Abstract
To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 × 10-50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10 -15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10 -7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10 -57) and GCK (rs4607517, P = 1.0 × 10-25) loci.
Original language | English (US) |
---|---|
Pages (from-to) | 77-81 |
Number of pages | 5 |
Journal | Nature genetics |
Volume | 41 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2009 |
Externally published | Yes |
ASJC Scopus subject areas
- Genetics
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Variants in MTNR1B influence fasting glucose levels. / Prokopenko, Inga; Langenberg, Claudia; Florez, Jose C.; Saxena, Richa; Soranzo, Nicole; Thorleifsson, Gudmar; Loos, Ruth J.F.; Manning, Alisa K.; Jackson, Anne U.; Aulchenko, Yurii; Potter, Simon C.; Erdos, Michael R.; Sanna, Serena; Hottenga, Jouke Jan; Wheeler, Eleanor; Kaakinen, Marika; Lyssenko, Valeriya; Chen, Wei Min; Ahmadi, Kourosh; Beckmann, Jacques S.; Bergman, Richard N.; Bochud, Murielle; Bonnycastle, Lori L.; Buchanan, Thomas A.; Cao, Antonio; Cervino, Alessandra; Coin, Lachlan; Collins, Francis S.; Crisponi, Laura; De Geus, Eco J.C.; Dehghan, Abbas; Deloukas, Panos; Doney, Alex S.F.; Elliott, Paul; Freimer, Nelson; Gateva, Vesela; Herder, Christian; Hofman, Albert; Hughes, Thomas E.; Hunt, Sarah; Illig, Thomas; Inouye, Michael; Isomaa, Bo; Johnson, Toby; Kong, Augustine; Krestyaninova, Maria; Kuusisto, Johanna; Laakso, Markku; Lim, Noha; Lindblad, Ulf; Lindgren, Cecilia M.; McCann, Owen T.; Mohlke, Karen L.; Morris, Andrew D.; Naitza, Silvia; Orrù, Marco; Palmer, Colin N.A.; Pouta, Anneli; Randall, Joshua; Rathmann, Wolfgang; Saramies, Jouko; Scheet, Paul; Scott, Laura J.; Scuteri, Angelo; Sharp, Stephen; Sijbrands, Eric; Smit, Jan H.; Song, Kijoung; Steinthorsdottir, Valgerdur; Stringham, Heather M.; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Uitterlinden, André G.; Voight, Benjamin F.; Waterworth, Dawn; Wichmann, H. Erich; Willemsen, Gonneke; Witteman, Jacqueline C.M.; Yuan, Xin; Zhao, Jing Hua; Zeggini, Eleftheria; Schlessinger, David; Sandhu, Manjinder; Boomsma, Dorret I.; Uda, Manuela; Spector, Tim D.; Penninx, Brenda W.J.H.; Altshuler, David; Vollenweider, Peter; Jarvelin, Marjo Riitta; Lakatta, Edward; Waeber, Gerard; Fox, Caroline S.; Peltonen, Leena; Groop, Leif C.; Mooser, Vincent; Cupples, L. Adrienne; Thorsteinsdottir, Unnur; Boehnke, Michael; Barroso, Inês; Van Duijn, Cornelia; Dupuis, Josée; Watanabe, Richard M.; Stefansson, Kari; McCarthy, Mark I.; Wareham, Nicholas J.; Meigs, James B.; Abecasis, Gonçalo R.
In: Nature genetics, Vol. 41, No. 1, 01.2009, p. 77-81.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Variants in MTNR1B influence fasting glucose levels
AU - Prokopenko, Inga
AU - Langenberg, Claudia
AU - Florez, Jose C.
AU - Saxena, Richa
AU - Soranzo, Nicole
AU - Thorleifsson, Gudmar
AU - Loos, Ruth J.F.
AU - Manning, Alisa K.
AU - Jackson, Anne U.
AU - Aulchenko, Yurii
AU - Potter, Simon C.
AU - Erdos, Michael R.
AU - Sanna, Serena
AU - Hottenga, Jouke Jan
AU - Wheeler, Eleanor
AU - Kaakinen, Marika
AU - Lyssenko, Valeriya
AU - Chen, Wei Min
AU - Ahmadi, Kourosh
AU - Beckmann, Jacques S.
AU - Bergman, Richard N.
AU - Bochud, Murielle
AU - Bonnycastle, Lori L.
AU - Buchanan, Thomas A.
AU - Cao, Antonio
AU - Cervino, Alessandra
AU - Coin, Lachlan
AU - Collins, Francis S.
AU - Crisponi, Laura
AU - De Geus, Eco J.C.
AU - Dehghan, Abbas
AU - Deloukas, Panos
AU - Doney, Alex S.F.
AU - Elliott, Paul
AU - Freimer, Nelson
AU - Gateva, Vesela
AU - Herder, Christian
AU - Hofman, Albert
AU - Hughes, Thomas E.
AU - Hunt, Sarah
AU - Illig, Thomas
AU - Inouye, Michael
AU - Isomaa, Bo
AU - Johnson, Toby
AU - Kong, Augustine
AU - Krestyaninova, Maria
AU - Kuusisto, Johanna
AU - Laakso, Markku
AU - Lim, Noha
AU - Lindblad, Ulf
AU - Lindgren, Cecilia M.
AU - McCann, Owen T.
AU - Mohlke, Karen L.
AU - Morris, Andrew D.
AU - Naitza, Silvia
AU - Orrù, Marco
AU - Palmer, Colin N.A.
AU - Pouta, Anneli
AU - Randall, Joshua
AU - Rathmann, Wolfgang
AU - Saramies, Jouko
AU - Scheet, Paul
AU - Scott, Laura J.
AU - Scuteri, Angelo
AU - Sharp, Stephen
AU - Sijbrands, Eric
AU - Smit, Jan H.
AU - Song, Kijoung
AU - Steinthorsdottir, Valgerdur
AU - Stringham, Heather M.
AU - Tuomi, Tiinamaija
AU - Tuomilehto, Jaakko
AU - Uitterlinden, André G.
AU - Voight, Benjamin F.
AU - Waterworth, Dawn
AU - Wichmann, H. Erich
AU - Willemsen, Gonneke
AU - Witteman, Jacqueline C.M.
AU - Yuan, Xin
AU - Zhao, Jing Hua
AU - Zeggini, Eleftheria
AU - Schlessinger, David
AU - Sandhu, Manjinder
AU - Boomsma, Dorret I.
AU - Uda, Manuela
AU - Spector, Tim D.
AU - Penninx, Brenda W.J.H.
AU - Altshuler, David
AU - Vollenweider, Peter
AU - Jarvelin, Marjo Riitta
AU - Lakatta, Edward
AU - Waeber, Gerard
AU - Fox, Caroline S.
AU - Peltonen, Leena
AU - Groop, Leif C.
AU - Mooser, Vincent
AU - Cupples, L. Adrienne
AU - Thorsteinsdottir, Unnur
AU - Boehnke, Michael
AU - Barroso, Inês
AU - Van Duijn, Cornelia
AU - Dupuis, Josée
AU - Watanabe, Richard M.
AU - Stefansson, Kari
AU - McCarthy, Mark I.
AU - Wareham, Nicholas J.
AU - Meigs, James B.
AU - Abecasis, Gonçalo R.
N1 - Funding Information: The authors would like to thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of the GWA data. They would also like to acknowledge those who agreed to participate in these studies. Major funding for the work described in this paper comes from Academy of Finland (124243); the Administration of Lanusei, Ilbono, Arzana and Elini (Sardinia, Italy); American Diabetes Association (1-05-RA-140); the Center for Inherited Disease Research; Clinical Research Institute (HUCH); Diabetes UK; the European Bioinformatics Institute; the European Commission (contracts LSHM-CT-2006-037197, LSHM-CT-2003-503041, QLK6-CT-2002-02629, QLG2-CT-2002-01254, HEALTH-F4-2007-201413, LSHG-CT-2004-512066, QLRT-2001-01254, LSHG-CT-2004-518153); the Faculty of Biology and Medicine of Lausanne; Finnish Diabetes Research Foundation; Folkhalsan Research Foundation; Foundation of the NIH (GAIN initiative); German Federal Ministry of Education and Research; German Federal Ministry of Health and Social Security; German National Genome Research Network; GlaxoSmithKline; GSF-National Research Center for Environment and Health; LMUinnovativ; Ministry of Science and Research of the State North-Rhine Westphalia; Municipality of Rotterdam; US National Institutes of Health (HG-02651, HL-084729, HL-087679, HC-25195, N02-HL-6-4278, DK-078616, DK-080140, DK-065978, RR-163736, MH059160, DK069922, DA-021519, DK-062370, DK-072193, US National Human Genome Research Institute intramural project HG-000024; and the Intramural Program of the National Institute on Aging); the UK National Institute for Health Research (Oxford Biomedical Research Centre and Guys and St. Thomas’ Biomedical Research Centre); the Netherlands Ministry of Education, Culture and Science; the Netherlands Ministry of Health, Welfare and Sports; Novartis; NWO (904-61-090, 904-61-193, 480-04-004, 400-05-717); NWOGenomics; NWOInvestments; Research Institute for Diseases in the Elderly (RIDE); Sigrid Juselius Foundation; Spinozapremie; Swedish Research Council (349-2006-237); UK Medical Research Council (G0500539, G0000649, G016121); UK National Health Services Research and Development; the Wellcome Trust (including intramural support for the Wellcome Trust Sanger Institute, GR069224, Strategic Awards 076113 and 083948, Biomedical Collections Grant GR072960); and ZonMw (10-000-1002). A full list of acknowledgments is provided in the Supplementary Note.
PY - 2009/1
Y1 - 2009/1
N2 - To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 × 10-50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10 -15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10 -7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10 -57) and GCK (rs4607517, P = 1.0 × 10-25) loci.
AB - To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 × 10-50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10 -15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10 -7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10 -57) and GCK (rs4607517, P = 1.0 × 10-25) loci.
UR - http://www.scopus.com/inward/record.url?scp=58149156287&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58149156287&partnerID=8YFLogxK
U2 - 10.1038/ng.290
DO - 10.1038/ng.290
M3 - Article
C2 - 19060907
AN - SCOPUS:58149156287
VL - 41
SP - 77
EP - 81
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 1
ER -