Genetics of Addiction: New Findings From Sequencing Studies and Beyond

Overall Abstract Genome-wide association studies (GWAS) of alcoholism and other substance use disorders have led to the discovery of variants associated with alcohol drinking, tobacco smoking, opioid use, and a host of other related traits. However, it was soon realized that GWAS of such phenotypes demand a very large sample and benefit from detailed phenotypes. In addition, it is believed that part of the “missing” heritability is due to rare variants. Due to advancements in DNA biotechnology, whole exome and whole genome sequencing have become an attractive alternative approach. This symposium will provide recent evidence of sequence variation, especially rare variants, and functional gene studies of brain regions and of differentiated iPS cells to characterize the neurobiology of AUDs. First, Howard Edenberg (Indiana University School of Medicine) will present recent sequencing data from the Collaborative Study on the Genetics of Alcoholism that has focused on studies of large families with multiple alcoholic members. They have recently turned to whole exome sequencing (WES) of key affected individuals in these families to discover rare variants that might have stronger influences on risk, as well as on endophenotypes related to risk. In parallel, they have done RNA sequencing to examine the effects of ethanol on gene expression in lymphoblastoid cell lines from some of these subjects. Bringing together different approaches (common variants, rare variants, functional studies) will help us better understand alcohol use disorders. Second, R. Dayne Mayfield (University of Texas, Austin) will discuss the results of a large-scale RNA sequencing analysis from 60 post mortem human brain samples. The effects of alcohol on the central nucleus of amygdala, basolateral amygdala, the nucleus accumbens and superior prefrontal cortex were studied. They used a systems approach to identify gene networks specific to the novel isoforms. In addition, they identified splicing signatures that could be driving the generation of these novel isoforms. Next, Joel Gelernter (Yale University School of Medicine) will present the Yale-Penn study that was designed to investigate genetics of opioid, cocaine, and alcohol dependence, and has previously employed methods including genetic linkage and GWAS. A WES study of opioid dependence is currently in progress, and here, he will present initial results from their WES study, which so far includes >1700 subjects. Then, Zhiping Pang (Rutgers University Robert Wood Johnson School of Medicine) will discuss the results of their study of generated human neurons from 7 subjects carrying either homozygous mu-opioid receptor (MOR) N40 or MOR D40 in the OPRM1gene. Their preliminary data suggest that human neurons carrying D40 show defective re-sensitization after MOR activation by DAMGO ([D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin), suggesting defective trafficking of MORs. Finally, John Nurnberger (Indiana University School of Medicine) will serve as the discussant, describing how the results of these studies will help us to understand the genetic variations contributing to the risk of alcohol and substance use disorders, and how such data might provide avenues for novel therapeutic approaches in clinical practice.