Transcript-aware analysis of rare predicted loss-of-function variants in the UK Biobank elucidate new isoform-trait associations.

A single gene can produce multiple transcripts with distinct molecular functions. Rare-variant association tests often aggregate all coding variants across individual genes, without accounting for the variants' presence or consequence in resulting transcript isoforms. To evaluate the utility of transcript-aware variant sets, rare predicted loss-of-function (pLOF) variants were aggregated for 17,035 protein-coding genes using 55,558 distinct transcript-specific variant sets. These sets were tested for their association with 728 circulating proteins and 188 quantitative phenotypes across 406,921 individuals in the UK Biobank. The transcript-specific approach resulted in larger estimated effects of pLOF variants decreasing serum cis-protein levels compared to the gene-based approach (pbinom ≤ 2x10-16). Additionally, 251 quantitative trait associations were identified as being significant using the transcript-specific approach but not the gene-based approach, including PCSK5 transcript ENST00000376752 and standing height (transcript-specific statistic, P = 1.3x10-16, effect = 0.7 SD decrease; gene-based statistic, P = 0.02, effect = 0.05 SD decrease) and LDLR transcript ENST00000252444 and apolipoprotein B (transcript-specific statistic, P = 5.7x10-20, effect = 1.0 SD increase; gene-based statistic, P = 3.0x10-4, effect = 0.2 SD increase). This approach demonstrates the importance of considering the effect of pLOFs on specific transcript isoforms when performing rare-variant association studies.

Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity.

Identifying genetic variants associated with lower waist-to-hip ratio can reveal new therapeutic targets for abdominal obesity. We use exome sequences from 362,679 individuals to identify genes associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI), a surrogate for abdominal fat that is causally linked to type 2 diabetes and coronary heart disease. Predicted loss of function (pLOF) variants in INHBE associate with lower WHRadjBMI and this association replicates in data from AMP-T2D-GENES. INHBE encodes a secreted protein, the hepatokine activin E. In vitro characterization of the most common INHBE pLOF variant in our study, indicates an in-frame deletion resulting in a 90% reduction in secreted protein levels. We detect associations with lower WHRadjBMI for variants in ACVR1C, encoding an activin receptor, further highlighting the involvement of activins in regulating fat distribution. These findings highlight activin E as a potential therapeutic target for abdominal obesity, a phenotype linked to cardiometabolic disease.