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Addict Biol. 2016 Nov;21(6):1217-1232. doi: 10.1111/adb.12286. Epub 2015 Jul 23.

KAT2B polymorphism identified for drug abuse in African Americans with regulatory links to drug abuse pathways in human prefrontal cortex.

Author information

1
Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA. ejohnson@rti.org.
2
Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA.
3
Research Computing Division, RTI International, Research Triangle Park, NC, USA.
4
Fellow Program, Center for Genomics in Public Health and Medicine, and Genomics, Statistical Genetics, and Environmental Research Program, RTI International, Atlanta, GA, USA.
5
Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
6
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
7
Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, San Francisco, CA, USA.

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

PMID:
26202629
PMCID:
PMC4724343
DOI:
10.1111/adb.12286
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Eric O. Johnson, Dana B. Hancock, Joshua L. Levy, Nathan C. Gaddis, Grier P. Page, Cristie Glasheen, Nancy L. Saccone, Laura J. Bierut, and Alex H. Kral declare no conflicts of interest.

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