Multi‐tissue transcriptome‐wide association study reveals susceptibility genes and drug targets for insulin resistance‐relevant phenotypes

Abstract Aim Genome‐wide association studies ( GWAS ) have identified multiple susceptibility loci associated with insulin resistance ( IR )‐relevant phenotypes. However, the genes responsible for these associations remain largely unknown. We aim to identify susceptibility genes for IR ‐relevant phenotypes via a transcriptome‐wide association study. Materials and Methods We conducted a large‐scale multi‐tissue transcriptome‐wide association study for IR (Insulin Sensitivity Index, homeostasis model assessment‐IR, fasting insulin) and lipid‐relevant traits (high‐density lipoprotein cholesterol, triglycerides, low‐density lipoprotein cholesterol and total cholesterol) using the largest GWAS summary statistics and precomputed gene expression weights of 49 human tissues. Conditional and joint analyses were implemented to identify significantly independent genes. Furthermore, we estimated the causal effects of independent genes by Mendelian randomization causal inference analysis. Results We identified 1190 susceptibility genes causally associated with IR‐relevant phenotypes, including 58 genes that were not implicated in the original GWAS. Among them, 11 genes were further supported in differential expression analyses or a gene knockout mice database, such as KRIT1 showed both significantly differential expression and IR‐related phenotypic effects in knockout mice. Meanwhile, seven proteins encoded by susceptibility genes were targeted by clinically approved drugs, and three of these genes ( H6PD , CACNB2 and DRD2 ) have been served as drug targets for IR‐related diseases/traits. Moreover, drug repurposing analysis identified four compounds with profiles opposing the expression of genes associated with IR risk. Conclusions Our study provided new insights into IR aetiology and avenues for therapeutic development.