Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes
Open accessAbstract
We have identified a variant in ADCY3 (encoding adenylate cyclase 3) associated with markedly increased risk of obesity and type 2 diabetes in the Greenlandic population. The variant disrupts a splice acceptor site, and carriers have decreased ADCY3 RNA expression. Additionally, we observe an enrichment of rare ADCY3 loss-of-function variants among individuals with type 2 diabetes in trans-ancestry cohorts. These findings provide new information on disease etiology relevant for future treatment strategies.
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These developments have enabled researchers to bridge the gap between monogenic and polygenic realms, identifying common variant modifiers of monogenic phenotypes and low-frequency and rare variants influencing common multifactorial traits.
“These developments have enabled researchers to bridge the gap between the monogenic and polygenic realms, identifying common variant modifiers of monogenic phenotypes contributing to the variable expression of rare, large-effect alleles26,93, and low-frequency and rare variants that influence common multifactorial traits94,95.”
From A brief history of human disease genetics (2020) · cites this paper as [94]
ADCY3 variants are linked to increased type 2 diabetes, BMI, fat percentage, fasting plasma glucose, and acute plasma glucose in a Greenlandic cohort.
“Variants of the ADCY3 gene have been linked to increased body mass index (BMI, corrected for height) in children (157); increased type 2 diabetes, BMI, fat percentage, fasting plasma glucose, and acute plasma glucose in a Greenlandic cohort (158); and increased BMI in obese adult subjects (159).”
From Physiological roles of mammalian transmembrane adenylyl cyclase isoforms (2022) · cites this paper as [158]
Human genetic data, animal models, and AC3 location provide compelling evidence for AC3 as a unique therapeutic target for obesity disorders.
“The human genetic data, coupled with the animal models and AC3 location, provide compelling evidence for AC3 as a unique therapeutic target for obesity disorders.”
From Physiological roles of mammalian transmembrane adenylyl cyclase isoforms (2022) · cites this paper as [158]
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- Authors
- Grarup, N., Moltke, I., Andersen, M. K., Dalby, M., Vitting-Seerup, K., Kern, T., Mahendran, Y., Jørsboe, E., Larsen, C. V. L., Dahl-Petersen, I. K., Gilly, A., Suveges, D., Dedoussis, G., Zeggini, E., Pedersen, O., Andersson, R., Bjerregaard, P., Jørgensen, M. E., Albrechtsen, A., & Hansen, T.
- Affiliations
- University of Copenhagen (DK)
- Ilisimatusarfik (GL)
- Wellcome Sanger Institute (GB)
- Harokopio University of Athens (GR)
- Corresponding author
- Jørgensen, Marit E.
- Albrechtsen, Anders
- Hansen, Torben
- ORCID
- Venue
- Nature Genetics
- Published
- 2018-01-08
- Volume
- 50
- Issue
- 2
- Pages
- 172-174
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5828106
- OpenAlex
- W2781623981
- Cited by
- 216
- References
- 43
- Citations by year
- 2026: 18 · 2025: 20 · 2024: 28 · 2023: 24 · 2022: 18 · 2021: 31 · 2020: 46 · 2019: 12 · 2018: 19
- FWCI
- 16.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, other-oa)
- Funders
- Broad Institute
- Steno Diabetes Center Copenhagen (SDCC 3. B Epidemiology)
- European Commission (HORIZON2020)
- Lundbeckfonden (R215‐2015‐4174)
- Novo Nordisk (NNF16OC0019986)
- Danmarks Frie Forskningsfond (DFF-4090-00244, DFF-4181- 00383, 6108-00038B)
- Copenhagen Graduate School for Nanoscience and Nanotechnology
- Novo Nordisk Fonden (NNF16OC0019986, #NNF17OC0028136, NNF17SH0027192, NNF15SA0018486, NNFCC0018486, NNF15OC0017918)
- Simon Fougner Hartmanns Familiefond
- Novo Nordisk Foundation Center for Basic Metabolic Research
- H. Lundbeck A/S
- Medical Research Council
- Comisión de Investigaciones Científicas
- H2020 European Research Council (638173)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- ADCY3, loss-of-function mutations, obesity, type 2 diabetes, splice acceptor site, RNA expression, Greenlandic Inuit, rare variants, disease risk
- MeSH terms
- Loss of Function Mutation, Adenylyl Cyclases, Adult, Aged, Aged, 80 and over, Diabetes Mellitus, Type 2, Inuit, Female, Gene Frequency, Genotype, Greenland, Humans, Male, Middle Aged, Obesity, Risk Factors, Cohort Studies, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Young Adult
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