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Background.Genetic influences contribute significantly to co-morbidity between conduct disorder and substance use disorders. Estimating the extent of overlap can assist in the development of phenotypes for genomic analyses.Method.Multivariate quantitative genetic analyses were conducted using data from 9577 individuals, including 3982 complete twin pairs and 1613 individuals whose co-twin was not interviewed (aged 24–37 years) from two Australian twin samples. Analyses examined the genetic correlation between alcohol dependence, nicotine dependence and cannabis abuse/dependence and the extent to which the correlations were attributable to genetic influences shared with conduct disorder.Results.Additive genetic (a2 = 0.48–0.65) and non-shared environmental factors explained variance in substance use disorders. Familial effects on conduct disorder were due to additive genetic (a2 = 0.39) and shared environmental (c2 = 0.15) factors. All substance use disorders were influenced by shared genetic factors (rg = 0.38–0.56), with all genetic overlap between substances attributable to genetic influences shared with conduct disorder. Genes influencing individual substance use disorders were also significant, explaining 40–73% of the genetic variance per substance.Conclusions.Among substance users in this sample, the well-documented clinical co-morbidity between conduct disorder and substance use disorders is primarily attributable to shared genetic liability. Interventions targeted at generally reducing deviant behaviors may address the risk posed by this shared genetic liability. However, there is also evidence for genetic and environmental influences specific to each substance. The identification of these substance-specific risk factors (as well as potential protective factors) is critical to the future development of targeted treatment protocols. [ABSTRACT FROM PUBLISHER]

Background Alcohol and nicotine codependence can be considered as a more severe subtype of alcohol dependence. A portion of its risk may be attributable to genetic factors. Methods We searched for significant risk genomic regions specific for this disorder using a genome-wide association study. A total of 8,847 subjects underwent gene-disease association analysis, including (i) a discovery cohort of 818 European American cases with alcohol and nicotine codependence and 1,396 European American controls, (ii) a replication cohort of 5,704 Australian family subjects with 907 affected offspring, and (iii) a replication cohort of 449 African American cases and 480 African American controls. Additionally, a total of 38,714 subjects of European or African descent in 18 independent cohorts with 10 other nonalcoholism neuropsychiatric disorders were analyzed as contrast. Furthermore, 90 unrelated Hap Map CEU individuals, 93 European brain tissue samples, and 80 European peripheral blood mononuclear cell samples underwent cis-acting expression quantitative locus ( cis-e QTL) analysis. Results We identified a significant risk region for alcohol and nicotine codependence between IPO11 and HTR1 A on chromosome 5q that was reported to be suggestively associated with alcohol dependence previously. In the European American discovery cohort, 381 single nucleotide polymorphisms (SNPs) in this region were nominally associated with alcohol and nicotine codependence ( p < 0.05); 57 associations of them survived region- and cohort-wide correction (α = 3.6 × 10−6); and the top SNP (rs7445832) was significantly associated with alcohol and nicotine codependence at the genome-wide significance level ( p = 6.2 × 10−9). Furthermore, associations for 34 and 11 SNPs were replicated in the Australian and African American replication cohorts, respectively. Among these replicable associations, 4 reached genome-wide significance level in the meta-analysis of European Americans and European Australians: rs7445832 ( p = 9.6 × 10−10), rs13361996 ( p = 8.2 × 10−9), rs62380518 ( p = 2.3 × 10−8), and rs7714850 ( p = 3.4 × 10−8). Cis-e QTL analysis showed that many risk SNPs in this region had nominally significant cis-acting regulatory effects on HTR1 A or IPO11 m RNA expression. Finally, no markers were significantly associated with any other neuropsychiatric disorder examined. Conclusions We speculate that this IPO11- HTR1 A region might harbor a causal variant for alcohol and nicotine codependence. [ABSTRACT FROM AUTHOR]