Adipogenic transcription factors are implicated in the regulation of sex-specific eQTLs. (A) We applied Fisher's exact test to evaluate the functions associated with transcription factors overlapping SNPs in sex-specific eQTLs. Adipogenesis was the functional annotation with the largest odds ratio, suggesting that factors regulating sex-specific eQTL genes are implicated in adipogenesis. Point sizes correspond to the number of genes in each annotation (> 10) and intensity corresponds to the FET false discovery rate (FDR < 0.001). (B–E) An illustrative case in which sex differences in the expression of a transcription factor that binds to a sex-specific eQTL SNP can explain the sex-specificity of the eQTL. (B) Data-driven model indicating that male-specific binding of the anti-adipogenic transcription factor EGR1 to the GG allele of an eQTL SNP augments the expression of the associated eQTL gene FLT3. (C) The EGR1 consensus motif corresponds to the reference allele G but not the alternate allele C at rs61944702 (see box). (D) FLT3 expression is associated with the genotype at rs61944702 in males, such that the homozygous reference genotype (GG) is associated with elevated expression as well as enhanced predicted binding of EGR1. (E) Elevated EGR1 expression in males (FDR = 0.02) is consistent with the sex-specificity of the eQTL observed for the rs61944702 SNP located within an EGR1 binding motif. (F) For an eQTL relating the genotype at rs28372757 with the expression of BRD4, the SNP at rs28372757 resides within a binding motif for the PPARG-RXRA dimer. Further, the SNP at rs28372757 resides within an open chromatin region in human pre-adipocytes, adipocytes and subcutaneous adipose tissue. The G allele is associated with enhanced predicted binding of the PPARG-RXRA dimer based on sequence conformity to the consensus motif. (G) The G allele is associated with elevated BRD4 expression in females and reduced BRD4 expression in males. (H) Examples of adipogenesis genes enriched in transcription factors (TFs) with binding motifs overlapping sex-specific eQTL SNPs or eSNPs. Also shown are adipogenesis genes enriched in sex-specific eQTL genes or eGenes that overlap with sex-by-genotype interaction genes identified in mouse.