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 direc 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 repsubstance dependent and control African-American samples from a community representative sample from the Prevention Study. 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 responses to prevention interventions. We continued to make major advances in providing simulations and modeling for the power of genome-wide and focused association/linkage-disequilibrium based genome scanning. 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)

Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2011
Total Cost
$515,043
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
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
Musci, Rashelle J; Bradshaw, Catherine P; Maher, Brion et al. (2014) Erratum to: Reducing Aggression and Impulsivity Through School-Based Prevention Programs: A Gene by Intervention Interaction. Prev Sci :
Uhl, George R; Drgonova, Jana (2014) Cell adhesion molecules: druggable targets for modulating the connectome and brain disorders? Neuropsychopharmacology 39:235
Uhl, George R; Drgonova, Jana; Hall, F Scott (2014) Curious cases: Altered dose-response relationships in addiction genetics. Pharmacol Ther 141:335-46
Musci, Rashelle J; Bradshaw, Catherine P; Maher, Brion et al. (2014) Reducing aggression and impulsivity through school-based prevention programs: a gene by intervention interaction. Prev Sci 15:831-40
Uhl, G R; Walther, D; Musci, R et al. (2014) Smoking quit success genotype score predicts quit success and distinct patterns of developmental involvement with common addictive substances. Mol Psychiatry 19:50-4
Bruehl, Stephen; Apkarian, A Vania; Ballantyne, Jane C et al. (2013) Personalized medicine and opioid analgesic prescribing for chronic pain: opportunities and challenges. J Pain 14:103-13
Bough, K J; Lerman, C; Rose, J E et al. (2013) Biomarkers for smoking cessation. Clin Pharmacol Ther 93:526-38
Hall, F Scott; Drgonova, Jana; Jain, Siddharth et al. (2013) Implications of genome wide association studies for addiction: are our a priori assumptions all wrong? Pharmacol Ther 140:267-79
Hall, F Scott; Markou, Athina; Levin, Edward D et al. (2012) Mouse models for studying genetic influences on factors determining smoking cessation success in humans. Ann N Y Acad Sci 1248:39-70

Showing the most recent 10 out of 35 publications