Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
23725790
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.
DATE PUBLISHED
2013 Aug
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2013/06/03
entrez 2013/06/04 06:00
pubmed 2013/06/04 06:00
medline 2013/11/06 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Rentería ME Rentería Miguel E ME Queensland Institute of Medical Research, Brisbane, Queensland, Australia. Miguel.Renteria@qimr.edu.au
Coolen MW Coolen Marcel W MW
Statham AL Statham Aaron L AL
Choi RS Choi R Seong Min RS
Qu W Qu Wenjia W
Campbell MJ Campbell Megan J MJ
Smith S Smith Sara S
Henders AK Henders Anjali K AK
Montgomery GW Montgomery Grant W GW
Clark SJ Clark Susan J SJ
Martin NG Martin Nicholas G NG
Medland SE Medland Sarah E SE
INVESTIGATORS
JOURNAL
VOLUME: 16
ISSUE: 4
TITLE: Twin research and human genetics : the official journal of the International Society for Twin Studies
ISOABBREVIATION: Twin Res Hum Genet
YEAR: 2013
MONTH: Aug
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Print
ISSN: 1832-4274
ISSNTYPE: Print
MEDLINE JOURNAL
MEDLINETA: Twin Res Hum Genet
COUNTRY: England
ISSNLINKING: 1832-4274
NLMUNIQUEID: 101244624
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
Twin Study
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adolescent
Adult
Child
Chromosome Mapping
DNA Methylation
Epigenesis, Genetic
Female
GTP-Binding Protein alpha Subunits, Gs genetics
Genome-Wide Association Study genetics
Genomic Imprinting genetics
Humans genetics
Insulin-Like Growth Factor II genetics
Male genetics
Parents genetics
Polymorphism, Single Nucleotide genetics
Potassium Channels, Voltage-Gated genetics
Quantitative Trait Loci genetics
RNA, Long Noncoding genetics
Regulatory Sequences, Nucleic Acid genetics
Twins genetics
Young Adult genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 H19 long non-coding RNA
0 IGF2 protein, human
0 KCNQ1OT1 protein, human
0 Potassium Channels, Voltage-Gated
0 RNA, Long Noncoding
67763-97-7 Insulin-Like Growth Factor II
EC 3.6.5.1 GTP-Binding Protein alpha Subunits, Gs
OTHER ID's