Figure 3.

Study design to derive a list of high-confidence effector genes for the type 2 diabetes and osteoarthritis comorbidity

In each of the unique 18 genomic loci that colocalized between type 2 diabetes and osteoarthritis with a posterior probability of a single shared causal variant (PP4) ≥ 0.8, we explored all genes in a 1-Mb window on either side of the lead variants of the 95% credible set for the causal variant of the colocalization analysis. For each gene, we searched databases for knockout mice and rare and syndromic human diseases for pre-defined type 2 diabetes- and musculoskeletal-related phenotypes. We also examined differentially expressed genes (DEGs) in pancreatic islets of healthy versus diabetic individuals and of degraded versus intact osteoarthritis cartilage. We also assessed whether the genes were already previously defined as established effector genes for the individual diseases. We examined all variants in the 95% credible set for the causal variant of each colocalization locus for missense variants within genes located in the colocalized genomic loci. We performed regional multi-trait colocalization analyses between type 2 diabetes, each osteoarthritis phenotype, and molecular QTLs from disease-relevant tissues.