@article{4f715ee01b07479498382f923c0c38e9,
title = "KAT2B polymorphism identified for drug abuse in African Americans with regulatory links to drug abuse pathways in human prefrontal cortex",
abstract = "Drug abuse is a common and heritable set of disorders, but the underlying genetic factors are largely unknown. We conducted genome-wide association studies of drug abuse using 7 million imputed single nucleotide polymorphisms (SNPs) and insertions/deletions in African Americans (AAs; n = 3742) and European Americans (EAs; n = 6845). Cases were drawn from the Urban Health Study of street-recruited people, who injected drugs and reported abusing opioids, cocaine, marijuana, stimulants and/or other drugs 10 or more times in the past 30 days, and were compared with population controls. Independent replication testing was conducted in 755 AAs and 1131 EAs from the Genetic Association Information Network. An intronic SNP (rs9829896) in the K(lysine) acetyltransferase 2B (KAT2B) gene was significantly associated with drug abuse in AAs (P = 4.63 × 10−8) and independently replicated in AAs (P = 0.0019). The rs9829896-C allele (frequency = 12%) had odds ratios of 0.68 and 0.53 across the AA cohorts: meta-analysis P = 3.93 × 10−10. Rs9829896-C was not associated with drug abuse across the EA cohorts: frequency = 36% and meta-analysis P = 0.12. Using dorsolateral prefrontal cortex data from the BrainCloud cohort, we found that rs9829896-C was associated with reduced KAT2B expression in AAs (n = 113, P = 0.050) but not EAs (n = 110, P = 0.39). KAT2B encodes a transcriptional regulator in the cyclic adenosine monophosphate and dopamine signaling pathways, and rs9829896-C was associated with expression of genes in these pathways: reduced CREBBP expression (P = 0.011) and increased OPRM1 expression (P = 0.016), both in AAs only. Our study identified the KAT2B SNP rs9829896 as having novel and biologically plausible associations with drug abuse and gene expression in AAs but not EAs, suggesting ancestry-specific effects.",
keywords = "African American, GWAS, KAT2B and substance abuse, gene expression",
author = "Johnson, {Eric O.} and Hancock, {Dana B.} and Levy, {Joshua L.} and Gaddis, {Nathan C.} and Page, {Grier P.} and Cristie Glasheen and Saccone, {Nancy L.} and Bierut, {Laura J.} and Kral, {Alex H.}",
note = "Funding Information: Our GWAS of drug abuse, with its use of Urban Health Study participants, was supported by the National Institute of Drug Abuse (NIDA) grant numbers R33 DA027486 and R01 DA026141. Study controls were drawn from the following six cohorts in the database of Genotypes and Phenotypes (dbGaP, http://www.ncbi.nlm.nih.gov/gap). Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the GWAS 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). Assistance with data cleaning was provided by the National Center for Biotechnology Information (NCBI). 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 support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR), was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, NIDA and the NIH contract {\textquoteleft}High throughput genotyping for studying the genetic contributions to human disease{\textquoteright} (HHSN268200782096C). The datasets used for the analyses described in this manuscript were obtained via dbGaP accession number phs000092.v1.p1. The authors acknowledge the contribution of data from {\textquoteleft}Genetic Architecture of Smoking and Smoking Cessation{\textquoteright} accessed through dbGAP accession number phs000404.v1.p1. Funding support for genotyping, which was performed at CIDR, was provided by 1 X01 HG005274-01. CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Funding support for collection of datasets and samples was provided by COGEND (P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). Funding support for the GWAS of Ischemic Stroke study was provided through the NIH GEI (U01HG004436). The GWAS of Ischemic Stroke study is one of the GWAS funded as part of 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). Assistance with data cleaning was provided by the NCBI. Funding support for genotyping, which was performed at The Johns Hopkins University CIDR, was provided by the NIH GEI (U01HG004438) and the NIH contract {\textquoteleft}High throughput genotyping for studying the genetic contributions to human disease{\textquoteright}(HHSN268200782096C). Field work for this project was supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and Prevention; the National Institute of Neurological Disorders and Stroke (NINDS) and the NIH Office of Research on Women's Health (ORWH) (R01 NS45012); Office of Research and Development, Medical Research Service, Department of Veterans Affairs; and the University of Maryland General Clinical Research Center (M01 RR 165001), National Center for Research Resources, NIH. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds). The data sets used for the analyses described in this manuscript were obtained via dbGaP accession number phs000292.v1.p1. Funding support for the GENEVA Prostate Cancer study was provided through the National Cancer Institute (R37CA54281, R01CA63464, P01CA33619, U01CA136792, U01CA98758 and RC2 CA148085) and the National Human Genome Research Institute (U01HG004726). Assistance with phenotype harmonization, SNP selection, data cleaning, meta-analyses, data management and dissemination and general study coordination, was provided by the GENEVA Coordinating Center (U01HG004789-01). The datasets used for the analyses described in this manuscript were obtained from dbGaP at phs000306.v2.p1. This work utilized in part data from the NINDS dbGaP database from the CIDR NeuroGenetics Research Consortium (NGRC) Parkinson's disease study (accession number phs000196.v2.p1). For the {\textquoteleft}High Density SNP Association Analysis of Melanoma: Case-control and Outcomes Investigation{\textquoteright}, research support to collect data and develop an application to support this project was provided by P50CA093459, 5P50CA097007, 5R01ES011740 and 5R01CA133996 (dbGaP accession number phs000187.v1.p1). The replication cohort with drug abuse cases and controls was also obtained from dbGaP. For the first replication cohort, funding support for the Genome-Wide Association of Schizophrenia Study was provided by the National Institute of Mental Health (NIMH) (R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289, U01 MH46318, U01 MH79469 and U01 MH79470) and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The datasets used for the analyses described in this manuscript were obtained from dbGaP through accession number phs000021.v3.p2. Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (PI: Pablo V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL, USA). Lastly, the BrainCloud cohort was used to test SNP associations with mRNA expression levels. The BrainCloud genotype data were obtained from the 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 NIMH Intramural Research Program. The gene expression data are available in the BrainCloud software application (downloadable at http://braincloud.jhmi.edu/) as well as the NCBI Gene Expression Omnibus (series number GSE30272). Publisher Copyright: {\textcopyright} 2015 Society for the Study of Addiction",
year = "2016",
month = nov,
day = "1",
doi = "10.1111/adb.12286",
language = "English",
volume = "21",
pages = "1217--1232",
journal = "Addiction Biology",
issn = "1355-6215",
number = "6",
}