Genome Wide Association for Addiction: Replicated Results and Comparisons of Two Analytic Approaches

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

Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs

BACKGROUND: Classical genetic studies indicate that nicotine dependence is a substantially heritable complex disorder. Genetic vulnerabilities to nicotine dependence largely overlap with genetic vulnerabilities to dependence on other addictive substances. Successful abstinence from nicotine displays substantial heritable components as well. Some of the heritability for the ability to quit smoking appears to overlap with the genetics of nicotine dependence and some does not. We now report genome wide association studies of nicotine dependent individuals who were successful in abstaining from cigarette smoking, nicotine dependent individuals who were not successful in abstaining and ethnically-matched control subjects free from substantial lifetime use of any addictive substance. RESULTS: These data, and their comparison with data that we have previously obtained from comparisons of four other substance dependent vs control samples support two main ideas: 1) Single nucleotide polymorphisms (SNPs) whose allele frequencies distinguish nicotine-dependent from control individuals identify a set of genes that overlaps significantly with the set of genes that contain markers whose allelic frequencies distinguish the four other substance dependent vs control groups (p < 0.018). 2) SNPs whose allelic frequencies distinguish successful vs unsuccessful abstainers cluster in small genomic regions in ways that are highly unlikely to be due to chance (Monte Carlo p < 0.00001). CONCLUSION: These clustered SNPs nominate candidate genes for successful abstinence from smoking that are implicated in interesting functions: cell adhesion, enzymes, transcriptional regulators, neurotransmitters and receptors and regulation of DNA, RNA and proteins. As these observations are replicated, they will provide an increasingly-strong basis for understanding mechanisms of successful abstinence, for identifying individuals more or less likely to succeed in smoking cessation efforts and for tailoring therapies so that genotypes can help match smokers with the treatments that are most likely to benefit them

Genome wide association for substance dependence: convergent results from epidemiologic and research volunteer samples

<p>Abstract</p> <p>Background</p> <p>Dependences on addictive substances are substantially-heritable complex disorders whose molecular genetic bases have been partially elucidated by studies that have largely focused on research volunteers, including those recruited in Baltimore. Maryland. Subjects recruited from the Baltimore site of the Epidemiological Catchment Area (ECA) study provide a potentially-useful comparison group for possible confounding features that might arise from selecting research volunteer samples of substance dependent and control individuals. We now report novel SNP (single nucleotide polymorphism) genome wide association (GWA) results for vulnerability to substance dependence in ECA participants, who were initially ascertained as members of a probability sample from Baltimore, and compare the results to those from ethnically-matched Baltimore research volunteers.</p> <p>Results</p> <p>We identify substantial overlap between the home address zip codes reported by members of these two samples. We find overlapping clusters of SNPs whose allele frequencies differ with nominal significance between substance dependent <it>vs </it>control individuals in both samples. These overlapping clusters of nominally-positive SNPs identify 172 genes in ways that are never found by chance in Monte Carlo simulation studies. Comparison with data from human expressed sequence tags suggests that these genes are expressed in brain, especially in hippocampus and amygdala, to extents that are greater than chance.</p> <p>Conclusion</p> <p>The convergent results from these probability sample and research volunteer sample datasets support prior genome wide association results. They fail to support the idea that large portions of the molecular genetic results for vulnerability to substance dependence derive from factors that are limited to research volunteers.</p

Common Human 5′ Dopamine Transporter (SLC6A3) Haplotypes Yield Varying Expression Levels In Vivo

1. Individuals display significant differences in their levels of expression of the dopamine transporter (DAT; SLC6A3). These differences in DAT are strong candidates to contribute to individual differences in motor, mnemonic and reward functions. To identify “cis”-acting genetic mechanisms for these individual differences, we have sought variants in 5′ aspects of the human DAT gene and identified the haplotypes that these variants define.2. We report (i) significant relationships between 5′ DAT haplotypes and human individual differences in ventral striatal DAT expression assessed in vivo using [11C] cocaine PET and (ii) apparent confirmation of these results in studies of DAT expression in postmortem striatum using [3H] carboxyflurotropane binding.3. These observations support the idea that cis-acting variation in 5′ aspects of the human DAT/SLC6A3 locus contributes to individual differences in levels of DAT expression in vivo. 5′ DAT variation is thus a good candidate to contribute to individual differences in a number of human phenotypes