KAT2Bpolymorphism 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=3,742) and European Americans (EAs; n=6,845). 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 to population controls. Independent replication testing was conducted in 755 AAs and 1,131 EAs from the Genetic Association Information Network. An intronic SNP (rs9829896) in the 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.

Genome-wide association meta-analysis of cocaine dependence: Shared genetics with comorbid conditions

“…However, based on the prevalence of cocaine dependence (about 1.1%), the probability of false negative results due to this effect is low, and similar controls were used in other GWAS of drug addiction (Johnson et al 2016). …”

Human Genetics of Addiction: New Insights and Future Directions

“…Next, GWAS of people who inject drugs vs. controls, revealed an African American-specific association for the intronic SNP rs9829896 in the lysine acetyltransferase gene ( KAT2B ; P=4.6×10 −8 , N=3,742), which replicated in an independent dataset (P=0.0016, N=755) [119]. Follow-up analyses in postmortem human PFC implicated rs9829896 as a cis -eQTL SNP, specifically in African Americans, for KAT2B and other genes in KAT2B -containing pathways, including OPRM1 and the CREB binding protein ( CREBBP ) genes [119] that have been highlighted in prior SNP- or pathway-based analyses of opioid phenotypes [109, 112, 116].…”

“…Given the high levels of co-morbidity across drugs of abuse and the plausible shared heritability underlying susceptibility to developing addiction in general, three GWAS have combined cases addicted to any illicit drug [18, 118, 119]. Two of these GWAS reported genome-wide significant and replicable associations.…”

A Review of Genome-Wide Association Studies of Stimulant and Opioid Use Disorders

“…Johnson et al [60] conducted a GWAS of drug abuse in a sample that included 3,742 AA and 6,845 EA subjects. The majority of cases were recent opioid (>60%) and cocaine (>25%) users, while the control subjects included unassessed population controls and subjects that were negative for SUDs based on an assessment that used DSM-IV criteria.…”

“…No significant effects were detected in the EA sample. In interesting follow-up studies, Johnson et al [60] showed that rs9829896 was associated with KAT2B mRNA expression in postmortem brains from AA subjects, but not EA subjects. A KAT2B -centric network of 20 proteins that share pathways, physical interactions and protein domains was predicted.…”