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)
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Genetics of Health and Disease Study Section (GHD)
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Caulder, Mark
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Yale University
Schools of Medicine
New Haven
United States
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Polimanti, Renato; Agrawal, Arpana; Gelernter, Joel (2017) Schizophrenia and substance use comorbidity: a genome-wide perspective. Genome Med 9:25
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Hancock, D B; Guo, Y; Reginsson, G W et al. (2017) Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. Mol Psychiatry :
Yang, Bao-Zhu; Arias, Albert J; Feinn, Richard et al. (2017) GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers. Alcohol Clin Exp Res 41:2025-2032
Polimanti, Renato; Gelernter, Joel (2017) Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder. PLoS Genet 13:e1006618
Polimanti, Renato; Zhang, Huiping; Smith, Andrew H et al. (2017) Genome-wide association study of body mass index in subjects with alcohol dependence. Addict Biol 22:535-549

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