Exome Sequencing in Alcohol Dependence

Brien Riley and Kenneth Kendler

Alcohol Dependence (AD) is a major public health problem with a substantial genetic risk component. Prior research, including our P20-funded GWAS in Irish case/controls and work by other groups have identified promising candidate intervals for common genetic risk variants, undergoing further assessment including meta-analysis currently. A number of the specific genes identified in our GWAS have already produced new connections with the gene networks emerging from the P20-funded work of other VCU-ARC components, most notably the two invertebrate groups. Our GWAS dataset was imputed to the latest 1000 Genomes reference panel and the 8.2 million common variants [with MAF ≥ 1% or information ≥ 0.3] resulting from this analysis represent a thorough survey of common variation in this ascertained sample. In this P50 Center Research Component, we focus on the role of rarer coding variation accessible by exome sequencing. There is substantial evidence across a wide variety of other complex human traits that rare variation is responsible for an important component of trait risk, but this component of human genetic variation remains largely unstudied in AD risk. This P50 Center Research Component has four principal goals: first, to sequence the exomes of 500 severely affected AD cases using cost-effective protocols; second, to process the sequence reads through our mapping and variant calling pipeline, validate variant calls, and impute variants onto existing GWAS framework data in unsequenced samples to produce exomic variant calls down to MAF of [NN%], third to perform global burden, genome-wide gene-based and VCU-ARC network targeted analyses of the variant data, and fourth to replicate results in other human samples and to validate specific gene impact on alcohol-related phenotypes in other organisms.