Using dimensional models of externalizing psychopathology to aid in gene identification

Context: Twin studies provide compelling evidence that alcohol and drug dependence, childhood conduct disorder, adult antisocial behavior, and disinhibitory personality traits share an underlying genetic liability that contributes to a spectrum of externalizing behaviors. However, this information has not been widely used in gene identification efforts, which have focused on specific disorders diagnosed using traditional psychiatric classification systems. Objective: To test the utility of using a multivariate externalizing phenotype in (1) linkage analyses and (2) association analyses to identify genes that contribute broadly to a spectrum of externalizing disorders. Design: Data were analyzed from the Collaborative Study on the Genetics of Alcoholism. Linkage analyses were conducted using data from a genome-wide 10-cM microsatellite scan. Association analyses were conducted on 27 single-nucleotide polymorphisms genotyped across a candidate gene, the muscarinic acetylcholine receptor M2 gene (CHRM2). Setting: Six centers across the United States. Other Participants: Approximately 2300 individuals from 262 families. Main Outcome Measures: Lifetime symptom counts of alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder and novelty seeking, sensation seeking, and general externalizing component scores consisting of a composite of the previous 6 variables. Results: Principal component analyses indicated that the 6 individual variables loaded on a single externalizing factor. Linkage analyses using the resultant component scores identified a region on chromosome 7 consistent with a gene that broadly predisposes individuals to externalizing behavior. Association analyses of a candidate gene, CHRM2, previously of interest in the Collaborative Study on the Genetics of Alcoholism, suggest that it is involved in a general externalizing phenotype. Conclusions: Broader conceptualizations of psychiatric disorders, such as studying a spectrum of externalizing psychopathology, may aid in identifying susceptibility genes and understanding the pathways through which genetic factors affect vulnerability for a variety of poor outcomes.