The gene-environment interactions that underlie development and progression of psychiatric illness are poorly understood. Despite a century of progress, genetic approaches have failed to identify new treatment modalities, perhaps because of the heterogeneity of the disorders and lack of understanding of mechanisms. Recent exploration into epigenetic mechanisms in health and disease has uncovered changes in DNA methylation and chromatin structure that may contribute to psychiatric disorders. Epigenetic changes suggest a variety of new therapeutic options due to their reversible chemistry. However, distinguishing causal links between epigenetic changes and disease from changes consequent to life experience has remained problematic. Here we define epigenetics and explore aspects of epigenetics relevant to causes and mechanisms of psychiatric disease, and speculate on future directions.

Earlier initiation of smoking correlates with higher risk of nicotine dependence, mental health problems, and cognitive impairments. Additionally, exposure to nicotine and/or tobacco smoke during critical developmental periods is associated with lasting epigenetic modifications and altered gene expression. This study examined whether adolescent nicotine exposure alters adult hippocampus-dependent learning, involving persistent changes in hippocampal DNA methylation and if choline, a dietary methyl donor, would reverse and mitigate these alterations. Mice were chronically treated with nicotine (12.6 mg/kg/day) starting at post-natal day 23 (pre-adolescent), p38 (late adolescent), or p54 (adult) for 12 days followed by a 30-day period during which they consumed either standard chow or chow supplemented with choline (9 g/kg). Mice then were tested for fear-conditioning and dorsal hippocampi were dissected for whole genome methylation and selected gene expression analyses. Nicotine exposure starting at p21 or p38, but not p54, disrupted adult hippocampus-dependent fear conditioning. Choline supplementation ameliorated these deficits. 462 genes in adult dorsal hippocampus from mice exposed to nicotine as adolescents showed altered promoter methylation that was reversed by choline supplementation. Gene network analysis revealed that chromatin remodeling genes were the most enriched category whose methylation was altered by nicotine and reversed by choline dietary supplementation. Two key chromatin remodeling genes, Smarca2 and Bahcc1, exhibited inversely correlated changes in methylation and expression due to nicotine exposure; this was reversed by choline. Our findings support a role for epigenetic modification of hippocampal chromatin remodeling genes in long-term learning deficits induced by adolescent nicotine and their amelioration by dietary choline supplementation.

Background:Reduction in brain volume, especially gray matter volume, has been shown to be one of the many deleterious effects of prolonged alcohol consumption. High variance in the degree of gray matter tissue shrinkage among alcohol-dependent individuals and a previous neuroimaging genetics report suggest the involvement of environmental and/or genetic factors, such as superoxide dismutase 2 (SOD2). Identification of such underlying factors will help in the clinical management of alcohol dependence.Methods:We analyzed quantitative magnetic resonance imaging and genotype data from 103 alcohol users, including both light drinkers and treatment-seeking alcohol-dependent individuals. Genotyping was performed using a custom gene array that included genes selected from 8 pathways relevant to chronic alcohol-related brain volume loss.Results:We replicated a significant association of a functional SOD2 single nucleotide polymorphism with normalized gray matter volume, which had been reported previously in an independent smaller sample of alcohol-dependent individuals. The SOD2-related genetic protection was observed only at the cohort’s lower drinking range. Additional associations between normalized gray matter volume and other candidate genes such as alcohol dehydrogenase gene cluster (ADH), GCLC, NOS3, and SYT1 were observed across the entire sample but did not survive corrections for multiple comparisons.Conclusion:Converging independent evidence for a SOD2 gene association with gray matter volume shrinkage in chronic alcohol users suggests that SOD2 genetic variants predict differential brain volume loss mediated by free radicals. This study also provides the first catalog of genetic variations relevant to gray matter loss in chronic alcohol users. The identified gene-brain structure relationships are functionally pertinent and merit replication.

The Genomics Workgroup of the National Advisory Mental Health Council (NAMHC) recently issued a set of recommendations for advancing the NIMH psychiatric genetics research program and prioritizing subsequent follow-up studies. The report emphasized the primacy of rigorous statistical support from properly designed, well-powered studies for pursuing genetic variants robustly associated with disease. Here we discuss the major points NIMH program staff consider when assessing research applications based on common and rare variants, as well as genetic syndromes, associated with psychiatric disorders. These are broad guiding principles for investigators to consider prior to submission of their applications. NIMH staff weigh these points in the context of reviewer comments, the existing literature, and current investments in related projects. Following the recommendations of the NAMHC, statistical strength and robustness of the underlying genetic discovery weighs heavily in our funding considerations as does the suitability of the proposed experimental approach. We specifically address our evaluation of applications motivated in whole, or in part, by an association between human DNA sequence variation and a disease or trait relevant to the mission of the NIMH.

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