A genetic association study of DNA methylation levels in the DRD4 gene region finds associations with nearby SNPs.
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.
King's College London, MRC Social, Genetic and Developmental Psychiatry Centre,, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK. sophia.docherty@iop.kcl.ac.uk
Sophia J
SJ
Docherty
Oliver Sp
OS
Davis
Claire Ma
CM
Haworth
Robert
R
Plomin
Ursula
U
D'Souza
Jonathan
J
Mill
D000544:Alzheimer Disease / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D050638:Receptors, Dopamine D4 / Q000235:genetics*
C493599:DRD4 protein, human; D050638:Receptors, Dopamine D4