Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes.
Grarup N., Moltke I., Andersen MK., Dalby M., Vitting-Seerup K., Kern T., Mahendran Y., Jørsboe E., Larsen CVL., Dahl-Petersen IK., Gilly A., Suveges D., Dedoussis G., Zeggini E., Pedersen O., Andersson R., Bjerregaard P., Jørgensen ME., Albrechtsen A., Hansen T.
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.