Individual differences in drug abuse vulnerabilities among humans display genetic as well as environmental components. During this year, these investigators continued to explore roles of allelic variants at gene loci in contributing to human individual differences in drug abuse vulnerability and in individual differences in related phenotypes. We reported that results of GWA approaces using 1M SNP arrays from our laboratory overlapped (eg identified many of the same genes as) those now available in dbGAP for cocaine dependence and for alcohol dependence. We reported the first direct evidence that many of the allelic variants that predispose to addiction vulnerability differ substantially between dependent individuals of African- vs European-American ancestries, as well as noting that some variants are also similar. We completed analyses of substance dependent and control African-American samples from a community representative sample from the Prevention Study. In these samples, we identified individual differences in rate at which use of addictive substances is taken up during adolescence using a latent class approach. Individual differences in probabilities of membership in two of these classes were strongly associated with individual differences in a quit success genotype score, linking (for the first time) genetic influences on uptake of addictive substance use with those on abilities to quit (smoking, at least) . Taken together, these data provide substantial support for many gene loci as containing allelic variants that confer vulnerability to substance abuse in individuals of African-American, European-American and Asian genetic backgrounds, as well as overlaps between these loci and those that may provide individual differences in rate of uptake of substance use and even responses to prevention interventions. In new work reported this year, we also identify the first human variants that predispose to individual differences in preference for menthol among smokers. This work implicates a common haplotype in the TRPA1 gene that provides one of the principal menthol """"""""receptors"""""""", and provides one possible genetic contributor to racial/ethnic differences in prefernce for mentholated cigarettes. Several chromosomal regions previously nomninated by our studies have been replicated in new work completed during this year, and in datasets from other laboratories that became available during this year. Fine mapping studies have identified particular haplotypes at several gene loci that represent the strongest candidates for addiction vulnerability genes in humans. These studies point toward a role for individual differences in brain structures, as well as functions, in vulnerability to addictions and especial roles for genes encoding molecules that participate in cell adhesion mechanisms. These human data for the most strongly supported genes are now supported by results from studies in mouse models (see other annual reports)

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Lee, Chun-Ting; Bendriem, Raphael M; Kindberg, Abigail A et al. (2015) Functional consequences of 17q21.31/WNT3-WNT9B amplification in hPSCs with respect to neural differentiation. Cell Rep 10:616-32
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