KAT2Bpolymorphism identified for drug abuse in African Americans with regulatory links to drug abuse pathways in human prefrontal cortex
Year: 2015
Type: article
Study design: Observational Study
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.
Source: Addiction Biology
DOI: 10.1111/adb.12286
Institutions: RTI International, Washington University in St. Louis
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Foundation for the National Institutes of Health, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
Awards: G1034519783, G1054787755, G1083756078, G132635143, G1621215609, G1691445938, G1794460117, G1799808449, G1900459709, G2149630760, G2265115783, G2313542652, G2447083100, G2548880556, DIAGNOSTIC CENTER FOR LINKAGE STUDIES OF SCHIZOPHRENIA, Study of Addiction: Genetics and Environment, G2763219833, M D Anderson Cancer Center Head & Neck SPORE, G2836672101, G2851966638, Molecular Epidemiology of DNA Repair in Head and Neck Cancer, G3120785097, G3225162496, Molecular Genetics of Schizophrenia, G3276551827, G3344726377, G34130399, G3453796565, G3457954119, G355565238, G364003555, G3799582765, G3995976717, G4528851193, Genome Wide Association Coordinating Center, G4808091200, G4828408400, G5039824773, G513541458, DIAGNOSTIC CENTER FOR SCHIZOPHRENIA LINKAGE STUDIES, G5303213021, G5743592490, JH/CIDR Genotyping for Genome-Wide Association Studies, Genetic Risk to Stroke in Smokers and Nonsmokers in Two Ethnic Groups, G6177097893, Molecular Genetics of Schizophrenia, G6587255222, FAMILY STUDY OF COCAINE DEPENDENCE, G6912126949, G693077865, G697048246, Mid-Atlantic Nutrition Obesity Research Center, Genome-wide Association Study of Schizophrenia, G721666067, G7248065091, G730432523, G7522350138, G792207106, Molecular Epidemiology of Nutrition and Cancer in the Multiethnic Cohort Study, G7941956784, G7998037458, G8267674335, G858805679, Genetics of Early Onset-Stroke, Molecular Genetics of Schizophrenia, G899224547, G948540326, The University of Texas M. D. Anderson Cancer Center SPORE in Melanoma
OpenAlex ID: W1515548539