The applicants proposed a whole-genome search for chromosomal loci containing genes influence early-onset dependence on drugs. Adolescent substance dependence (SD) usually is comorbid with Conduct Disorder (CD). SD is though to have considerable heritability. The Preliminary Studies show that (A) The PI is collecting clinically identified, well- described adolescents with severe SD and CD. The sample includes many females, in whom these disorders are relatively rare. (B) The Co- PI is characterizing family members of many of those same adolescent probands. (C ) A co-investigator has established CD's heritability at about 60 percent. The applicants will expand their sample to include 275 pairs of probands and siblings, well-characterized with widely-used instruments for severity of: SC, CD, and the often associated conditions of Attention-Deficit/ Hyperactivity Disorder (ADHD), Major Depression, and Anxiety Disorders. Sib pairs and at least one of the biological parents will provide DNA samples. Employing DNA analysis for 200 highly informative polymorphic markers distributed across the genome, the applicants will use the Co-PI's sib-pair procedure to identify Quantitative Trait Loci (QTLs) associated with early-onset SD. QTL searches may identify genes operating through unexpected biochemical mechanisms. SD probably is polygenic, and in sch disorders QTL can identify each involved region.
Specific aims are: (1) To identify several chromosomal regions, each a few centiMorgans (cM) in length, which are very likely to contain one or more genes influencing the development of early-onset dependence on drugs, including alcohol. (2) To identify several chromosomal regions, again a few cM in length, these being very likely to contain one or more genes influencing the development of adolescent Conduct Disorder. (3) To determine whether the chromosomal regions associated with drug dependence overlap those associated with Conduct Disorder; this would imply that tightly-linked or identical genes underlie the frequent association of early-onset drug-dependence and Conduct Disorder. (4) To make preliminary assessments of whether chromosomal regions associated with Conduct Disorder overlap those associated with conditions commonly comorbid with Conduct Disorder (ADHD, Major Depression, and Anxiety Disorders). These latter conditions appear to worsen SD in these patients. Reduced power in these latter analyses may render them ore tentative.
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