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.