Abstract
Substance dependence or addiction is a complex environmental and genetic disorder that results in serious health and socio-economic consequences. Multiple substance dependence categories together, rather than any one individual addiction outcome, may explain the genetic variability of such disorder. In our study, we defined a composite substance dependence phenotype derived from six individual diagnoses: addiction to nicotine, alcohol, marijuana, cocaine, opiates or other drugs as a whole. Using data from several genomewide case-control studies, we identified a strong (Odds ratio = 1.77) and significant (p-value = 7E-8) association signal with a novel gene, PBX/knotted 1 homeobox 2 (PKNOX2), on chromosome 11 with the composite phenotype in European-origin women. The association signal is not as significant when individual outcomes for addiction are considered, or in males or African-origin population. Our findings underscore the importance of considering multiple addiction types and the importance of considering population and gender stratification when analyzing data with heterogeneous population.
Highlights
Substance dependence or addiction is one of the most soughtafter phenomena in many populations because of its serious health and socio-economic consequences
Multiple variants at the aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH) loci have been well documented as genes of major genetic effect especially in East-Asian populations [12,13,14,15]
We further examined association of haplotypes with the composite phenotype in this region, but they did not enhance the strength of the associations; these results are not reported here
Summary
Substance dependence or addiction is one of the most soughtafter phenomena in many populations because of its serious health and socio-economic consequences. Well studied genes for alcohol dependence, such as GABRA2, CHRM2 and ADH4, have been replicated in many samples [7,8,9,10], while several newer candidate genes (GABRG3, TAS2R16, SNCA, OPRK1 and PDYN) remain to be confirmed [11]. Multiple variants at the aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH) loci have been well documented as genes of major genetic effect especially in East-Asian populations [12,13,14,15]. Li [20] reported thirteen regions on chromosomes 3–7, 9–11, 17, 20, and 22, to be significantly associated with nicotine dependence in at least two independent samples, a significant number of reported genomic regions did not reach the level of ‘‘suggestive’’ or ‘‘significant’’ linkage and failed to be replicated in other independent studies
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