Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation.

Obesity is a major risk factor for cardiovascular disease, stroke, and type 2 diabetes (T2D). Excessive accumulation of fat in the abdomen further increases T2D risk. Abdominal obesity is measured by calculating the ratio of waist-to-hip circumference adjusted for the body-mass index (WHRadjBMI), a trait with a significant genetic inheritance. Genetic loci associated with WHRadjBMI identified in genome-wide association studies are predicted to act through adipose tissues, but many of the exact molecular mechanisms underlying fat distribution and its consequences for T2D risk are poorly understood. Further, mechanisms that uncouple the genetic inheritance of abdominal obesity from T2D risk have not yet been described. Here we utilize multi-omic data to predict mechanisms of action at loci associated with discordant effects on abdominal obesity and T2D risk. We find six genetic signals in five loci associated with protection from T2D but also with increased abdominal obesity. We predict the tissues of action at these discordant loci and the likely effector Genes (eGenes) at three discordant loci, from which we predict significant involvement of adipose biology. We then evaluate the relationship between adipose gene expression of eGenes with adipogenesis, obesity, and diabetic physiological phenotypes. By integrating these analyses with prior literature, we propose models that resolve the discordant associations at two of the five loci. While experimental validation is required to validate predictions, these hypotheses provide potential mechanisms underlying T2D risk stratification within abdominal obesity.

Genetic Regulation of SMC Gene Expression and Splicing Predict Causal CAD Genes.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of death worldwide. Recent meta-analyses of genome-wide association studies have identified over 175 loci associated with CAD. The majority of these loci are in noncoding regions and are predicted to regulate gene expression. Given that vascular smooth muscle cells (SMCs) play critical roles in the development and progression of CAD, we aimed to identify the subset of the CAD loci associated with the regulation of transcription in distinct SMC phenotypes. METHODS: We measured gene expression in SMCs isolated from the ascending aortas of 151 heart transplant donors of various genetic ancestries in quiescent or proliferative conditions and calculated the association of their expression and splicing with ~6.3 million imputed single-nucleotide polymorphism markers across the genome. RESULTS: We identified 4910 expression and 4412 splicing quantitative trait loci (sQTLs) representing regions of the genome associated with transcript abundance and splicing. A total of 3660 expression quantitative trait loci (eQTLs) had not been observed in the publicly available Genotype-Tissue Expression dataset. Further, 29 and 880 eQTLs were SMC-specific and sex-biased, respectively. We made these results available for public query on a user-friendly website. To identify the effector transcript(s) regulated by CAD loci, we used 4 distinct colocalization approaches. We identified 84 eQTL and 164 sQTL that colocalized with CAD loci, highlighting the importance of genetic regulation of mRNA splicing as a molecular mechanism for CAD genetic risk. Notably, 20% and 35% of the eQTLs were unique to quiescent or proliferative SMCs, respectively. One CAD locus colocalized with a sex-specific eQTL (TERF2IP), and another locus colocalized with SMC-specific eQTL (ALKBH8). The most significantly associated CAD locus, 9p21, was an sQTL for the long noncoding RNA CDKN2B-AS1, also known as ANRIL, in proliferative SMCs. CONCLUSIONS: Collectively, our results provide evidence for the molecular mechanisms of genetic susceptibility to CAD in distinct SMC phenotypes.