Genes Correlated with Gonadal Fat Mass Illustrate Tissue-Specific Regulation of the Trait
In an effort to identify genes associated with the fat mass trait, but not necessarily candidate genes underlying the trait cQTLs, we fitted linear models to assess the degree of association between transcripts and gonadal fat mass. As with QTLs, sex-specific correlations were modeled. At an FDR of 1%, 4,613 genes were found to be significantly correlated with gonadal fat mass, of which 4,254 (98%) showed sex-biased correlation. As indicated in Tables 4 and 5, several genes with detectable cis-eQTLs are also significantly correlated with the trait and are even further prioritized as candidate genes.
Thus far, studies that have examined the “genetics of gene expression” are in good agreement regarding the increased power to detect cis-eQTLs relative to trans [5,9,15,16,31]. It is unclear at this time, however, what exactly is the significance of trans-eQTLs and the nature of the underlying polymorphisms associated with them. Furthermore, the eQTL hotspots reported in this and previous studies [5,9,10] largely represent trans-eQTLs. This localization suggests some functional significance to these regions. Of the 4,613 genes correlated with gonadal fat mass, 1,130 generate 1,478 significant eQTLs, of which 1,023 (69%) are trans-acting. These eQTLs are significantly enriched at one locus (Chromosome 19). Interestingly, this hotspot was coincident with a cQTL associated with fat mass reported in this study. Since these transcripts represent those significantly correlated with gonadal fat mass, the localization of their eQTLs to these regions strongly supports the notion that the genes with trans-eQTLs represent downstream targets of candidate regulatory genes located at the position of significant linkage. This means that the genes may be causal but downstream of the gene responsible for the cQTLs, or they may be reacting to the increased gonadal fat mass and associated metabolic changes. These data also suggest that identifying such loci that show overrepresentation of highly correlated genes is a means to identify which of the trait cQTLs are more likely controlled by the tissue arrayed. As expected, the Chromosome 19 locus was enriched for trans-eQTLs with substantially greater effects in females. Functional and promoter analysis of genes with a common trans-eQTL may prove enlightening. Furthermore, gene expression network construction and analysis may be improved by the incorporation of experimentally demonstrated cis versus trans regulation.