Abstract
BackgroundDependences 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.ResultsWe 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 vs 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.ConclusionThe 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.
Highlights
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
28,137 SNPs displayed "nominally positive" t values with p < 0.05 in these Epidemiological Catchment Area (ECA) samples. 7,620 of these nominally positive SNPs fell into 1660 clusters of at least 3 SNPs that came from both array types were separated from adjacent nominally-positive SNPs by less than 25,000 basepairs
When we examined the overlap between the 7620 clustered positive SNPs from the ECA samples and: 1) the 2.5% of the SNPs for which the noise in validating studies was highest and 2) the 2.5% of SNPs that displayed the largest differences between Baltimore African-American vs European American control individuals, we found 15 and 245, respectively, vs 185 expected by chance in each case
Summary
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. We 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. Combined data from linkage and genome wide association (GWA) datasets [6,7,8,9,10,11] suggest that most of the genetics of vulnerability to dependence on addictive substances is likely to be polygenic, arising from variants in genes whose influences on vulnerability, taken one at a time, are relatively modest. We have compared allele frequencies at ca 1500, 10,000, 100,000, 500,000 and 1,000,000 SNP markers in increasing numbers of substance dependent vs control individuals from this growing sample, including 680 substance dependent or control individuals with self reported European ancestries [6,7,8,9,11], (Drgon et al, submitted)
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