@article{b0e361cc48434f1194bac05e3aebdbab,
title = "Genome-wide association study of opioid dependence: Multiple associations mapped to calcium and potassium pathways",
abstract = "Background We report a genome-wide association study (GWAS) of two populations, African-American and European-American (AA, EA) for opioid dependence (OD) in three sets of subjects, to identify pathways, genes, and alleles important in OD risk. Methods The design employed three phases (on the basis of separate sample collections). Phase 1 included our discovery GWAS dataset consisting of 5697 subjects (58% AA) diagnosed with opioid and/or other substance dependence and control subjects. Subjects were genotyped with the Illumina OmniQuad microarray, yielding 890,000 single nucleotide polymorphisms (SNPs) suitable for analysis. Additional genotypes were imputed with the 1000 Genomes reference panel. Top-ranked findings were further evaluated in Phase 2 by incorporating information from the publicly available Study of Addiction: Genetics and Environment dataset, with GWAS data from 4063 subjects (32% AA). In Phase 3, the most significant SNPs from Phase 2 were genotyped in 2549 independent subjects (32% AA). Analyses were performed with case-control and ordinal trait designs. Results Most significant results emerged from the AA subgroup. Genome-wide-significant associations (p < 5.0 × 10 -8) were observed with SNPs from multiple loci-KCNG2*rs62103177 was most significant after combining results from datasets in every phase of the study. The most compelling results were obtained with genes involved in potassium signaling pathways (e.g., KCNC1 and KCNG2). Pathway analysis also implicated genes involved in calcium signaling and long-term potentiation. Conclusions This is the first study to identify risk variants for OD with GWAS. Our results strongly implicate risk pathways and provide insights into novel therapeutic and prevention strategies and might biologically bridge OD and other non-substance dependence psychiatric traits where similar pathways have been implicated.",
keywords = "Calcium signaling, complex traits, convergence, genome-wide association, opioid dependence, potassium",
author = "Joel Gelernter and Kranzler, {Henry R.} and Richard Sherva and Ryan Koesterer and Laura Almasy and Hongyu Zhao and Farrer, {Lindsay A.}",
note = "Funding Information: This study was supported by National Institutes of Health Grants RC2 DA028909 , R01 DA12690 , R01 DA12849 , R01 DA18432 , R01 AA11330 , and R01 AA017535 and the VA Connecticut and Philadelphia VA Mental Illness Research, Education and Clinical Centers. Funding Information: Dr. Kranzler has served as a consultant or advisory board member for Alkermes, Lilly, Lundbeck, Pfizer, and Roche. He is also a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which is supported by Lilly, Lundbeck, Abbott, and Pfizer. The other authors declare no biomedical financial interests or potential conflicts of interest. Funding Information: Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Funding Information: We appreciate the work in recruitment and assessment provided at Yale University School of Medicine and the APT Foundation by James Poling, Ph.D.; at McLean Hospital by Roger Weiss, M.D.; at the Medical University of South Carolina by Kathleen Brady, M.D., Ph.D., and Raymond Anton, M.D.; and at the University of Pennsylvania by David Oslin, M.D. Genotyping services for a part of our genome-wide association study were provided by the Center for Inherited Disease Research and Yale University (Center for Genome Analysis) CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (contract number N01-HG-65403). We are grateful to Ann Marie Lacobelle, Michelle Cucinelli, Christa Robinson, and Greg Dalton-Kay for their excellent technical assistance; to the Semi-Structured Assessment for Drug Dependence and Alcoholism interviewers, led by Yari Nu{\~n}ez and Michelle Slivinsky, who devoted substantial time and effort to phenotype the study sample; and to John Farrell and Alexan Mardigan for database management assistance. Funding Information: Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392), and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract “High throughput genotyping for studying the genetic contributions to human disease” (HHSN268200782096C). ",
year = "2014",
month = jul,
day = "1",
doi = "10.1016/j.biopsych.2013.08.034",
language = "English (US)",
volume = "76",
pages = "66--74",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "1",
}