A multi-tissue analysis identifies HLA complex group 9 gene methylation differences in bipolar disorder

The Krembil Family Epigenetics Laboratory, Neuroscience Department, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Molecular Psychiatry (Impact Factor: 14.5). 06/2011; 17(7):728-40. DOI: 10.1038/mp.2011.64
Source: PubMed


Epigenetic studies of DNA and histone modifications represent a new and important activity in molecular investigations of human disease. Our previous epigenome-wide scan identified numerous DNA methylation differences in post-mortem brain samples from individuals affected with major psychosis. In this article, we present the results of fine mapping DNA methylation differences at the human leukocyte antigen (HLA) complex group 9 gene (HCG9) in bipolar disorder (BPD). Sodium bisulfite conversion coupled with pyrosequencing was used to interrogate 28 CpGs spanning ∼700 bp region of HCG9 in 1402 DNA samples from post-mortem brains, peripheral blood cells and germline (sperm) of bipolar disease patients and controls. The analysis of nearly 40 000 CpGs revealed complex relationships between DNA methylation and age, medication as well as DNA sequence variation (rs1128306). Two brain tissue cohorts exhibited lower DNA methylation in bipolar disease patients compared with controls at an extended HCG9 region (P=0.026). Logistic regression modeling of BPD as a function of rs1128306 genotype, age and DNA methylation uncovered an independent effect of DNA methylation in white blood cells (odds ratio (OR)=1.08, P=0.0077) and the overall sample (OR=1.24, P=0.0011). Receiver operating characteristic curve A prime statistics estimated a 69-72% probability of correct BPD prediction from a case vs control pool. Finally, sperm DNA demonstrated a significant association (P=0.018) with BPD at one of the regions demonstrating epigenetic changes in the post-mortem brain and peripheral blood samples. The consistent multi-tissue epigenetic differences at HCG9 argue for a causal association with BPD.

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Available from: Ilya Ioshikhes, May 01, 2014
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    • "In the human genome, 5hmC is highly enriched on exons and untranslated regions, but depleted on introns and intergenic regions (Wang et al., 2012). In addition, fetus-specific and adult-specific differentially hydroxymethylated regions in exons and CpG islands have been identified (Kaminsky et al., 2012). In the adult brain, 5hmC has been implicated in the regulation of activity-dependent plasticity and gene expression critical for consolidation of memory. "
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    • "ST6GALNAC1 encodes α-N-acetylgalactosaminide α-2,6-sialyltransferase 1, an enzyme that transfers sialic acid to O-linked N-acetylgalactosamine residues, but its function has not been fully elucidated. Similarly, studies of bipolar disorder also demonstrated that methylation status at specific CpG sites in SLC6A4 (which encodes a serotonin transporter, one of the main targets of antidepressants) and human leukocyte antigen complex group 9 gene (HCG9, which is located within the MHC class I region) showed a common pattern in brain and blood samples [63,64]. More recently, Davies et al. [65] also reported that DNA methylation differences in blood samples and those in postmortem brain samples were well correlated in the investigated genomic regions, indicating the utility of peripheral tissue samples in studying mental disorders. "
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