Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a genegeneenvironment interaction

abstract: ...Epistatic genegene interactions could contribute to the heritability of complex multigenic disorders, but few examples have been reported. Here, we focus on the role of aberrant dopaminergic signaling, involving the dopamine transporter DAT, a cocaine target, and the dopamine D2 receptor, which physically interacts with DAT. Splicing polymorphism rs2283265 of DRD2, encoding D2 receptors, were shown to confer risk of cocaine overdose/death (odds ratio 3) in subjects and controls from the Miami Dade County Brain Bank. 1 Risk of cocaine-related death attributable to the minor allele of rs2283265 was significantly enhanced to OR=7.5 ( P =0.0008) in homozygous carriers of the main 6-repeat allele of DAT rs3836790, a regulatory VNTR in intron8 lacking significant effect itself. In contrast, carriers of the minor 5-repeat DAT allele showed no significant risk (OR=1.1, P =0.84). DAT rs3836790 and DRD2 rs2283265 also interacted by modulating DAT protein activity in the ventral putamen of cocaine abusers. In high-linkage disequilibrium with the VNTR, DAT rs6347 in exon9 yielded similar results. Assessing the impact of DAT alone, a rare DAT haplotype formed by the minor alleles of rs3836790 and rs27072, a regulatory DAT variant in the 3-UTR, occurred in nearly one-third of the cocaine abusers but was absent in African American controls, apparently conferring strong risk. These results demonstrate genegenedrug interaction affecting risk of fatal cocaine intoxication.

... significant effect itself. In contrast, carriers of the minor 5-repeat DAT allele showed no significant risk (OR=1.1, P =0.84). DAT rs3836790 and DRD2 rs2283265 also interacted by modulating DAT protein activity in the ventral putamen of cocaine abusers. In high-linkage disequilibrium with the VNTR, DAT rs6347 in exon9 yielded similar results. Assessing the impact of DAT alone, a rare DAT haplotype formed by the minor alleles of rs3836790 and rs27072, a regulatory DAT variant in the 3-UTR, occurred in

... shown that the intron8 5-repeat is associated with reduced DAT mRNA levels in human substantia nigra; however, exon9 rs6347 is in high LD with the 5/6-repeat, and therefore, cannot be excluded as a contributor to altered expression. 24 Moreover, the 3-UTR SNP rs27072 (MAF 18%) affects DAT mRNA expression and translation, the latter regulated by the overall DAT mRNA levela mechanism that may involve microRNA regulation and translational control. 24 No evidence was obtained for a regulatory role of

... records, hospital and treatment admissions). Drug-free age-matched control subjects were selected from accidental or cardiac sudden deaths with negative urine screens for all common drugs, with no history of psychiatric disorders or licit or illicit drug use prior to death. Genotyping methods DNA was extracted from all tissues as described. 33 Three DRD2 and four DAT variants (SNPs and repeat polymorphisms) ( Table 1 ) were genotyped using several methods: rs27072 and rs6347 were genotyped by SNaPshot

... infrequent to yield robust results. Having intermediate allele frequency, DAT rs27072 was considered independently, particularly in the context of DAT haplotypes, whereas our previous results had failed to assign a regulatory function to the 9/10 repeat rs28363170; for comparison to earlier studies, the 9/10 repeat was included here as well. Measured genotypes were lacking in a few samples ( Table 2 ), assumed missing completely at random, and available-case analysis was implemented to reflect all available data. 38 STATA 11 (StataCorp LP, College Station, TX, USA) was used for statistical analyses. Haplotype analysis Haplotype frequencies of DAT variants (rs6347, intron8 rs38366790, rs27072, 9/10 repeat rs2836317) were estimated using the EM algorithm separately by race, and case status, with both STATA's haplologit command and R's haplo.em (haplo.stats package from R software; http://cran.r-project.org/ ). R's haplo.stats package served to estimate posterior probabilities of diplotypes. STATA's

...). In contrast, the 5-repeat of DAT rs3836790 was more prevalent in African Americans (66 versus 25%). Being in LD with rs3836790, DAT rs6347 has similar distributions ( Supplementary Table 2 ). The 3UTR variant rs27072 was nearly equal in frequency in Caucasians and African Americans (MAF 15 and 17%, respectively), while the 9-repeat of rs28363170 was more frequent in Caucasians than African Americans (30 versus 22%). Single variant cocaine case-control associations Logistic regression results were

... and intron 8 5/6-repeat ( D =0.8, r 2 =0.56, Supplementary Table 2 ), we cannot ascertain whether rs6347 has independent effects. Haplotype-associated risk in African Americans The finding of possible risk of cocaine-related death associated with DAT 3UTR rs27072 with potentially opposite effects in Caucasians and African Americans ( Table 2 ; but lacking nominal significance) prompted analysis of haplotype structures. Haplotype frequencies estimated from the four DAT variants (rs6347, intron8

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