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Dissecting ancestry genomic background in substance dependence genome-wide association studies.

ABSTRACT: AIMS:To understand the role of ancestral genomic background in substance dependence (SD) genome-wide association studies (GWAS), we analyzed population diversity at genetic loci associated with SD traits and evaluated its effect on GWAS outcomes. MATERIALS & METHODS:We investigated 24 genes with variants associated with SD by GWAS; and 82 loci with putative subordinate roles with respect to SD-associated genes. RESULTS:We observed high ancestry-related frequency differences in common functional alleles in GWAS relevant genes and their interactive partners. Common functional alleles with high frequency differences demonstrated significant effects on the GWAS outcomes. CONCLUSION:Population differences in SD GWAS outcomes seem not to be influenced by general variation across the genome, but by ancestry-related local haplotype structures at SD-associated loci.

SUBMITTER: Polimanti R

PROVIDER: S-EPMC4632979 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Dissecting ancestry genomic background in substance dependence genome-wide association studies.

Polimanti Renato R Yang Can C Yang Can C Zhao Hongyu H Gelernter Joel J

Pharmacogenomics 20150812 13

<h4>Aims</h4>To understand the role of ancestral genomic background in substance dependence (SD) genome-wide association studies (GWAS), we analyzed population diversity at genetic loci associated with SD traits and evaluated its effect on GWAS outcomes.<h4>Materials & methods</h4>We investigated 24 genes with variants associated with SD by GWAS; and 82 loci with putative subordinate roles with respect to SD-associated genes.<h4>Results</h4>We observed high ancestry-related frequency differences ...[more]

PMID: 26267224

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Project description:Drug addiction, or substance use disorder (SUD), is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behaviour persist despite serious negative consequences. Drug abuse represents a problem that deserves great attention from a social point of view, and focuses on the importance of genetic studies to help in understanding the genetic basis of addiction and its medical treatment. Despite the complexity of drug addiction disorders, and the high number of environmental variables playing a role in the onset, recurrence, and duration of the symptoms, several studies have highlighted the non-negligible role of genetics, as demonstrated by heritability and genome-wide association studies. A correlation between the relative risk of addiction to specific substances and heritability has been recently observed, suggesting that neurobiological mechanisms may be, at least in part, inherited. All these observations point towards a scenario where the core neurobiological factors of addiction, involving the reward system, impulsivity, compulsivity, stress, and anxiety response, are transmitted, and therefore, genes and mutations underlying their variation might be detected. In the last few years, the development of new and more efficient sequencing technologies has paved the way for large-scale studies in searching for genetic and epigenetic factors affecting drug addiction disorders and their treatments. These studies have been crucial to pinpoint single nucleotide polymorphisms (SNPs) in genes that affect the reaction to medical treatments. This is critically important to identify pharmacogenomic approaches for substance use disorder, such as OPRM1 SNPs and methadone required doses for maintenance treatment (MMT). Nevertheless, despite the promising results obtained by genome-wide association and pharmacogenomic studies, specific studies related to population genetics diversity are lacking, undermining the overall applicability of the preliminary findings, and thus potentially affecting the portability and the accuracy of the genetic studies. In this review, focusing on cannabis, cocaine and heroin use, we report the state-of-the-art genomics and pharmacogenomics of SUDs, and the possible future perspectives related to medical treatment response in people that ask for assistance in solving drug-related problems.

Project description:Declaring "replication" from results of genome wide association (GWA) studies is straightforward when major gene effects provide genome-wide significance for association of the same allele of the same SNP in each of multiple independent samples. However, such unambiguous replication is unlikely when phenotypes display polygenic genetic architecture, allelic heterogeneity, locus heterogeneity and when different samples display linkage disequilibria with different fine structures. We seek chromosomal regions that are tagged by clustered SNPs that display nominally-significant association in each of several independent samples. This approach provides one "nontemplate" approach to identifying overall replication of groups of GWA results in the face of difficult genetic architectures. We apply this strategy to 1 M SNP GWA results for dependence on: a) alcohol (including many individuals with dependence on other addictive substances) and b) at least one illegal substance (including many individuals dependent on alcohol). This approach provides high confidence in rejecting the null hypothesis that chance alone accounts for the extent to which clustered, nominally-significant SNPs from samples of the same racial/ethnic background identify the same sets of chromosomal regions. It identifies several genes that are also reported in other independent alcohol-dependence GWA datasets. There is more modest confidence in: a) identification of individual chromosomal regions and genes that are not also identified by data from other independent samples, b) the more modest overlap between results from samples of different racial/ethnic backgrounds and c) the extent to which any gene not identified herein is excluded, since the power of each of these individual samples is modest. Nevertheless, the strong overlap identified among the samples with similar racial/ethnic backgrounds supports contributions to individual differences in vulnerability to addictions that come from newer allelic variants that are common in subsets of current humans.

Dataset Information

Dissecting ancestry genomic background in substance dependence genome-wide association studies.

Publications

Dissecting ancestry genomic background in substance dependence genome-wide association studies.

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