Abundant Parent-of-origin Effect eQTL in Humans: The Framingham Heart Study

Abstract Parent-of-origin effect (POE) is a phenomenon whereby an allele’s effect on a phenotype depends both on its allelic identity and parent from whom the allele is inherited, as exemplified by the polar overdominance in the ovine callypyge locus and the human obesity DLK1 locus. Systematic studies of POE of expression quantitative trait loci (eQTL) are lacking. In this study we use trios among participants in the Framingham Heart Study to examine to what extend POE exists for gene expression of whole blood using whole genome sequencing and RNA sequencing. For each gene and the SNPs in cis, we performed eQTL analysis using genotype, paternal, maternal, and joint models, where the genotype model enforces the identical effect sizes on paternal and maternal alleles, and the joint model allows them to have different effect sizes. We compared models using Bayes factors to identify paternal, maternal, and opposing eQTL, where paternal and maternal effects have opposite directions. The resultant variants are collectively called POE eQTL. The highlights of our study include: 1) There are more than 2, 000 genes harbor POE eQTL and majority POE eQTL are not in the vicinity of known imprinted genes; 2) Among 180 genes harboring opposing eQTL, 99 harbor exclusively opposing eQTL, and 58 of the 99 are phosphoprotein coding genes, reflecting significant enrichment; 3) Paternal eQTL are enriched with GWAS hits, and genes harboring paternal eQTL are enriched with drug targets. Our study demonstrates the abundance of POE in gene expression, illustrates the complexity of gene expression regulation, and provides a resource that is complementary to existing resources such as GTEx. We revisited two previous POE findings in light of our POE results. A SNP residing in KCNQ1 that is maternally associated with diabetes is a maternal eQTL of CDKN1C , not KCNQ1 . A SNP residing in DLK1 that showed paternal polar overdominance for human obesity is a maternal eQTL of MEG3 , offering an explanation for the baseline risk of homozygous samples through association between MEG3 expression and obesity. Finally, we advised caution on conducting Mendelian randomization using gene expression as the exposure.