likely to be missed. This can be circumvented by analytic methods such as studying the global effect of trans-variants using proportion of true positives (π1) as presented here. By applying this approach and with thorough replication we found evidence of multiple trans-variants acting as multi-gene regulators predominantly in a tissue-dependent manner similar to our previously reported example of the KLF14 locus in adipose tissue 29. For instance, the rs7595947 SNP on chromosome 2 was associated with 27 transcripts in the MuTHER adipose samples and successfully replicated in independent cohorts. In skin, the rs1215608 trans-SNP located within the NUAK1 gene, defined as a multi-gene regulator and associated with three genes (FMO6P, PPM1F, LECT1) in the MuTHER discovery sample, was successfully replicated in the fibroblast cohort. Interestingly, the rs1215608 SNP is also a cis-acting SNP regulating NUAK expression. NUAK1 was recently identified as a key player for cellular senescence and cellular ploidy, mechanisms known to be important in aging30. These examples underscore the potential of utilizing the full transcriptomic architecture to understand biology. However, as demonstrated here by the relative low replication rate the dissection of trans effects and their characteristics such as tissue-dependent are indeed challenging as they are highly complex
