A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes
Open accessAbstract
The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l(-1), P = 2.5 × 10(-35)) and serum insulin (β = 165 pmol l(-1), P = 1.5 × 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = -0.18 mmol l(-1), P = 1.1 × 10(-6)) and fasting serum insulin (β = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l(-1), P = 5.3 × 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.
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Founder populations such as those from Finland and Iceland have provided multiple examples of otherwise rare risk alleles driven to higher frequency locally through drift and/or selection.
“Founder populations (such as those from Finland and Iceland) have provided multiple examples of otherwise rare risk alleles driven to higher frequency locally through drift and/or selection49–52.”
From A brief history of human disease genetics (2020) · cites this paper as [50]
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- Authors
- Moltke, I., Grarup, N., Jørgensen, M. E., Bjerregaard, P., Treebak, J. T., Fumagalli, M., Korneliussen, T. S., Andersen, M. A., Nielsen, T. S., Krarup, N. T., Gjesing, A. P., Zierath, J. R., Linneberg, A., Wu, X., Sun, G., Jin, X., Al-Aama, J., Wang, J., Borch-Johnsen, K., Pedersen, O., Nielsen, R., Albrechtsen, A., & Hansen, T.
- Affiliations
- University of Copenhagen (DK)
- University of Southern Denmark (DK)
- University of California, Berkeley (US)
- Glostrup Hospital (DK)
- BGI Group (China) (CN)
- Macau University of Science and Technology (MO)
- Corresponding author
- Albrechtsen, Anders
- Hansen, Torben
- ORCID
- Moltke, Ida
- Grarup, Niels
- Jørgensen, Marit E.
- Bjerregaard, Peter
- Treebak, Jonas T.
- Fumagalli, Matteo
- Korneliussen, Thorfinn S.
- Andersen, Marianne A.
- Nielsen, Thomas S.
- Krarup, Nikolaj T.
- Gjesing, Anette P.
- Zierath, Juleen R.
- Linneberg, Allan
- Jin, Xin
- Al-Aama, Jumana
- Wang, Jun
- Pedersen, Oluf
- Nielsen, Rasmus
- Albrechtsen, Anders
- Hansen, Torben
- Venue
- Nature
- Published
- 2014-06-18
- Volume
- 512
- Issue
- 7513
- Pages
- 190-193
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1991241396
- Cited by
- 418
- References
- 29
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 38 · 2023: 32 · 2022: 30 · 2021: 38 · 2020: 29 · 2019: 41 · 2018: 43 · 2017: 36 · 2016: 48 · 2015: 27 · 2014: 7
- FWCI
- 25.77
- Type
- journal article
- Language
- en
- Open access
- green
- escholarship.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Villum Fonden (00007171)
- Novo Nordisk Fonden
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- TBC1D4, type 2 diabetes, muscle insulin resistance, nonsense mutation, founder populations, plasma glucose, serum insulin, oral glucose tolerance, genetic association, insulin signaling
- MeSH terms
- Adult, Blood Glucose, Diabetes Mellitus, Type 2, Gene Frequency, Genotype, Greenland, Humans, Insulin, Insulin Resistance, Middle Aged, Genetic Variation, Codon, Nonsense, Muscle, Skeletal, GTPase-Activating Proteins, Genome-Wide Association Study
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