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

Abstract

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.

Sensitive Periods in Epigenetics: Bringing us Closer to Complex Behavioral Phenotypes

“…For example, the same genomic region was found to be hypomethylated in post-mortem brain tissue from people with psychosis as compared with leukocyte DNA taken from their MZ twins with psychosis [60]. Other studies have shown similar results, such as a consistent difference in DNA methylation of the HLA complex group 9 genes across multiple tissues in bipolar disorder [116]. On the other hand, there are many studies that have shown that there are important differences of DNA methylation across cell types.…”

Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain

“…Methylation is highly tissue specific for some CpG sites (56)(57)(58)(59), and when studying healthy humans, we are limited to assessments from peripheral tissue rather than the causal tissue for the social phenotype, the brain. However, recent studies have demonstrated that, for some CpG sites, methylation may be correlated between tissues and stable across the lifespan (60)(61)(62)(63). For the CpG site tested here, there is evidence for the maintenance of methylation levels between brain and blood (36), suggesting our peripheral marker is likely to correlate with methylation levels in the brain.…”

Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease

“…[80][81][82] Preliminary genetic, epigenetic, and neurobiological findings suggest that this process may be part of the pathogenesis of MDD and BD rather than being a secondary epiphenomenon. [83][84][85][86][87] Given the adult literature on this topic, excessive inflammation could underlie some of the association of depression with cardiovascular risk in youth. Indeed, in a handful of small case-control studies, clinically depressed adolescents have shown higher serum levels of some proinflammatory cytokines (eg, interleukin [IL]-1β and IL-6) than healthy control participants.…”