Journal
NATURE GENETICS
Volume 41, Issue 10, Pages 1110-U89Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.443
Keywords
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Categories
Funding
- Genome Canada
- Genome Quebec
- Canada Foundation for Innovation
- French Government (Agence Nationale de la Recherche)
- French Region of Nord Pas De Calais (Contrat de Projets Etat-Region)
- Caisse Nationale d'Assurance Maladie des Travailleurs Salaries
- Lilly
- Novartis Pharma
- Sanofi-Aventis
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Association Diabete Risque Vasculaire
- Federation Francaise de Cardiologie
- Fondation de France
- Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques
- Office National Interprofessionnel des Vins
- Ardix Medical
- Bayer Diagnostics
- Becton Dickinson
- Cardionics
- Merck Sante
- Novo Nordisk
- Pierre Fabre
- Roche and Topcon
- Oulu University Hospital, Finland
- Academy of Finland
- European Commission [QLG1-CT-2000-01643]
- Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction
- Prevention and Care (LUCAMP)
- European Union [LSHM-CT-2004-512013, LSHM-CT-2004-005272, LSHM-CT-2006-518153]
- Danish Diabetes Association
- Danish Agency for Science, Technology and Innovation [271-06-0539]
- Canadian Chair in diabetes and metabolism
- Fonds de la recherche en sante du Quebec
- Montreal General Hospital Foundation
- MRC [G0801056, G0600331] Funding Source: UKRI
- Medical Research Council [G0801056B, G0600331, G0801056] Funding Source: researchfish
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Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 x 10(-12), OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.
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