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.

Niels Grarup ¹, Ida Moltke ², Mette K Andersen ¹, Maria Dalby ², Kristoffer Vitting-Seerup ² ³, Timo Kern ¹, Yuvaraj Mahendran ¹, Emil Jørsboe ², Christina V L Larsen ⁴ ⁵, Inger K Dahl-Petersen ⁴, Arthur Gilly ⁶, Daniel Suveges ⁶, George Dedoussis ⁷, Eleftheria Zeggini ⁶, Oluf Pedersen ¹, Robin Andersson ², Peter Bjerregaard ⁴ ⁵, Marit E Jørgensen ⁸ ⁹ ¹⁰, Anders Albrechtsen ¹¹, 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].

PMID: 29311636 DOI: 10.1038/s41588-017-0022-7

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.

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