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

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          Abstract

          Background

          Dopamine receptor D 4 (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.

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          Most cited references45

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          Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry.

          Mathias Ehrich, Matthew R. Nelson, Patrick Stanssens … (2005)
          Methylation is one of the major epigenetic processes pivotal to our understanding of carcinogenesis. It is now widely accepted that there is a relationship between DNA methylation, chromatin structure, and human malignancies. DNA methylation is potentially an important clinical marker in cancer molecular diagnostics. Understanding epigenetic modifications in their biological context involves several aspects of DNA methylation analysis. These aspects include the de novo discovery of differentially methylated genes, the analysis of methylation patterns, and the determination of differences in the degree of methylation. Here we present a previously uncharacterized method for high-throughput DNA methylation analysis that utilizes MALDI-TOF mass spectrometry (MS) analysis of base-specifically cleaved amplification products. We use the IGF2/H19 region to show that a single base-specific cleavage reaction is sufficient to discover methylation sites and to determine methylation ratios within a selected target region. A combination of cleavage reactions enables the complete evaluation of all relevant aspects of DNA methylation, with most CpGs represented in multiple reactions. We successfully applied this technology under high-throughput conditions to quantitatively assess methylation differences between normal and neoplastic lung cancer tissue samples from 48 patients in 47 genes and demonstrate that the quantitative methylation results allow accurate classification of samples according to their histopathology.
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            Widespread monoallelic expression on human autosomes.

            Alexander Gimelbrant, John N Hutchinson, Benjamin Thompson … (2007)
            Monoallelic expression with random choice between the maternal and paternal alleles defines an unusual class of genes comprising X-inactivated genes and a few autosomal gene families. Using a genome-wide approach, we assessed allele-specific transcription of about 4000 human genes in clonal cell lines and found that more than 300 were subject to random monoallelic expression. For a majority of monoallelic genes, we also observed some clonal lines displaying biallelic expression. Clonal cell lines reflect an independent choice to express the maternal, the paternal, or both alleles for each of these genes. This can lead to differences in expressed protein sequence and to differences in levels of gene expression. Unexpectedly widespread monoallelic expression suggests a mechanism that generates diversity in individual cells and their clonal descendants.
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              A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.

              Simonetta Friso, Sang-Woon Choi, Domenico Girelli … (2002)
              DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/T genotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/microg DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T/T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status.
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                Author and article information

                Contributors
                Sophia J Docherty
                Oliver SP Davis
                Claire MA Haworth
                Robert Plomin
                Ursula D’Souza
                Jonathan Mill
                Journal
                Journal ID (nlm-ta): Behav Brain Funct
                Journal ID (iso-abbrev): Behav Brain Funct
                Title: Behavioral and Brain Functions : BBF
                Publisher: BioMed Central
                ISSN (Electronic): 1744-9081
                Publication date Collection: 2012
                Publication date (Electronic): 12 June 2012
                Volume: 8
                Page: 31
                Affiliations
                [1 ]King’s College London, MRC Social, Genetic and Developmental Psychiatry Centre,, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK
                Article
                Publisher ID: 1744-9081-8-31
                DOI: 10.1186/1744-9081-8-31
                PMC ID: 3538530
                PubMed ID: 22691691
                SO-VID: 05f4ea3a-52b2-4721-84c7-2073e6a3d897
                Copyright © Copyright ©2012 Docherty et al.; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 5 January 2012
                Date accepted : 28 May 2012
                Categories
                Subject: Research

                ScienceOpen disciplines: Neurology
                Data availability:
                ScienceOpen disciplines: Neurology

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