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

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.

Figure 1. ADCY3 isoforms, observed loss-of-function variants and functional consequences based on RNA sequencing of leukocytes from 17 Greenlandic individuals.

a. Schematic representation of ADCY3 displaying the three relevant transcript isoforms and their predicted functional consequences annotated to the left (“Coding” or “nonsense mediated decay (NMD) sensitive”). The exons that correspond to the protein domain, Guanylate cyclase, are shown as gray filled boxes, while the rest of the exons are shown as black filled boxes. The red square encapsulates the exons affected by the Greenlandic ADCY3 c.2433-1G>A variant. The locations of the identified loss-of-function variants in ADCY3 in the Greenlandic and trans-ancestry cohorts are shown with arrows in red and black, respectively. Variants were annotated to canonical transcript ADCY3-201 (NM_004036) except c.1072-1G>A, which is annotated to alternative transcript ADCY3-202 (NM_001320613). b. ADCY3 Transcripts Per Million (TPM) normalized gene expression, stratified according to ADCY3 c.2433-1G>A variant genotype groups (WT, wild type; HE, heterozygous; and HO, homozygous). c. ADCY3 transcript isoform fractions for the three quantified isoforms, the canonical isoform, the novel exon skipping and intron retention splice version stratified according to ADCY3 c.2433-1G>A variant genotype groups. Number of individuals in each group in b and c are: WT: 7 GG carriers, HE: 6 GA carriers, and HO: 4 AA carriers. The lower and upper hinges of boxes in b and c correspond to the first and third quartiles of data, respectively, while the middle line is the median and the whiskers extends to the largest and smallest data points no further away than 1.5 times the interquartile range.