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.
We gratefully acknowledge the participants in the Greenlandic health surveys. We thank J. Flannick (Broad Institute) for help with obtaining the AMP-T2D exome sequencing data. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk). This project was also funded by the Danish Council for Independent Research (Sapere Aude DFF-Ung Eliteforsker grant 11-120909 from FSS to I.M.; DFF-4090-00244 from FNU to I.M.; Sapere Aude DFF-Forskningsleder 6108-00038B from FNU to R.A.; DFF-4181-00383 to A.A.), the Steno Diabetes Center Copenhagen (http://www.steno.dk), Simon Fougner Hartmanns Familiefond to N.G., the Lundbeck Foundation (R215-2015-4174) to A.A., the Novo Nordisk Foundation (NNF15OC0017918 to N.G.; NNF16OC0019986 to N.G.; NNFCC0018486 to T.H.) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement 638173) to R.A. The Greenlandic health surveys (IHIT and B99) were supported by Karen Elise Jensen’s Foundation, the Department of Health in Greenland, NunaFonden, the Medical Research Council of Denmark, the Medical Research Council of Greenland and the Commission for Scientific Research in Greenland.