@article{f5afc5c8cb7746b9bf7fbd29f95782de,
title = "Cis-expression quantitative trait loci mapping reveals replicable associations with heroin addiction in OPRM1",
abstract = "Background No opioid receptor, mu 1 (OPRM1) gene polymorphisms, including the functional single nucleotide polymorphism (SNP) rs1799971, have been conclusively associated with heroin/other opioid addiction, despite their biological plausibility. We used evidence of polymorphisms altering OPRM1 expression in normal human brain tissue to nominate and then test associations with heroin addiction. Methods We tested 103 OPRM1 SNPs for association with OPRM1 messenger RNA expression in prefrontal cortex from 224 European Americans and African Americans of the BrainCloud cohort. We then tested the 16 putative cis-expression quantitative trait loci (cis-eQTL) SNPs for association with heroin addiction in the Urban Health Study and two replication cohorts, totaling 16,729 European Americans, African Americans, and Australians of European ancestry. Results Four putative cis-eQTL SNPs were significantly associated with heroin addiction in the Urban Health Study (smallest p = 8.9 × 10-5): rs9478495, rs3778150, rs9384169, and rs562859. Rs3778150, located in OPRM1 intron 1, was significantly replicated (p = 6.3 × 10-5). Meta-analysis across all case-control cohorts resulted in p = 4.3 × 10-8: the rs3778150-C allele (frequency = 16%-19%) being associated with increased heroin addiction risk. Importantly, the functional SNP allele rs1799971-A was associated with heroin addiction only in the presence of rs3778150-C (p = 1.48 × 10-6 for rs1799971-A/rs3778150-C and p =.79 for rs1799971-A/rs3778150-T haplotypes). Lastly, replication was observed for six other intron 1 SNPs that had prior suggestive associations with heroin addiction (smallest p = 2.7 × 10-8 for rs3823010). Conclusions Our findings show that common OPRM1 intron 1 SNPs have replicable associations with heroin addiction. The haplotype structure of rs3778150 and nearby SNPs may underlie the inconsistent associations between rs1799971 and heroin addiction.",
keywords = "Genetic association study, Heroin, Multiancestry, OPRM1, Opioid, Prefrontal cortex",
author = "Hancock, {Dana B.} and Levy, {Joshua L.} and Gaddis, {Nathan C.} and Cristie Glasheen and Saccone, {Nancy L.} and Page, {Grier P.} and Hulse, {Gary K.} and Dieter Wildenauer and Kelty, {Erin A.} and Schwab, {Sibylle G.} and Louisa Degenhardt and Martin, {Nicholas G.} and Montgomery, {Grant W.} and John Attia and Holliday, {Elizabeth G.} and Mark McEvoy and Scott, {Rodney J.} and Bierut, {Laura J.} and Nelson, {Elliot C.} and Kral, {Alex H.} and Johnson, {Eric O.}",
note = "Funding Information: The second replication cohort included cases who met lifetime DSM-IV criteria for heroin dependence compared with general population control subjects. Cases and control subjects, many of which are available in dbGaP under “A Genome-Wide Association Study of Heroin Dependence” (accession number phs000277.v1.p1), were derived from the following datasets: 1) The Comorbidity and Trauma Study was funded by National Institute on Alcohol Abuse and Alcoholism Grant number R01 DA17305; 2) The Western Australia Study on Heroin Dependence was funded by the Australia Government{\textquoteright}s National Health and Medical Research Council (Grant number 513862); 3) The Twin Study of Mole Development in Adolescence (principal investigator [PI]: Nick Martin) was funded by the Australian Government{\textquoteright}s National Health and Medical Research Council (Grant number 389891); and 4) Support for the Hunter Community Study has been previously described ( 68 ). Lastly, GWAS genotyping services for “A Genome-Wide Association Study of Heroin Dependence” at CIDR, located at The Johns Hopkins University, were supported by NIH contract number N01 HG65403. Funding Information: Two additional cohorts with heroin addiction cases and control subjects were used for replication testing. For the first replication cohort, funding support was provided through the Center for Inherited Disease Research and the Genetics of Alcohol Dependence in American Populations. This CIDR-Gelernter Study is a GWAS funded as part of the “Genetics of Alcohol Dependence in American Populations” cohort, and its investigators provided assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination. Assistance with data cleaning was provided by the NCBI. Support for collection of datasets and samples was provided by the National Institute on Alcohol Abuse and Alcoholism Grant number R01 AA011330. Funding support for genotyping, which was performed at the Johns Hopkins University CIDR, was provided by the NIH GEI (U01 HG004438), the NIAAA, and the NIH contract number HHSN268200782096C. The datasets used for the analyses described in this article were obtained via dbGaP accession number phs000425.v1.p1. Funding Information: The BrainCloud dataset used for the expression quantitative trait loci mapping described in this article was obtained from database of Genotypes and Phenotypes (dbGaP) ( http://www.ncbi.nlm.nih.gov/gap ) via accession number phs000417.v1.p1. Submission of the data to dbGaP was provided by Drs. Barbara Lipska and Joel Kleinman. Collection of the data was through a collaborative study sponsored by the National Institute of Mental Health Intramural Research Program. The BrainCloud applications were downloaded from http://braincloud.jhmi.edu/ . Funding Information: This genetic study of heroin addiction cases from the Urban Health Study was supported by the National Institute of Drug Abuse Grant numbers R33 DA027486 and R01 DA026141. Genotyping was conducted at the Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Funding Information: Financial support for this study was provided by the following Grants and contracts by the National Institutes of Health, an agency of the United States Department of Health and Human Services: R33 DA027486 (PI: EOJ), R01 DA026141 (PI: EOJ), R01 DA026911 (PI:NLS), U01 HG004422, U01 HG004446, U10 AA008401, P01 CA089392 (PI: LJB), R01 DA013423 (PI: LJB), R01 DA019963 (PI: LJB), R01 DA025888 (Co-PIs: LJB and EOJ), R01 DA036583 (PI: LJB), U01 HG004438, HHSN268200782096C, X01 HG005274, P50 DA019706, P50 CA084724, U01 HG004436, R01 NS45012, M01 RR165001, R37 CA54281, R01 CA63464, P01 CA33619, U01 CA136792, U01 CA98758, RC2 CA148085, U01 HG004726, U01 HG004789, P50 CA093459, P50 CA097007, R01 ES011740, R01 CA133996, R01 AA011330, R01 DA17305 (PI: ECN), and N01 HG65403. This study was also supported by the Australia Government{\textquoteright}s National Health and Medical Research Council (Grant number 513862 with PI: SGS and fellowship number 1041742 with PI: LD), National Health and Medical Research Council (Grant number 389891) (PI: NGM), and National Drug and Alcohol Research Centre, which was supported by funding from the Australian Government under the Substance Misuse and Service Improvements Grants Fund. Publisher Copyright: {\textcopyright} 2015 Society of Biological Psychiatry.",
year = "2015",
month = oct,
day = "1",
doi = "10.1016/j.biopsych.2015.01.003",
language = "English",
volume = "78",
pages = "474--484",
journal = "Biological Psychiatry",
issn = "0006-3223",
number = "7",
}