The goal of this Research Career Award is to investigate the possible genetic link between executive cognitive function (ECF) and clinical antecedents of substance use disorders, namely conduct disorder (CD) and attention deficit hyperactivity disorder (ADHD); psychiatric syndromes which show high comorbidity. Although the association between ECF deficits and these developmental disorders has been demonstrated in previous work, little research has been done to uncover the source of this association. Understanding the etiology of these frequently comorbid syndromes may begin to bridge an important neurobiological gap between genetic and environment risk/protective factors and clinical outcomes. The training application includes: 1) direct instruction and supervision by experts in neuropsychology, developmental psychopathology, and methodology; 2) completion of several courses and seminars aimed at gaining a foundation in neuroscience and neuropsychology; 3) participation in workshops offering training in twin research methodology as well as genetic association and linkage analysis; and 4) participation in professional conferences. The research application aims to study 600 male and female adolescent twins (300 pairs), selected for indicators of risk for the development of these disorders. These twins will be a subsample of twins participating in an ongoing study of heritable early indicators of risk for drug dependence (DA-11015), who have been assessed for a wide-range of child psychopathology and substance use patterns, as well as measures of personality and behavioral development. The proposed research will supplement these previously collected assessments with a battery of standardized measures of ECF in order to examine the role of ECF in the development of CD, ADHD and substance use (SU). The study design employs a multi-stage analysis. First, we will test phenotypic models to identify which characteristics of ECF best predict severity of clinical outcome. We hypothesize that deficits in the ability to inhibit inappropriate responding (e.g., impulse control) will strongly predict symptom severity of CD, ADHD and SU, and will be significant markers of comorbidity among the disorders.
The second aim i s to use multivariate behavior genetic analyses to examine the extent to which variation in ECF is mediated by genetic and/or environmental factors.
Our final aim i s to determine the extent to which the covariation between ECF deficits and comorbid psychopathology is due to genetic and/or environmental factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01MH001865-02
Application #
6621847
Study Section
Special Emphasis Panel (ZRG1-BBBP-6 (01))
Program Officer
James, Regina Smith
Project Start
2001-12-17
Project End
2006-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
2
Fiscal Year
2003
Total Cost
$108,063
Indirect Cost
Name
University of Colorado at Boulder
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
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Hartman, Christie A; Hopfer, Christian J; Haberstick, Brett et al. (2009) The association between cannabinoid receptor 1 gene (CNR1) and cannabis dependence symptoms in adolescents and young adults. Drug Alcohol Depend 104:11-6
Gelhorn, Heather; Hartman, Christie; Sakai, Joseph et al. (2009) An item response theory analysis of DSM-IV conduct disorder. J Am Acad Child Adolesc Psychiatry 48:42-50
Young, Susan E; Friedman, Naomi P; Miyake, Akira et al. (2009) Behavioral disinhibition: liability for externalizing spectrum disorders and its genetic and environmental relation to response inhibition across adolescence. J Abnorm Psychol 118:117-30
Hartman, Christie A; Gelhorn, Heather; Crowley, Thomas J et al. (2008) Item response theory analysis of DSM-IV cannabis abuse and dependence criteria in adolescents. J Am Acad Child Adolesc Psychiatry 47:165-73
Friedman, Naomi P; Miyake, Akira; Young, Susan E et al. (2008) Individual differences in executive functions are almost entirely genetic in origin. J Exp Psychol Gen 137:201-25
Gelhorn, Heather; Hartman, Christie; Sakai, Joseph et al. (2008) Toward DSM-V: an item response theory analysis of the diagnostic process for DSM-IV alcohol abuse and dependence in adolescents. J Am Acad Child Adolesc Psychiatry 47:1329-39
Schlaepfer, Isabel R; Hoft, Nicole R; Collins, Allan C et al. (2008) The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults. Biol Psychiatry 63:1039-46
Sakai, Joseph T; Hopfer, Christian J; Hartman, Christie et al. (2007) Test of association between TaqIA A1 allele and alcohol use disorder phenotypes in a sample of adolescent patients with serious substance and behavioral problems. Drug Alcohol Depend 88:130-7
Ehringer, Marissa A; Clegg, Hilary V; Collins, Allan C et al. (2007) Association of the neuronal nicotinic receptor beta2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine. Am J Med Genet B Neuropsychiatr Genet 144B:596-604

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