Exome Sequencing and Genomic Studies To Better Understand Alcohol Dependence

Abstract

The Collaborative Study on the Genetics of Alcoholism (COGA) has focused on studies of large families with multiple alcoholic members. We have conducted genome-wide association studies (GWAS) to identify common variants that affect risk for alcohol dependence and related phenotypes, including electrophysiological endophenotypes. Because we have studied families from different ethnic groups, we are meta-analyzing our results across these groups. We are also contributing to larger meta-analyses through the Psychiatric Genomics Consortium.Recently, we have turned to exome sequencing of key affected individuals in these families to discover rare variants that may have stronger influences on risk, as well as on related endophenotypes. We developed a new phenotype to complement the DSM diagnostic phenotype; it includes items related to heavy drinking and its biological consequences. We used this new quantitative phenotype in order to select the more severe cases among those who met DSM-IV criteria for this sequencing. Studying large, densely affected families has several advantages: a) they are more likely to carry variants conferring risk, b) segregation of the variants within a family provides support for their contribution to risk and c) having GWAS data on the same families allows imputation of even rare variants for family members who are not sequenced.Functional studies are an important complement to the genetic studies. We have conducted RNA sequencing to examine the effects of controlled ethanol exposure on gene expression in lymphoblastoid cell lines from some of the COGA subjects. Measuring gene expression in the paired (exposed and unexposed) samples is a powerful design. We are also examining differences between alcoholics and controls in gene expression in several brain regions. In addition, we are investigating the biological effects of transitioning from abstinence or very little drinking to heavy drinking during adolescence and young adulthood. This involves examining differences in gene expression and DNA methylation in blood samples taken 2 years apart (before and after the transition), comparing adolescents who have transitioned to heavy drinking during those years to an age- and sex-matched control group who have not.Bringing together different approaches (common variants, rare variants, and functional studies) will help us better understand alcohol use disorders.