Polysubstance Abuse–Vulnerability Genes: Genome Scans for Association, Using 1,004 Subjects and 1,494 Single-Nucleotide Polymorphisms

Abstract

Strong genetic contributions to drug abuse vulnerability are well documented, but few chromosomal locations for human drug-abuse vulnerability alleles have been confirmed. We now identify chromosomal markers whose alleles distinguish drug abusers from control individuals in each of two samples, on the basis of pooled-sample microarray and association analyses. Reproducibly positive chromosomal regions defined by these markers in conjunction with previous results were especially unlikely to have been identified by chance. Positive markers identify the alcohol dehydrogenase (ADH) locus, flank the brain-derived neurotropic factor (BDNF) locus, and mark seven other regions previously linked to vulnerability to nicotine or alcohol abuse. These data support polygenic contributions of common allelic variants to polysubstance abuse vulnerability.

Molecular genetics of addiction vulnerability

“…[22][23][24][25][26][27][28][29][30][31][32][33][34] Only a few of the results of these studies have converged convincingly, with the major linkage peak produced by a number of studies being poorly, if at all, supported by subsequent data (e.g., see [22][23][24][25][26] ). Indeed, assemblies of current results from at least some linkage-based genomes can produce results that cover the majority of the genome with data that derive from at least some reported linkage peak in at least one study (C Johnson, GR Uhl, unpublished observations, 2005).…”

“…Our addiction vulnerability association genome scans compared allelic frequencies beginning with 1494 and progressing to 11,522, then 126,000, and, more recently, 520,000 single nucleotide polymorphisms (SNPs) in each of two growing samples of unrelated polysubstance abusers and controls who reported no substantial lifetime use of any addictive substance. 34,35 Initial data identified 41 of 1494 SNPs and 38 of 11,522 SNPs that displayed nominally "reproducibly positive" allele frequency differences between abuser and controls in both European-and AfricanAmerican samples using increasingly stringent criteria. These "reproducibly positive" markers (Table 1) clustered much closer to positive markers from linkage studies of addictions than anticipated by chance.…”

“…These "reproducibly positive" markers (Table 1) clustered much closer to positive markers from linkage studies of addictions than anticipated by chance. [33][34][35] However, this total of 13,015 SNPs provided information about possible associations with addiction for only a modest number of the blocks of restricted haplotype diversity found in these subjects' genomes and thus only modest power (FIG. 1).…”

“…38 First, we began fine mapping studies of the region of chromosome 7 that contained one of the more strongly associated SNPs from our initial study of 1500 microarray data in a region that also contained the strongest linkage to alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (wave I). 23,34 After typing many markers in this region, we identified 5= NrCAM haplotypes that are associated with substance abuse vulnerabilities in each of four samples of abusers versus controls, with the same "phase" of association in abuser/control comparisons from European-American, African-American, and Asian samples. 38 Independently, we had also isolated NrCAM as a gene whose expression levels were regulated by morphine based on a subtracted hybridization/ differential display assay, data that also characterize Nr-CAM as a drug-regulated gene.…”

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

“…In other investigations of interest to the current study, cigarette smoking with or without AD, were linked to broad regions of chromosomes 9 and 11. [4][5][6][7][8][9] Among the candidate addiction susceptibility genes defined by these linkage signals were those that encode the neurotrophin, brainderived neurotrophic factor (BDNF, chromosome 11), and its cognate receptor, neurotrophic tyrosine kinase receptor B (TrkB) (NTRK2, chromosome 9).…”