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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.

SUBMITTER: Johnson EO

PROVIDER: S-EPMC4724343 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Johnson Eric O EO Hancock Dana B DB Levy Joshua L JL Gaddis Nathan C NC Page Grier P GP Glasheen Cristie C Saccone Nancy L NL Bierut Laura J LJ Kral Alex H AH

Addiction biology 20150723 6

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 ...[more]

PMID: 26202629

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Project description:BackgroundNeuropsychiatric disorders afflict a large portion of the global population and constitute a significant source of disability worldwide. Although Genome-wide Association Studies (GWAS) have identified many disorder-associated variants, the underlying regulatory mechanisms linking them to disorders remain elusive, especially those involving distant genomic elements. Expression quantitative trait loci (eQTLs) constitute a powerful means of providing this missing link. However, most eQTL studies in human brains have focused exclusively on cis-eQTLs, which link variants to nearby genes (i.e., those within 1 Mb of a variant). A complete understanding of disease etiology requires a clearer understanding of trans-regulatory mechanisms, which, in turn, entails a detailed analysis of the relationships between variants and expression changes in distant genes.MethodsBy leveraging large datasets from the PsychENCODE consortium, we conducted a genome-wide survey of trans-eQTLs in the human dorsolateral prefrontal cortex. We also performed colocalization and mediation analyses to identify mediators in trans-regulation and use trans-eQTLs to link GWAS loci to schizophrenia risk genes.ResultsWe identified ~80,000 candidate trans-eQTLs (at FDR<0.25) that influence the expression of ~10K target genes (i.e., "trans-eGenes"). We found that many variants associated with these candidate trans-eQTLs overlap with known cis-eQTLs. Moreover, for >60% of these variants (by colocalization), the cis-eQTL's target gene acts as a mediator for the trans-eQTL SNP's effect on the trans-eGene, highlighting examples of cis-mediation as essential for trans-regulation. Furthermore, many of these colocalized variants fall into a discernable pattern wherein cis-eQTL's target is a transcription factor or RNA-binding protein, which, in turn, targets the gene associated with the candidate trans-eQTL. Finally, we show that trans-regulatory mechanisms provide valuable insights into psychiatric disorders: beyond what had been possible using only cis-eQTLs, we link an additional 23 GWAS loci and 90 risk genes (using colocalization between candidate trans-eQTLs and schizophrenia GWAS loci).ConclusionsWe demonstrate that the transcriptional architecture of the human brain is orchestrated by both cis- and trans-regulatory variants and found that trans-eQTLs provide insights into brain-disease biology.

Dataset Information

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

Publications

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

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