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.
authors.affiliation: Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA. ejohnson@rti.org.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Johnson
authors.affiliation: Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA.
authors.forename: Dana B
authors.initials: DB
authors.lastname: Hancock
authors.affiliation: Research Computing Division, RTI International, Research Triangle Park, NC, USA.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Levy
authors.affiliation: Research Computing Division, RTI International, Research Triangle Park, NC, USA.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Gaddis
authors.affiliation: Fellow Program, Center for Genomics in Public Health and Medicine, and Genomics, Statistical Genetics, and Environmental Research Program, RTI International, Atlanta, GA, USA.
authors.forename: Grier P
authors.initials: GP
authors.lastname: Page
authors.affiliation: Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA.
authors.forename: Cristie
authors.initials: C
authors.lastname: Glasheen
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Saccone
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.affiliation: Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, San Francisco, CA, USA.
authors.forename: Alex H
authors.initials: AH
authors.lastname: Kral
mesh_terms: D001741:Black or African American / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000187:drug effects*; D019966:Substance-Related Disorders / Q000235:genetics*; D014505:Urban Population; D044465:White People / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000235:genetics*; D000099224:p300-CBP-Associated Factor
chemical_list: D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
keywords: African American; GWAS; KAT2B and substance abuse; gene expression