
Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP.
Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD.
Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10–12 risk alleles was associated with a reduction in FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 10−5).
Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.
doi:10.1164/rccm.201102-0192OC
PMCID: PMC3398416  PMID: 21965014
FEV1; FVC; genome-wide association study; modeling risk
5.  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
6.  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
7.  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
8.  Genome-wide association study identifies five loci associated with lung function 
Repapi, Emmanouela | Sayers, Ian | Wain, Louise V | Burton, Paul R | Johnson, Toby | Obeidat, Ma’en | Zhao, Jing Hua | Ramasamy, Adaikalavan | Zhai, Guangju | Vitart, Veronique | Huffman, Jennifer E | Igl, Wilmar | Albrecht, Eva | Deloukas, Panos | Henderson, John | Granell, Raquel | McArdle, Wendy L | Rudnicka, Alicja R | Barroso, Inês | Loos, Ruth J F | Wareham, Nicholas J | Mustelin, Linda | Rantanen, Taina | Surakka, Ida | Imboden, Medea | Wichmann, H Erich | Grkovic, Ivica | Jankovic, Stipan | Zgaga, Lina | Hartikainen, Anna-Liisa | Peltonen, Leena | Gyllensten, Ulf | Johansson, Åsa | Zaboli, Ghazal | Campbell, Harry | Wild, Sarah H | Wilson, James F | Gläser, Sven | Homuth, Georg | Völzke, Henry | Mangino, Massimo | Soranzo, Nicole | Spector, Tim D | Polašek, Ozren | Rudan, Igor | Wright, Alan F | Heliövaara, Markku | Ripatti, Samuli | Pouta, Anneli | Naluai, Åsa Torinsson | Olin, Anna-Carin | Torén, Kjell | Cooper, Matthew N | James, Alan L | Palmer, Lyle J | Hingorani, Aroon D | Wannamethee, S Goya | Whincup, Peter H | Smith, George Davey | Ebrahim, Shah | McKeever, Tricia M | Pavord, Ian D | MacLeod, Andrew K | Morris, Andrew D | Porteous, David J | Cooper, Cyrus | Dennison, Elaine | Shaheen, Seif | Karrasch, Stefan | Schnabel, Eva | Schulz, Holger | Grallert, Harald | Bouatia-Naji, Nabila | Delplanque, Jérôme | Froguel, Philippe | Blakey, John D | Britton, John R | Morris, Richard W | Holloway, John W | Lawlor, Debbie A | Hui, Jennie | Nyberg, Fredrik | Jarvelin, Marjo-Riitta | Jackson, Cathy | Kähönen, Mika | Kaprio, Jaakko | Probst-Hensch, Nicole M | Koch, Beate | Hayward, Caroline | Evans, David M | Elliott, Paul | Strachan, David P | Hall, Ian P | Tobin, Martin D
Nature genetics  2009;42(1):36-44.
Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 10−15). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
doi:10.1038/ng.501
PMCID: PMC2862965  PMID: 20010834
9.  Evaluating the Role of LPIN1 Variation in Insulin Resistance, Body Weight, and Human Lipodystrophy in U.K. Populations 
Diabetes  2008;57(9):2527-2533.
OBJECTIVE— Loss of lipin 1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence adiposity and insulin sensitivity in humans. We aimed to conduct a comprehensive association study to clarify the influence of common LPIN1 variation on adiposity and insulin sensitivity in U.K. populations and to examine the role of LPIN1 mutations in insulin resistance syndromes.
RESEARCH DESIGN AND METHOD— Twenty-two single nucleotide polymorphisms tagging common LPIN1 variation were genotyped in Medical Research Council (MRC) Ely (n = 1,709) and Hertfordshire (n = 2,901) population-based cohorts. LPIN1 exons, exon/intron boundaries, and 3′ untranslated region were sequenced in 158 patients with idiopathic severe insulin resistance (including 23 lipodystrophic patients) and 48 control subjects.
RESULTS— We found no association between LPIN1 single nucleotide polymorphisms and fasting insulin but report a nominal association between rs13412852 and BMI (P = 0.042) in a meta-analysis of 8,504 samples from in-house and publicly available studies. Three rare nonsynonymous variants (A353T, R552K, and G582R) were detected in severely insulin-resistant patients. However, these did not cosegregate with disease in affected families, and Lipin1 protein expression and phosphorylation in patients with variants were indistinguishable from those in control subjects.
CONCLUSIONS— Our data do not support a major effect of common LPIN1 variation on metabolic traits and suggest that mutations in LPIN1 are not a common cause of lipodystrophy in humans. The nominal associations with BMI and other metabolic traits in U.K. cohorts require replication in larger cohorts.
doi:10.2337/db08-0422
PMCID: PMC2518506  PMID: 18591397
10.  Correction: Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution 
Lindgren, Cecilia M. | Heid, Iris M. | Randall, Joshua C. | Lamina, Claudia | Steinthorsdottir, Valgerdur | Qi, Lu | Speliotes, Elizabeth K. | Thorleifsson, Gudmar | Willer, Cristen J. | Herrera, Blanca M. | Jackson, Anne U. | Lim, Noha | Scheet, Paul | Soranzo, Nicole | Amin, Najaf | Aulchenko, Yurii S. | Chambers, John C. | Drong, Alexander | Luan, Jian'an | Lyon, Helen N. | Rivadeneira, Fernando | Sanna, Serena | Timpson, Nicholas J. | Zillikens, M. Carola | Zhao, Jing Hua | Almgren, Peter | Bandinelli, Stefania | Bennett, Amanda J. | Bergman, Richard N. | Bonnycastle, Lori L. | Bumpstead, Suzannah J. | Chanock, Stephen J. | Cherkas, Lynn | Chines, Peter | Coin, Lachlan | Cooper, Cyrus | Crawford, Gabriel | Doering, Angela | Dominiczak, Anna | Doney, Alex S. F. | Ebrahim, Shah | Elliott, Paul | Erdos, Michael R. | Estrada, Karol | Ferrucci, Luigi | Fischer, Guido | Forouhi, Nita G. | Gieger, Christian | Grallert, Harald | Groves, Christopher J. | Grundy, Scott | Guiducci, Candace | Hadley, David | Hamsten, Anders | Havulinna, Aki S. | Hofman, Albert | Holle, Rolf | Holloway, John W. | Illig, Thomas | Isomaa, Bo | Jacobs, Leonie C. | Jameson, Karen | Jousilahti, Pekka | Karpe, Fredrik | Kuusisto, Johanna | Laitinen, Jaana | Lathrop, G. Mark | Lawlor, Debbie A. | Mangino, Massimo | McArdle, Wendy L. | Meitinger, Thomas | Morken, Mario A. | Morris, Andrew P. | Munroe, Patricia | Narisu, Narisu | Nordström, Anna | Nordström, Peter | Oostra, Ben A. | Palmer, Colin N. A. | Payne, Felicity | Peden, John F. | Prokopenko, Inga | Renström, Frida | Ruokonen, Aimo | Salomaa, Veikko | Sandhu, Manjinder S. | Scott, Laura J. | Scuteri, Angelo | Silander, Kaisa | Song, Kijoung | Yuan, Xin | Stringham, Heather M. | Swift, Amy J. | Tuomi, Tiinamaija | Uda, Manuela | Vollenweider, Peter | Waeber, Gerard | Wallace, Chris | Walters, G. Bragi | Weedon, Michael N. | Witteman, Jacqueline C. M. | Zhang, Cuilin | Zhang, Weihua | Caulfield, Mark J. | Collins, Francis S. | Davey Smith, George | Day, Ian N. M. | Franks, Paul W. | Hattersley, Andrew T. | Hu, Frank B. | Jarvelin, Marjo-Riitta | Kong, Augustine | Kooner, Jaspal S. | Laakso, Markku | Lakatta, Edward | Mooser, Vincent | Morris, Andrew D. | Peltonen, Leena | Samani, Nilesh J. | Spector, Timothy D. | Strachan, David P. | Tanaka, Toshiko | Tuomilehto, Jaakko | Uitterlinden, André G. | van Duijn, Cornelia M. | Wareham, Nicholas J. | Watkins for the PROCARDIS consortia, Hugh | Waterworth, Dawn M. | Boehnke, Michael | Deloukas, Panos | Groop, Leif | Hunter, David J. | Thorsteinsdottir, Unnur | Schlessinger, David | Wichmann, H.-Erich | Frayling, Timothy M. | Abecasis, Gonçalo R. | Hirschhorn, Joel N. | Loos, Ruth J. F. | Stefansson, Kari | Mohlke, Karen L. | Barroso, Inês | McCarthy for the GIANT consortium, Mark I.
PLoS Genetics  2009;5(7):10.1371/annotation/b6e8f9f6-2496-4a40-b0e3-e1d1390c1928.
doi:10.1371/annotation/b6e8f9f6-2496-4a40-b0e3-e1d1390c1928
PMCID: PMC2722420
11.  Six new loci associated with body mass index highlight a neuronal influence on body weight regulation 
Willer, Cristen J | Speliotes, Elizabeth K | Loos, Ruth J F | Li, Shengxu | Lindgren, Cecilia M | Heid, Iris M | Berndt, Sonja I | Elliott, Amanda L | Jackson, Anne U | Lamina, Claudia | Lettre, Guillaume | Lim, Noha | Lyon, Helen N | McCarroll, Steven A | Papadakis, Konstantinos | Qi, Lu | Randall, Joshua C | Roccasecca, Rosa Maria | Sanna, Serena | Scheet, Paul | Weedon, Michael N | Wheeler, Eleanor | Zhao, Jing Hua | Jacobs, Leonie C | Prokopenko, Inga | Soranzo, Nicole | Tanaka, Toshiko | Timpson, Nicholas J | Almgren, Peter | Bennett, Amanda | Bergman, Richard N | Bingham, Sheila A | Bonnycastle, Lori L | Brown, Morris | Burtt, Noël P | Chines, Peter | Coin, Lachlan | Collins, Francis S | Connell, John M | Cooper, Cyrus | Smith, George Davey | Dennison, Elaine M | Deodhar, Parimal | Elliott, Paul | Erdos, Michael R | Estrada, Karol | Evans, David M | Gianniny, Lauren | Gieger, Christian | Gillson, Christopher J | Guiducci, Candace | Hackett, Rachel | Hadley, David | Hall, Alistair S | Havulinna, Aki S | Hebebrand, Johannes | Hofman, Albert | Isomaa, Bo | Jacobs, Kevin B | Johnson, Toby | Jousilahti, Pekka | Jovanovic, Zorica | Khaw, Kay-Tee | Kraft, Peter | Kuokkanen, Mikko | Kuusisto, Johanna | Laitinen, Jaana | Lakatta, Edward G | Luan, Jian'an | Luben, Robert N | Mangino, Massimo | McArdle, Wendy L | Meitinger, Thomas | Mulas, Antonella | Munroe, Patricia B | Narisu, Narisu | Ness, Andrew R | Northstone, Kate | O'Rahilly, Stephen | Purmann, Carolin | Rees, Matthew G | Ridderstråle, Martin | Ring, Susan M | Rivadeneira, Fernando | Ruokonen, Aimo | Sandhu, Manjinder S | Saramies, Jouko | Scott, Laura J | Scuteri, Angelo | Silander, Kaisa | Sims, Matthew A | Song, Kijoung | Stephens, Jonathan | Stevens, Suzanne | Stringham, Heather M | Tung, Y C Loraine | Valle, Timo T | Van Duijn, Cornelia M | Vimaleswaran, Karani S | Vollenweider, Peter | Waeber, Gerard | Wallace, Chris | Watanabe, Richard M | Waterworth, Dawn M | Watkins, Nicholas | Witteman, Jacqueline C M | Zeggini, Eleftheria | Zhai, Guangju | Zillikens, M Carola | Altshuler, David | Caulfield, Mark J | Chanock, Stephen J | Farooqi, I Sadaf | Ferrucci, Luigi | Guralnik, Jack M | Hattersley, Andrew T | Hu, Frank B | Jarvelin, Marjo-Riitta | Laakso, Markku | Mooser, Vincent | Ong, Ken K | Ouwehand, Willem H | Salomaa, Veikko | Samani, Nilesh J | Spector, Timothy D | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Uda, Manuela | Uitterlinden, André G | Wareham, Nicholas J | Deloukas, Panagiotis | Frayling, Timothy M | Groop, Leif C | Hayes, Richard B | Hunter, David J | Mohlke, Karen L | Peltonen, Leena | Schlessinger, David | Strachan, David P | Wichmann, H-Erich | McCarthy, Mark I | Boehnke, Michael | Barroso, Inês | Abecasis, Gonçalo R | Hirschhorn, Joel N
Nature genetics  2008;41(1):25-34.
Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
doi:10.1038/ng.287
PMCID: PMC2695662  PMID: 19079261
12.  Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution 
Lindgren, Cecilia M. | Heid, Iris M. | Randall, Joshua C. | Lamina, Claudia | Steinthorsdottir, Valgerdur | Qi, Lu | Speliotes, Elizabeth K. | Thorleifsson, Gudmar | Willer, Cristen J. | Herrera, Blanca M. | Jackson, Anne U. | Lim, Noha | Scheet, Paul | Soranzo, Nicole | Amin, Najaf | Aulchenko, Yurii S. | Chambers, John C. | Drong, Alexander | Luan, Jian'an | Lyon, Helen N. | Rivadeneira, Fernando | Sanna, Serena | Timpson, Nicholas J. | Zillikens, M. Carola | Zhao, Jing Hua | Almgren, Peter | Bandinelli, Stefania | Bennett, Amanda J. | Bergman, Richard N. | Bonnycastle, Lori L. | Bumpstead, Suzannah J. | Chanock, Stephen J. | Cherkas, Lynn | Chines, Peter | Coin, Lachlan | Cooper, Cyrus | Crawford, Gabriel | Doering, Angela | Dominiczak, Anna | Doney, Alex S. F. | Ebrahim, Shah | Elliott, Paul | Erdos, Michael R. | Estrada, Karol | Ferrucci, Luigi | Fischer, Guido | Forouhi, Nita G. | Gieger, Christian | Grallert, Harald | Groves, Christopher J. | Grundy, Scott | Guiducci, Candace | Hadley, David | Hamsten, Anders | Havulinna, Aki S. | Hofman, Albert | Holle, Rolf | Holloway, John W. | Illig, Thomas | Isomaa, Bo | Jacobs, Leonie C. | Jameson, Karen | Jousilahti, Pekka | Karpe, Fredrik | Kuusisto, Johanna | Laitinen, Jaana | Lathrop, G. Mark | Lawlor, Debbie A. | Mangino, Massimo | McArdle, Wendy L. | Meitinger, Thomas | Morken, Mario A. | Morris, Andrew P. | Munroe, Patricia | Narisu, Narisu | Nordström, Anna | Nordström, Peter | Oostra, Ben A. | Palmer, Colin N. A. | Payne, Felicity | Peden, John F. | Prokopenko, Inga | Renström, Frida | Ruokonen, Aimo | Salomaa, Veikko | Sandhu, Manjinder S. | Scott, Laura J. | Scuteri, Angelo | Silander, Kaisa | Song, Kijoung | Yuan, Xin | Stringham, Heather M. | Swift, Amy J. | Tuomi, Tiinamaija | Uda, Manuela | Vollenweider, Peter | Waeber, Gerard | Wallace, Chris | Walters, G. Bragi | Weedon, Michael N. | Witteman, Jacqueline C. M. | Zhang, Cuilin | Zhang, Weihua | Caulfield, Mark J. | Collins, Francis S. | Davey Smith, George | Day, Ian N. M. | Franks, Paul W. | Hattersley, Andrew T. | Hu, Frank B. | Jarvelin, Marjo-Riitta | Kong, Augustine | Kooner, Jaspal S. | Laakso, Markku | Lakatta, Edward | Mooser, Vincent | Morris, Andrew D. | Peltonen, Leena | Samani, Nilesh J. | Spector, Timothy D. | Strachan, David P. | Tanaka, Toshiko | Tuomilehto, Jaakko | Uitterlinden, André G. | van Duijn, Cornelia M. | Wareham, Nicholas J. | Watkins for the PROCARDIS consortia, Hugh | Waterworth, Dawn M. | Boehnke, Michael | Deloukas, Panos | Groop, Leif | Hunter, David J. | Thorsteinsdottir, Unnur | Schlessinger, David | Wichmann, H.-Erich | Frayling, Timothy M. | Abecasis, Gonçalo R. | Hirschhorn, Joel N. | Loos, Ruth J. F. | Stefansson, Kari | Mohlke, Karen L. | Barroso, Inês | McCarthy for the GIANT consortium, Mark I.
PLoS Genetics  2009;5(6):e1000508.
To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10−11) and MSRA (WC, P = 8.9×10−9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10−8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Author Summary
Here, we describe a meta-analysis of genome-wide association data from 38,580 individuals, followed by large-scale replication (in up to 70,689 individuals) designed to uncover variants influencing anthropometric measures of central obesity and fat distribution, namely waist circumference (WC) and waist–hip ratio (WHR). This work complements parallel efforts that have been successful in defining variants impacting overall adiposity and focuses on the visceral fat accumulation which has particularly strong relationships to metabolic and cardiovascular disease. Our analyses have identified two loci (TFAP2B and MSRA) associated with WC, and a further locus, near LYPLAL1, which shows gender-specific relationships with WHR (all to levels of genome-wide significance). These loci vary in the strength of their associations with overall adiposity, and LYPLAL1 in particular appears to have a specific effect on patterns of fat distribution. All in all, these three loci provide novel insights into human physiology and the development of obesity.
doi:10.1371/journal.pgen.1000508
PMCID: PMC2695778  PMID: 19557161
13.  Evaluating the role of LPIN1 variation on insulin resistance, body weight and human lipodystrophy in UK populations 
Diabetes  2008;57(9):2527-2533.
OBJECTIVE:
Loss of Lpin1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence adiposity and insulin sensitivity in humans. We aimed to conduct a comprehensive association study to clarify the influence of LPIN1 common variation on adiposity and insulin sensitivity in UK populations, and to examine the role of LPIN1 mutations in insulin resistance syndromes.
RESEARCH DESIGN AND METHOD:
Twenty-two SNPs tagging LPIN1 common variation were genotyped in MRC Ely (N = 1709) and Hertfordshire (N = 2901) population-based cohorts. LPIN1 exons, exon/intron boundaries and 3′UTR were sequenced in 158 patients with idiopathic severe insulin resistance (including 23 lipodystrophic patients), and 48 controls.
RESULTS:
We found no association between LPIN1 SNPs and fasting insulin, but report a nominal association between rs13412852 and BMI (P = 0.042) in a meta-analysis of 8504 samples from in-house and publicly available studies. Three rare nonsynonymous variants (A353T, R552K and G582R) were detected in severely insulin resistant patients. However, these did not co-segregate with disease in affected families and Lipin1 protein expression and phosphorylation in patients with variants was indistinguishable from controls.
CONCLUSIONS:
Our data do not support a major effect of LPIN1 common variation on metabolic traits and suggest that mutations in LPIN1 are not a common cause of lipodystrophy in humans. The nominal associations with BMI and other metabolic traits in UK cohorts require replication in larger cohorts.
doi:10.2337/db08-0422
PMCID: PMC2518506  PMID: 18591397
14.  Common variants near MC4R are associated with fat mass, weight and risk of obesity 
Loos, Ruth J F | Lindgren, Cecilia M | Li, Shengxu | Wheeler, Eleanor | Zhao, Jing Hua | Prokopenko, Inga | Inouye, Michael | Freathy, Rachel M | Attwood, Antony P | Beckmann, Jacques S | Berndt, Sonja I | Bergmann, Sven | Bennett, Amanda J | Bingham, Sheila A | Bochud, Murielle | Brown, Morris | Cauchi, Stéphane | Connell, John M | Cooper, Cyrus | Smith, George Davey | Day, Ian | Dina, Christian | De, Subhajyoti | Dermitzakis, Emmanouil T | Doney, Alex S F | Elliott, Katherine S | Elliott, Paul | Evans, David M | Farooqi, I Sadaf | Froguel, Philippe | Ghori, Jilur | Groves, Christopher J | Gwilliam, Rhian | Hadley, David | Hall, Alistair S | Hattersley, Andrew T | Hebebrand, Johannes | Heid, Iris M | Herrera, Blanca | Hinney, Anke | Hunt, Sarah E | Jarvelin, Marjo-Riitta | Johnson, Toby | Jolley, Jennifer D M | Karpe, Fredrik | Keniry, Andrew | Khaw, Kay-Tee | Luben, Robert N | Mangino, Massimo | Marchini, Jonathan | McArdle, Wendy L | McGinnis, Ralph | Meyre, David | Munroe, Patricia B | Morris, Andrew D | Ness, Andrew R | Neville, Matthew J | Nica, Alexandra C | Ong, Ken K | O'Rahilly, Stephen | Owen, Katharine R | Palmer, Colin N A | Papadakis, Konstantinos | Potter, Simon | Pouta, Anneli | Qi, Lu | Randall, Joshua C | Rayner, Nigel W | Ring, Susan M | Sandhu, Manjinder S | Scherag, André | Sims, Matthew A | Song, Kijoung | Soranzo, Nicole | Speliotes, Elizabeth K | Syddall, Holly E | Teichmann, Sarah A | Timpson, Nicholas J | Tobias, Jonathan H | Uda, Manuela | Vogel, Carla I Ganz | Wallace, Chris | Waterworth, Dawn M | Weedon, Michael N | Willer, Cristen J | Wraight, Vicki L | Yuan, Xin | Zeggini, Eleftheria | Hirschhorn, Joel N | Strachan, David P | Ouwehand, Willem H | Caulfield, Mark J | Samani, Nilesh J | Frayling, Timothy M | Vollenweider, Peter | Waeber, Gerard | Mooser, Vincent | Deloukas, Panos | McCarthy, Mark I | Wareham, Nicholas J | Barroso, Inês | Jacobs, Kevin B | Chanock, Stephen J | Hayes, Richard B | Lamina, Claudia | Gieger, Christian | Illig, Thomas | Meitinger, Thomas | Wichmann, H-Erich | Kraft, Peter | Hankinson, Susan E | Hunter, David J | Hu, Frank B | Lyon, Helen N | Voight, Benjamin F | Ridderstrale, Martin | Groop, Leif | Scheet, Paul | Sanna, Serena | Abecasis, Goncalo R | Albai, Giuseppe | Nagaraja, Ramaiah | Schlessinger, David | Jackson, Anne U | Tuomilehto, Jaakko | Collins, Francis S | Boehnke, Michael | Mohlke, Karen L
Nature genetics  2008;40(6):768-775.
To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 × 10−6) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 × 10−15) and 5,988 children aged 7–11 (0.13 Z-score units; P = 1.5 × 10−8). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 × 10−11). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 × 10−4). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
doi:10.1038/ng.140
PMCID: PMC2669167  PMID: 18454148

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