Author(s): Renato Polimanti aff1 aff2 , Can Yang aff1 aff3 , Hongyu Zhao aff3 aff4 , Joel Gelernter [*] aff1 aff2 aff4 aff5
African-Americans; ethnicity; European-Americans; substance dependence
Substance dependence (SD) is an important problem in the US population, and for many others worldwide, with a substantial impact on medical health, quality of life, security and economics [1 ]. Genetic epidemiology studies have shown that drug dependence has high hereditability, highlighting a genetic component regulating risk for these phenotypes [2,3 ]. Recent genome-wide association studies (GWAS) of SD traits have identified numerous significant risk alleles across the human genome [4-7 ]. Although replication studies and functional investigations have, in some cases, confirmed the role of these alleles in the predisposition to drug dependence [8-11 ], certain risk alleles have failed in replication efforts in independent study populations, likely due in part to the presence of heterogeneity and to other several confounding factors, including differences in ancestry in the samples being studied [12,13 ] (as well as, in some cases, the original results being false positives). Indeed, in studies of other complex phenotypes, including SD, there are three situations in which ancestry confounding effects are seen: genes significantly associated with the phenotype in one ancestry group, but not in other ancestry groups; genes associated with the phenotype in more than one ancestry group, but with different groups presenting specific associated alleles; and alleles associated with the phenotype in different ancestry groups with ancestry-related differences in association strength. These confounders are largely attributable to the basic genetic differences that are present among human populations and that distinguish them. Indeed, large allele frequency differences (ΔF) are, of course, present among human populations, generating human phenotype diversity [14 ]. Many studies have investigated human genetic variation to understand the role that population demographic history or the environment plays in shaping the evolution of the human genome through natural selection [15,16 ]. Furthermore, some investigations have deepened the understanding of the role ancestry-related genetic variation plays in identifying the significant differences in genetic predisposition to health-related phenotypes among human populations [17-20 ]. Regarding drug dependence specifically, genetic studies have highlighted significant differences in genetic predisposition among populations, especially between European and African ancestries, which are the most studied [4,5 ]. Furthermore, epidemiologic studies indicated ethnic disparities in the prevalence of substance dependence traits among ancestry groups [ 21-23 ]. However, to our knowledge, no studies have endeavored to explain the genetic mechanisms at the basis of ancestry-related differences in genetic predisposition to drug dependence. To do this, we hypothesized that common alleles with large interethnic ΔFs and/or interethnic variation in rare variants occurrences (i.e., instances where multiple rare alleles are observed in a gene in only one population) in genes associated to substance dependence traits may have effects on risk alleles, partially explaining the association differences observed among human populations. These differences may also be attributable to the ancestry-related variation of genes encoding proteins that interact with the protein products of other SD-associated genes via protein-protein interactions.
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