Abstract
Epistatic gene–gene 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 gene–gene–drug interaction affecting risk of fatal cocaine intoxication.
Highlights
Genetic factors contribute to complex human traits and diseases, but the extent of genetic influence often remains uncertain.[2]
Three DRD2 and four DAT variants (SNPs and repeat polymorphisms) (Table 1) were genotyped using several methods: rs27072 and rs6347 were genotyped by SNaPshot (Life Technologies, Carlsbad, CA, USA), rs12364283 was genotyped with allele-specific PCR, while rs2283265 and rs1076560 were genotyped via modified PCR-restriction fragment length polymorphism (RFLP) methods.[1,24,33]
The 30UTR 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%)
Summary
Genetic factors contribute to complex human traits and diseases, but the extent of genetic influence often remains uncertain.[2] Addressing the ‘mystery of missing heritability’, Zuk et al.[3] posit that interactions among loci (epistasis) may account at least in part for the gap between known genetic risk factors and estimated overall heritability in a population. In C. elegans, genetic variation in catechol/peptide receptors and environmental cues (npr-1/tyra-3/nutrient supply) converge to regulate behavioral decisions,[11] suggesting an ancient evolutionary role of catecholamine signaling—a rare example of a gene–gene–environment interaction. Several genes involved in behavioral modulation carry frequent variants, often regulating gene expression and mRNA processing or translation.[12,13] As these variants may be considered to reside within a normal range, they are typically not recognized as disease risk factors in GWAS analyses, but in the context of environmental challenge and epistatic interactions, may incur strong risk. We tested a gene–gene–drug (environment) interaction affecting risk of cocaine-induced death, using statistical genetics methods
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