June 15, 2015
Cancer Research Building Auditorium
Huiping Zhang, Ph.D.
Yale University School of Medicine
Department of Psychiatry
Division of Human Genetics
Beyond the Genetics of Alcohol Dependence
Alcohol dependence is a severe and common disorder causing substantial morbidity and mortality. Numerous studies have demonstrated that both genetic and environmental factors can modulate an individual’s susceptibility to alcohol dependence. There is a growing body of evidence suggesting that the interaction between genetic and environmental factors is mediated by epigenetic mechanisms such as DNA methylation. Additionally, chronic alcohol consumption can also lead to alcohol abuse or dependence by altering gene expression in reward-related brain regions.
We have used several approaches to investigate the genetic and epigenetic mechanisms of alcohol dependence. We performed genome-wide association studies (GWAS) to identify alcohol dependence-associated genetic variants. Considering that non-genetic factors (such as childhood adversity and chronic alcohol consumption) may also result in an increased risk for alcohol dependence via the epigenetic mechanism, we examined DNA methylation and/or gene expression changes in peripheral blood/postmortem brains of subjects affected with alcohol dependence or experienced childhood adversity. Some of the findings in human alcoholic subjects were validated using the drinking-in-dark mouse model. Given that specific brain neurons (e.g., the GABAergic neurons) participate in the reward circuit, we used human embryonic stem cell (hESC)-derived GABAergic neurons as models to examine alcohol-induced gene expression changes. Our findings suggest that genes involved biological pathways such as alcohol metabolism and neurotransmission play a critical role in the development of alcohol dependence.