title: 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 intra-domain 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 family-based 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.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Queensland, Australia. Miguel.Renteria@qimr.edu.au
authors.forename: Miguel E
authors.initials: ME
authors.lastname: Rentería
authors.forename: Marcel W
authors.initials: MW
authors.lastname: Coolen
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Statham
authors.forename: R Seong Min
authors.initials: RS
authors.lastname: Choi
authors.forename: Wenjia
authors.initials: W
authors.lastname: Qu
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Campbell
authors.forename: Sara
authors.initials: S
authors.lastname: Smith
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Clark
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002874:Chromosome Mapping; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008297:Male; D010290:Parents; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D040641:Quantitative Trait Loci; D062085:RNA, Long Noncoding / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D014427:Twins / Q000235:genetics*; D055815:Young Adult
chemical_list: C094335:H19 long non-coding RNA; C035170:IGF2 protein, human; C485621:KCNQ1OT1 long non-coding RNA, human; D024642:Potassium Channels, Voltage-Gated; D062085:RNA, Long Noncoding; D007335:Insulin-Like Growth Factor II; D019205:GTP-Binding Protein alpha Subunits, Gs