Given the large number of trans-eQTLs detected in testis, we investigated their possible regulatory mechanisms in more detail. Piwi-interacting RNAs (piRNAs) are small 24–31-bp RNAs that bind to piwi-class proteins and silence mobile elements by RNA degradation and DNA methylation. PiRNAs are strongly expressed in testis and may regulate gene expression and play a role in protection against transposable elements in germ line cells32. We tested for enrichment of trans-eVariants in piRNA clusters identified in testis33. We found that 38.6% of testis trans-eVariants, corresponding to 12 independent loci (R2 ≤ 0.2), directly overlapped piRNA clusters, a significant enrichment compared to the 2.5% of the genome covered by these regions (permutation test, P ≤ 1.0 × 10−4). In aggregate, eVariants from all tissues were enriched in piRNA clusters (permutation test, P ≤1.0×10−4), but this appeared to be almost entirely driven by testis eQTLs (Fig. 4c). This suggests a testis-specific functional effect of genetic variation in piRNA clusters, consistent with their biological role.
