Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia
Abstract
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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The failure to identify a qualitative or monogenic inheritance pattern and the findings from GWAS, Mendelian randomization, familial and twin studies suggest that the heritability of PCOS is likely due to the combination of multiple genes with small effect size.
“The failure to identify a qualitative or monogenic inheritance pattern and the findings from GWAS, MR, familial and twin studies, suggests that the heritability of PCOS is likely to be due to the combination of multiple genes with small effect size, as has been found with obesity and type 2 diabetes [79,80,94,95,96].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [94]
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Self-citation
- Authors
- Rung, J., Cauchi, S., Albrechtsen, A., Shen, L., Rocheleau, G., Cavalcanti-Proença, C., Bacot, F., Balkau, B., Belisle, A., Borch-Johnsen, K., Charpentier, G., Dina, C., Durand, E., Elliott, P., Hadjadj, S., Järvelin, M.-R., Laitinen, J., Lauritzen, T., Marre, M., Mazur, A., Meyre, D., Montpetit, A., Pisinger, C., Posner, B., Poulsen, P., Pouta, A., Prentki, M., Ribel-Madsen, R., Ruokonen, A., Sandbaek, A., Serre, D., Tichet, J., Vaxillaire, M., Wojtaszewski, J. F. P., Vaag, A., Hansen, T., Polychronakos, C., Pedersen, O., Froguel, P., & Sladek, R.
- Affiliations
- McGill University and Génome Québec Innovation Centre (CA)
- Centre National de la Recherche Scientifique (FR)
- University of Copenhagen (DK)
- Université Paris-Sud (FR)
- Centre Hospitalier Sud Francilien (FR)
- Imperial College London (GB)
- Inserm (FR)
- Finnish Institute of Occupational Health (FI)
- Aarhus University (DK)
- Glostrup Hospital (DK)
- McGill University (CA)
- Centre Hospitalier de l’Université de Montréal (CA)
- University of Oulu (FI)
- Lund University (SE)
- University of Southern Denmark (DK)
- Corresponding author
- Pedersen, Oluf
- Froguel, Philippe
- Sladek, Robert
- ORCID
- Rung, Johan
- Cauchi, Stéphane
- Albrechtsen, Anders
- Rocheleau, Ghislain
- Balkau, Beverley
- Charpentier, Guillaume
- Durand, Emmanuelle
- Elliott, Paul
- Hadjadj, Samy
- Järvelin, Marjo-Riitta
- Laitinen, Jaana
- Lauritzen, Torsten
- Marre, Michel
- Meyre, David
- Pisinger, Charlotta
- Prentki, Marc
- Serre, David
- Vaxillaire, Martine
- Wojtaszewski, Jørgen F P
- Vaag, Allan
- Hansen, Torben
- Polychronakos, Constantin
- Pedersen, Oluf
- Froguel, Philippe
- Sladek, Robert
- Venue
- Nature Genetics
- Published
- 2009-09-06
- Volume
- 41
- Issue
- 10
- Pages
- 1110-1115
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2044518560
- Cited by
- 479
- References
- 43
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 16 · 2023: 11 · 2022: 37 · 2021: 16 · 2020: 19 · 2019: 14 · 2018: 13 · 2017: 21 · 2016: 30 · 2015: 40 · 2014: 42 · 2013: 47 · 2012: 58
- FWCI
- 31.00
- Type
- journal article
- Language
- en
- Update notices
- erratum (2009-10-01)
- Open access
- closed
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type 2 diabetes, insulin resistance, hyperinsulinemia, IRS-1, genetic susceptibility, single nucleotide polymorphisms, insulin signaling, skeletal muscle, genetic susceptibility loci
- MeSH terms
- Adult, Alleles, Biopsy, Diabetes Mellitus, Type 2, Female, Humans, Hyperinsulinism, Insulin Resistance, Male, Middle Aged, Genome, Human, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Polymorphism, Single Nucleotide, White People, Genome-Wide Association Study, Insulin Receptor Substrate Proteins
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