Strikingly, many trans-SNPs at P< 5×10−8 are associated with multiple transcripts, suggesting their role as multi-gene regulators. In adipose tissue, 48 SNPs account for 169 (32%) of the trans-eQTLs and in LCL and skin tissue, 48 SNPs account for 121 (21%) and 44 SNPs for 164(27%) of the trans-eQTLs, respectively. These multi-gene regulators (defined here as trans-SNPs associated with at least two distinct transcripts at P< 5×10−8) consistently show enrichment for additional trans associations with low P-values beneath the 5×10−8 threshold (Fig.3A), indicating that trans-SNPs may regulate additional genes below our P-value threshold. In contrast, the P-value distribution across all measured transcripts in the other two tissues approximates the null (Fig.3). To quantify the genome-wide effect of these trans-SNPs we again used π1 for the estimation of the proportion of true positives in the distribution of P-values from each trans-SNP vs. all transcripts and compared it with similar calculations for trans-SNPs associated with only one transcript at P< 5×10−8 (i.e. single-gene regulators). We find that the multi-gene regulators are enriched for greater number of true positives compared to single-gene regulators
