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

Niels Grarup; Ida Moltke; Mette K Andersen; Maria Dalby; Kristoffer Vitting-Seerup; Timo Kern; Yuvaraj Mahendran; Emil Jørsboe; Christina V L Larsen; Inger K Dahl-Petersen; Arthur Gilly; Daniel Suveges; George Dedoussis; Eleftheria Zeggini; Oluf Pedersen; Robin Andersson; Peter Bjerregaard; Marit E Jørgensen; Anders Albrechtsen; Torben Hansen

doi:10.1038/s41588-017-0022-7

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

Nat Genet. 2018 Feb;50(2):172-174. doi: 10.1038/s41588-017-0022-7. Epub 2018 Jan 8.

Authors

Niels Grarup¹, Ida Moltke², Mette K Andersen¹, Maria Dalby², Kristoffer Vitting-Seerup^{2

3}, Timo Kern¹, Yuvaraj Mahendran¹, Emil Jørsboe², Christina V L Larsen^{4

5}, Inger K Dahl-Petersen⁴, Arthur Gilly⁶, Daniel Suveges⁶, George Dedoussis⁷, Eleftheria Zeggini⁶, Oluf Pedersen¹, Robin Andersson², Peter Bjerregaard^{4

5}, Marit E Jørgensen^{8

9

10}, Anders Albrechtsen¹¹, Torben Hansen^{12

13}

Affiliations

¹ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
² Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
³ Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
⁴ National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
⁵ Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland.
⁶ Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
⁷ Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece.
⁸ National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark. [email protected].
⁹ Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland. [email protected].
¹⁰ Steno Diabetes Center Copenhagen, Gentofte, Denmark. [email protected].
¹¹ Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark. [email protected].
¹² Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [email protected].
¹³ Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenylyl Cyclases / genetics*
Adult
Aged
Aged, 80 and over
Case-Control Studies
Cohort Studies
Diabetes Mellitus, Type 2 / complications
Diabetes Mellitus, Type 2 / epidemiology
Diabetes Mellitus, Type 2 / genetics*
Female
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Greenland / epidemiology
Humans
Inuit / genetics
Inuit / statistics & numerical data
Loss of Function Mutation*
Male
Middle Aged
Obesity / complications
Obesity / epidemiology
Obesity / genetics*
Risk Factors
Young Adult

Substances

Adenylyl Cyclases
adenylate cyclase 3

Grants and funding

638273/ERC_/European Research Council/International