Across all known risk loci in our data, 77% of genome-wide significant loci (defined as lead SNP +/−500kb) overlapped at least one gene with significant hg,cis2, and 36% overlapped at least one significant TWAS association (Supplementary Table 6). These results suggest that cis regulation of expression in blood and adipose tissue is an important mechanism through which genetic variation at known risk loci alters obesity related traits. We expect that expression studies from other tissues relevant to obesity-related traits will further increase the overlap. Focusing specifically on the 282 TWAS genes that were within 500kb of the lead SNP, 187 (66%) are not the nearest gene with many residing more than 100kb away from the lead GWAS SNP (Supplementary Figure 15). Since GWAS usually reports the nearest gene, these 187 genes can be considered new candidates for follow-up at known risk loci. We note that gene-trait associations at known risk loci will not be found by TWAS either due to a causal mechanism that does not involve cis-expression of the tested genes, or lack of power to identify and detect all cis-heritable genes at the locus.
