In a second example, two muscle-specific trans-eVariants at the 5q31 locus (rs2706381 and rs1012793; R2 = 0.84) were associated in trans with PSME1 (P ≤1.1×10−11) and PARP10 (P ≤7.8×10−10), and in cis with IRF1 (P ≤2.0×10−10; Fig. 6c), a transcription factor that facilitates regulation of the interferon-induced immune response51,52. Both variants are associated with circulating fibrinogen levels53 and influence muscle injury, Duchenne muscular dystrophy (DMD), multiple sclerosis and rheumatoid arthritis54,55, and have been shown to drive fibrosis in DMD, where they promote expression of IL1B and TGFB156. These variants were moderately associated with numerous genes in skeletal muscle (50 trans-eGenes at 20% FDR, assessed only among the three variants; Extended Data Fig. 17a). Additional candidate target genes (at 20% FDR) were enriched in multiple immune pathways from MsigDB57 (Extended Data Fig. 17b). Mendelian randomization analysis supported the idea that IRF1 regulates PSME1 (P ≤3.1×10−8) and PARP10 (P ≤1.9×10−7) through cis-eVariant rs2706381 with a consistent direction of effect (Fig. 6c). Moreover, the cis-eQTL signal for IRF1 co-localized with the trans-eQTL signals for both trans-eGenes (Fig. 6d; posterior probability >0.99)43. Together, these
