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Michael C. Stallings, PhD; Robin P. Corley, PhD; Briana Dennehey, PhD; John K. Hewitt, PhD; Kenneth S. Krauter, PhD; Jeffrey M. Lessem, PhD; Susan K. Mikulich-Gilbertson, PhD; Soo Hyun Rhee, PhD; Andrew Smolen, PhD; Susan E. Young, PhD; Thomas J. Crowley, MD

Arch Gen Psychiatry. 2005;62:1042-1051.

Background  Among adolescents, externalizing problem behavior and substance use disorders are often comorbid. Familial influences, including shared genetic risk factors, may account for part of this comorbidity. Previously we reported 2 chromosomal regions (3q24-3q25 and 9q34) likely to contain genes that influence substance dependence vulnerability (DV) in adolescence.

Objectives  To identify quantitative trait loci (QTLs) that influence externalizing problem behavior in adolescence and to determine whether any identified QTL overlap chromosomal regions that influence DV.

Design  Regression-based QTL mapping procedures designed for selected sibling pair samples.

Setting  Patient probands were drawn from consecutive admissions to residential and outpatient (milieu-type) treatment facilities for substance abuse and deliquency operated by the University of Colorado; most of these patients were referred for treatment by juvenile justice or social service agencies.

Patients  A total of 249 proband-sibling pairs from 191 families were selected for the study. Patient probands were 13 to 19 years of age; siblings of the probands ranged in age from 12 to 25 years.

Main Outcome Measures  A community-based sample of 4493 adolescents and young adults was used to define clinically significant, heritable, age- and sex-normed indexes of DV, conduct disorder symptoms (CDS), and a composite index of antisocial substance dependence (DV + CDS). Siblings and parents were genotyped for 374 microsatellite markers distributed across the 22 autosomes (mean intermarker distance, 9.2 centimorgans).

Results  For both DV and CDS, there was evidence of linkage to the same region on chromosome 9q34, as well as to 3q24-3q25 for DV, and a novel region on chromosome 17q12 for CDS. Our composite index (DV + CDS) yielded the strongest evidence for linkage (logarithm of odds = 2.65) to the chromosome 9q34 region.

Conclusion  These results provide the first evidence of a potential molecular genetic basis for the comorbidity between DV and antisocial behavior.

Author Affiliations: Institute for Behavioral Genetics (Drs Stallings, Corley, Hewitt, Lessem, Rhee, Smolen, and Young) and Department of Molecular, Cellular, and Developmental Biology (Drs Dennehey and Krauter), University of Colorado, Boulder; and Division of Substance Dependence, University of Colorado School of Medicine, Denver (Drs Mikulich-Gilbertson and Crowley).

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