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A genetic association study of DNA methylation levels in the DRD4 gene region finds associations with nearby SNPs.

Docherty, SJ; Davis, OS; Haworth, CM; Plomin, R; D'Souza, U; Mill, J; (2012) A genetic association study of DNA methylation levels in the DRD4 gene region finds associations with nearby SNPs. Behav Brain Funct , 8 31-. 10.1186/1744-9081-8-31.

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Abstract

BACKGROUND: Dopamine receptor D4(DRD4) polymorphisms have been associated with a number of psychiatric disorders, but little is known about the mechanism of these associations. DNA methylation is linked to the regulation of gene expression and plays a vital role in normal cellular function, with abnormal DNA methylation patterns implicated in a range of disorders. Recent evidence suggests DNA methylation can be influenced by cis-acting DNA sequence variation, that is, DNA sequence variation located nearby on the same chromosome. METHODS: To investigate the potential influence of cis-acting genetic elements within DRD4, we analysed DRD4 promoter DNA methylation levels in the transformed lymphoblastoid cell-line DNA of 89 individuals (from 30 family-trios). Five SNPs located +/- 10kb of the promoter region were interrogated for associations with DNA methylation levels. RESULTS: Four significant SNP associations were found with DNA methylation (rs3758653, rs752306, rs11246228 and rs936465). The associations of rs3758653 and rs936465 with DNA methylation were tested and nominally replicated (p-value < 0.05) in post-mortem brain tissue from an independent sample (N = 18). Interestingly, the DNA methylation patterns observed in post-mortem brain tissue were similar to those observed in transformed lymphoblastoid cell line DNA. CONCLUSIONS: The link reported between DNA sequence and DNA methylation offers a possible functional role to seemingly non-functional SNP associations. DRD4 has been implicated in several psychiatric disease phenotypes and our results shed light upon the possible mode of action of SNP associations in this region.

Type: Article
Title: A genetic association study of DNA methylation levels in the DRD4 gene region finds associations with nearby SNPs.
Location: England
DOI: 10.1186/1744-9081-8-31
Keywords: Alzheimer Disease, DNA Methylation, Female, Gene Expression, Genetic Association Studies, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Receptors, Dopamine D4
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: http://discovery.ucl.ac.uk/id/eprint/1385163
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