Search

Addictions are substantially heritable complex disorders. We now report whole genome association studies that identify 89 genes likely to contain variants that contribute to addiction vulnerability, using previously- and newly-validated microarray based pooling assays. Each gene contains clustered single nucleotide polymorphisms (SNPs) that display significant allele frequency differences between abusers and controls in each of the two samples studied with 639,401 SNP arrays and confirmatory SNPs from each of two other abuser/control samples. These genes are implicated in interesting functions, including "cell adhesion" processes that help to establish and maintain neuronal connections of special relevance to addiction's memory-like features., ((c) 2006 Wiley-Liss, Inc.)

Background: Vulnerabilities to dependence on addictive substances are substantially heritable complex disorders whose underlying genetic architecture is likely to be polygenic, with modest contributions from variants in many individual genes. ''Nontemplate'' genome wide association (GWA) approaches can identity groups of chromosomal regions and genes that, taken together, are much more likely to contain allelic variants that alter vulnerability to substance dependence than expected by chance. Methodology/Principal Findings: We report pooled ''nontemplate'' genome-wide association studies of two independent samples of substance dependent vs control research volunteers (n = 1620), one European-American and the other African- American using 1 million SNP (single nucleotide polymorphism) Affymetrix genotyping arrays. We assess convergence between results from these two samples using two related methods that seek clustering of nominally-positive results and assess significance levels with Monte Carlo and permutation approaches. Both ''converge then cluster'' and ''cluster then converge'' analyses document convergence between the results obtained from these two independent datasets in ways that are virtually never found by chance. The genes identified in this fashion are also identified by individually-genotyped dbGAP data that compare allele frequencies in cocaine dependent vs control individuals. Conclusions/Significance: These overlapping results identify small chromosomal regions that are also identified by genome wide data from studies of other relevant samples to extents much greater than chance. These chromosomal regions contain more genes related to ''cell adhesion'' processes than expected by chance. They also contain a number of genes that encode potential targets for anti-addiction pharmacotherapeutics. ''Nontemplate'' GWA approaches that seek chromosomal regions in which nominally-positive associations are found in multiple independent samples are likely to complement classical, ''template'' GWA approaches in which ''genome wide'' levels of significance are sought for SNP data from single case vs control comparisons. [ABSTRACT FROM AUTHOR]

Abundant evidence from family, adoption, and twin studies point to large genetic contributions to individual differences in vulnerability to develop dependence on one or more addictive substances. Twin data suggest that most of this genetic vulnerability is shared by individuals who are dependent on a variety of addictive substances. Molecular genetic studies, especially genomewide and candidate gene association studies, have elucidated common haplotypes in dozens of genes that appear to make polygenic contributions to vulnerability to developing dependence. Most genes that harbor currently identified addiction-associated haplotypes are expressed in the brain. Haplotypes in many of the same genes are identified in genomewide association studies that compare allele frequencies in substance dependent vs. control individuals from European, African, and Asian racial/ethnic backgrounds. Many of these addiction-associated haplotypes display pleiotropic influences on a variety of related brain-based phenotypes that display 1) substantial heritability and 2) clinical cooccurence with substance dependence. [ABSTRACT FROM AUTHOR]

Association genome scanning is of increasing interest for identifying the chromosomal regions that contain gene variants that contribute to vulnerability to complex disorders, including addictions. To improve the power and feasibility of this approach, we have validated "10k" microarray-based allelic frequency assessments in pooled DNA samples and have used this approach to seek allelic frequency differences between heavy polysubstance abusers and well characterized control individuals. Thirty-eight loci contain SNPs that display robust allele frequency differences between abusers and controls in both European- and Africa n- American samples. These loci identify an alcohol/acetaldehyde dehydrogenase gene cluster and genes implicated in cellular signaling, gene regulation, development, "cell adhesion," and Mendelian disorders. The results converge with previous linkage and association results for addictions. Pooled association genome scanning provides a useful tool for elucidating molecular genetic underpinnings of complex disorders and identifies both previously understood and previously unanticipated mechanisms for addiction vulnerability. [ABSTRACT FROM AUTHOR]