Dataset Information

Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes.

ABSTRACT: 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.

SUBMITTER: Grarup N

PROVIDER: S-EPMC5828106 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes.

Grarup Niels N Moltke Ida I Andersen Mette K MK Dalby Maria M Vitting-Seerup Kristoffer K Kern Timo T Mahendran Yuvaraj Y Jørsboe Emil E Larsen Christina V L CVL Dahl-Petersen Inger K IK Gilly Arthur A Suveges Daniel D Dedoussis George G Zeggini Eleftheria E Pedersen Oluf O Andersson Robin R Bjerregaard Peter P Jørgensen Marit E ME Albrechtsen Anders A Hansen Torben T

Nature genetics 20180108 2

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 ...[more]

PMID: 29311636

Similar Datasets

Project description:Genome-wide association (GWA) studies have identified hundreds of common genetic variants associated with obesity and type 2 diabetes. These studies have usually focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases.We performed a GWA study using a dominance deviation model for BMI, obesity (29,925 cases) and type 2 diabetes (4,040 cases) in 120,286 individuals of British ancestry from the UK Biobank study. We also investigated whether single nucleotide polymorphisms previously shown to be associated with these traits showed any enrichment for departures from additivity.Known obesity-associated variants in FTO showed strong evidence of deviation from additivity (p DOMDEV?=?3?×?10(-5)) through a recessive effect of the allele associated with higher BMI. The average BMI of individuals carrying zero, one or two BMI-raising alleles was 27.27?(95% CI 27.22, 27.31)?kg/m(2), 27.54?(95% CI 27.50, 27.58)?kg/m(2) and 28.07?(95% CI 28.00, 28.14)?kg/m(2), respectively. A similar effect was observed in 105,643 individuals from the GIANT Consortium (p DOMDEV?=?0.003; meta-analysis p DOMDEV?=?1?×?10(-7)). For type 2 diabetes, we detected a recessive effect (p DOMDEV?=?5?×?10(-4)) at CDKAL1. Relative to homozygous non-risk allele carriers, homozygous risk allele carriers had an OR of 1.48 (95% CI 1.32, 1.65), while the heterozygous group had an OR of 1.06 (95% CI 0.99, 1.14), a result consistent with that of a previous study. We did not identify any novel associations at genome-wide significance.Although we found no evidence of widespread non-additive genetic effects contributing to obesity and type 2 diabetes risk, we did find robust examples of recessive effects at the FTO and CDKAL1 loci.Summary statistics are available at www.t2diabetesgenes.org and by request (a.r.wood@exeter.ac.uk). All underlying data are available on application from the UK Biobank.

Project description:Prenatal exposure to famine and adulthood obesity have been independently related to the risk of type 2 diabetes; however, little is known about the joint effects of these risk factors at different stages of life on adulthood diabetes risk.The analysis included 88 830 participants of the China Kadoorie Biobank, who were born around the time of the Chinese Great Famine and without diabetes, cardiovascular diseases, or cancer at baseline. We defined famine exposure subgroups as nonexposed (born between 1 October 1962 and 30 September 964), fetal-exposed (born between 1 October 1959 and 30 September 1961) and early-childhood exposed (born between 1 October 1956 and 30 September 1958). General obesity was assessed by body mass index (BMI: overweight???24.0, obesity???28.0) and abdominal obesity assessed by waist-to-hip ratio (WHR, men/women: moderate???0.90/0.85, high???0.95/0.90).During a median 7.3 years (642 552 person-years) of follow-up, we identified 1372 incident cases of type 2 diabetes. Compared with nonexposed and early-childhood exposed participants combined as a single comparison group, fetal-exposed participants showed an increased risk of diabetes in adulthood [hazard ratio (HR)?=?1.25; 95% confidence interval (CI): 1.07-1.45]. The association between general obesity and diabetes was consistent across subgroups according to famine exposure (P for interaction?>?0.05). A stronger association between abdominal obesity and diabetes was observed in the fetal-exposed subgroup than in other subgroups (P for interaction?=?0.025 in the whole population). This interaction was more obvious in women (P?=?0.013) but not in men (P?=?0.699). Compared with normal-BMI and -WHR participants, those with both general (BMI???24.0) and abdominal (WHR???0.90/0.85) obesity in adulthood had 5.32 (95% CI: 3.81-7.43)-, 3.13 (2.48-3.94)- and 4.43 (3.45-5.68)-fold higher risks if these were carried during, before and after times of famine, respectively.Coexistence of prenatal experience of undernutrition and abdominal obesity in adulthood was associated with a higher risk of type 2 diabetes.

Dataset Information

Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes.

Publications

Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets