Opioid dependence (OD) is prevalent in the US and worldwide, and is highly destructive and costly to individuals and to society. It is also moderatel heritable. In prior iterations of this research program, we: 1) collected a sample of affected sibling pairs and carried out linkage analysis of OD and related traits and 2) collected a case-control sample and carried out numerous candidate gene investigations and a genomewide association study. Although we have identified chromosomal regions and specific risk alleles related to OD (both common and rare variants), our findings (and those of other investigators using similar approaches) have accounted for only a small part of OD heritability. Understanding the genetic risk of OD, like that of most complex traits, has proven refractory to the application of linkage and association techniques only. In this proposal, we describe a plan to identify additional OD risk factors. The clinical samples we have ascertained previously are distinguished by deep phenotypic characterization and high representation of African-Americans (AAs), who are underrepresented in GWAS, including substance dependence (SD) GWAS. We propose to identify rare (and possibly common) variants and structural (including copy number) variants by means of next generation sequencing of a set of these subjects: 3000 full exomes (2000 cases and 1000 controls, 1/3 of whom will be AA). Identified putative risk variants will be genotyped in our larger sample of >9500 subjects and evaluated for association to OD and other SD traits. We will follow up both our recent genomewide-significant GWAS results, and results identified by exome sequencing, with deep sequencing in the entire sample. Finally, all sequence data will be made publicly available. This project has the potential to identify the next significant pool of OD genetic risk variants, thus advancing the field, with resulting improved understanding of biology, and consequent applications to public health.

Public Health Relevance

Opioid dependence is a highly destructive form of substance dependence that is found in the US and many other places in the world. Risk for opioid dependence is influenced by genes. The main object of this study is to find genes that influence risk for opioid dependence by sequencing the entire exome (the part of the genome that is known to serve a coding function), in groups of people who are of European or African ancestry, with and without opioid dependence.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Caulder, Mark
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Li, Dawei; Zhao, Hongyu; Kranzler, Henry R et al. (2015) Genome-wide association study of copy number variations (CNVs) with opioid dependence. Neuropsychopharmacology 40:1016-26
DeVito, Elise E; Herman, Aryeh I; Waters, Andrew J et al. (2014) Subjective, physiological, and cognitive responses to intravenous nicotine: effects of sex and menstrual cycle phase. Neuropsychopharmacology 39:1431-40
Gelernter, Joel (2014) SLC6A4 polymorphism, population genetics, and psychiatric traits. Hum Genet 133:459-61
Yang, Can; Li, Cong; Kranzler, Henry R et al. (2014) Exploring the genetic architecture of alcohol dependence in African-Americans via analysis of a genomewide set of common variants. Hum Genet 133:617-24
Sun, Jiangwen; Bi, Jinbo; Kranzler, Henry R (2014) Multi-view singular value decomposition for disease subtyping and genetic associations. BMC Genet 15:73
Gelernter, J; Sherva, R; Koesterer, R et al. (2014) Genome-wide association study of cocaine dependence and related traits: FAM53B identified as a risk gene. Mol Psychiatry 19:717-23
Gelernter, Joel; Kranzler, Henry R; Sherva, Richard et al. (2014) Genome-wide association study of opioid dependence: multiple associations mapped to calcium and potassium pathways. Biol Psychiatry 76:66-74
Gelernter, J; Kranzler, H R; Sherva, R et al. (2014) Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci. Mol Psychiatry 19:41-9
Jensen, Kevin P; Kranzler, Henry R; Stein, Murray B et al. (2014) The effects of a MAP2K5 microRNA target site SNP on risk for anxiety and depressive disorders. Am J Med Genet B Neuropsychiatr Genet 165B:175-83
Chung, Dongjun; Yang, Can; Li, Cong et al. (2014) GPA: a statistical approach to prioritizing GWAS results by integrating pleiotropy and annotation. PLoS Genet 10:e1004787

Showing the most recent 10 out of 142 publications