Abstract
Parent-of-origin (PofO) effects, such as imprinting are a phenomenon in which homologous chromosomes exhibit differential gene expression and epigenetic modifications according to their parental origin. Such non-Mendelian inheritance patterns are generally ignored by conventional association studies, as these tests consider the maternal and paternal alleles as equivalent. To identify regulatory regions that show PofO effects on gene expression (imprinted expression Quantitative Trait Loci, ieQTLs), here we have developed a novel method in which we associate SNP genotypes of defined parental origin with gene expression levels. We applied this method to study 59 HapMap phase II parent-offspring trios. By analyzing mother/father/child trios, rules of Mendelian inheritance allowed the parental origin to be defined for ∼95% of SNPs in each child. We used 680,475 informative SNPs and corresponding expression data for 92,167 probe sets from Affymetrix GeneChip Human Exon 1.0 ST arrays and performed four independent cis-association analyses with the expression level of RefSeq genes within 1 Mb using PLINK. Independent analyses of maternal and paternal genotypes identified two significant cis-ieQTLs (p<10−7) at which expression of genes SFT2D2 and SRRT associated exclusively with maternally inherited SNPs rs3753292 and rs6945374, respectively. 28 additional suggestive cis-associations with only maternal or paternal SNPs were found at a lower stringency threshold of p<10−6, including associations with two known imprinted genes PEG10 and TRAPPC9, demonstrating the efficacy of our method. Furthermore, comparison of our method that utilizes independent analyses of maternal and paternal genotypes with the Likelihood Ratio Test (LRT) showed it to be more effective for detecting imprinting effects than the LRT. Our method represents a novel approach that can identify imprinted regulatory elements that control gene expression, suggesting novel PofO effects in the human genome.
Highlights
Genomic imprinting is an epigenetic mechanism that modifies the expression of genes dependent on their parental origin
We identified 30 putative cis-imprinted eQTLs (ieQTLs), with 2 SNPs showing significant associations with probe sets of the genes SRRT and SFT2D2, and 28 loci with suggestive associations (Table S1)
We have developed a novel method that allows the genomewide identification of ieQTLs that show regulatory effects on gene expression in a PofO specific manner
Summary
Genomic imprinting is an epigenetic mechanism that modifies the expression of genes dependent on their parental origin. To date ,60 imprinted genes have been identified in human (http:// www.geneimprint.com/), while some studies in mice have suggested that as many as 3% of genes show evidence of imprinting [1]. Recent studies have yielded robust evidence that imprinting effects may be pervasive in common disease. Icelanders identified a number of alleles within known imprinted loci that showed significant PofO effects influencing the risk of breast cancer, basal-cell carcinoma and type 2 diabetes [13]. A similar analysis of .7,500 type 1 diabetes cases identified a risk allele within the imprinted region on chromosome 14q32.2 that showed reduced paternal transmission, suggesting a parent or origin influence on disease risk [14]. Recently an expression quantitative trait locus (eQTL) of the maternally expressed transcription factor KLF14 was found to act as a master trans-regulator of adipose gene expression, influencing multiple metabolic phenotypes [15]
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