GWAS of DNA Methylation Variation Within Imprinting Control Regions Suggests Parent-of-Origin Association

Abstract

Imprinting control regions (ICRs) play a fundamental role in establishing and maintaining the non-random monoallelic expression of certain genes, via common regulatory elements such as non-coding RNAs and differentially methylated regions (DMRs) of DNA. We recently surveyed DNA methylation levels within four ICRs (H19-ICR, IGF2-DMR, KvDMR, and NESPAS-ICR) in whole-blood genomic DNA from 128 monozygotic (MZ) and 128 dizygotic (DZ) human twin pairs. Our analyses revealed high individual variation and intradomain covariation in methylation levels across CpGs and emphasized the interaction between epigenetic variation and the underlying genetic sequence in a parent-of-origin fashion. Here, we extend our analysis to conduct two genome-wide screenings of single nucleotide polymorphisms (SNPs) underlying either intra-domain covariation or parent-of-origin-dependent association with methylation status at individual CpG sites located within ICRs. Although genome-wide significance was not surpassed due to sample size limitations, the most significantly associated SNPs found through multiple-trait genome-wide association (MQFAM) included the previously described rs10732516, which is located in the vicinity of the H19-ICR. Similarly, we identified an association between rs965808 and methylation status within the NESPAS-ICR. This SNP is positioned within an intronic region of the overlapping genes GNAS and GNAS-AS1, which are imprinted genes regulated by the NESPAS-ICR. Sixteen other SNPs located in regions apart from the analyzed regions displayed suggestive association with intra-domain methylation. Additionally, we identified 13 SNPs displaying parent-of-origin association with individual methylation sites through familybased association testing. In this exploratory study, we show the value and feasibility of using alternative GWAS approaches in the study of the interaction between epigenetic state and genetic sequence within imprinting regulatory domains. Despite the relatively small sample size, we identified a number of SNPs displaying suggestive association either in a domain-wide or in a parent-of-origin fashion. Nevertheless, these associations will require future experimental validation or replication in larger and independent samples.

rs10732516 polymorphism at the IGF2/H19 locus associates with a genotype-specific trend in placental DNA methylation and head circumference of prenatally alcohol-exposed newborns

“…In this study we detected a single nucleotide polymorphism rs10732516 G/A in the sixth-binding sequence of CTCF (CTCF6), which associated with the DNA methylation level of H19 ICR in placenta. Our finding was consistent with earlier studies, where whole blood samples were used (Coolen et al , 2011; Renteria et al , 2013) and encouraged us to explore the effects of alcohol exposure in a genotype-specific manner. Altered DNA methylation level at the CTCF6 showed an association with changes in IGF2 and H19 expression in a previous human study (Takai et al , 2001).…”

Integrative analysis of genome‐wide DNA methylation and gene expression profiles reveals important epigenetic genes related to milk production traits in dairy cattle

“…It has been reported that allele‐specific methylation was strongly correlated with the genotypes at the sites (Zhang et al., 2009). Additionally, some studies have shown that epigenetic states interact with genetic sequences and suggested that SNPs within or outside some genes or regions are associated with the methylation states of these genes or regions (Murrell et al., 2004; Renteria et al., 2013). In these three genes, some DMSs are also SNPs and are close to GWAS SNPs.…”

Whole exome sequencing in thrombophilic pedigrees to identify genetic risk factors for venous thromboembolism

“…Variants located within the nearest upstream or the nearest downstream genes of the following candidate genes, PLEKHH2 , LRPPRC , and SRBD2 , all located in the 2p21 locus, have also been reported as associated with various phenotypes according to the GWAS catalog database. Variants in THADA have been associated with age-related hearing impairment[ 44 ], Crohn's disease[ 45 ], DNA methylation variation[ 46 ], hair morphology[ 47 ], inflammatory bowel disease[ 48 ], mitochondrial DNA levels[ 49 ], orofacial clefts[ 50 , 51 ], platelet counts[ 52 ], polycystic ovary syndrome[ 53 , 54 ], prostate cancer[ 55 ], response to amphetamines[ 56 ], and type 2 diabetes[ 57 ]. Variants in ABCG8 have been associated with LDL cholesterol[ 58 – 63 ], total cholesterol[ 58 – 60 ], campesterol levels[ 64 ], and gallstones[ 65 ].…”