The overarching goals of this proposal are twofold: 1) to support the candidate in gaining additional training in the use of molecular and statistical genetic methods to identify risk alleles for substance use disorders (SUD), and 2) conduct a genome wide association study (GWAS) for a novel phenotype, a pre-morbid liability index for SUDs, and replication studies in two independent samples. The advantage of focusing on indicators of pre-morbid risk (i.e. prior to initiation of substance use) is that analyses are based on underlying rather than expressed risk and so may provide a more sensitive measure of genetic liability than manifest or "post-morbid" measures of SUDs. Focusing on pre-morbid liability also provides a sound theoretical framework to examine developmental processes associated with the emergence of SUDs such as exposure to environmental risk (gene-environment correlations) and sensitivity to environmental adversity (gene x environment interactions). The training portion of the proposal focuses on gaining skills in bioinformatics to identify candidate gene systems and select informative polymorphisms (e.g. SNPs) as well as expertise in statistical analyses to detect associations between genetic markers and complex phenotypes such as SUDs. The research plan entails conducting a GWAS of 61 OK SNPs on a measure of pre-morbid liability to SUDs on approximately 6000 participants. Replication studies of significant findings from the GWAS will then be conducted in two independent samples of high-risk youth. The research plan also includes studies examining mechanisms of G-E interplay that underlie the development of SUDs by utilizing a longitudinal twin design. The award will also assist the candidate in pursuing his long-term goal of becoming an independent researcher and is likely to yield important insights into the etiology of SUDs.

Public Health Relevance

We propose a novel approach to identifying genes associated with substance abuse by focusing on risk factors present prior to initiation of substance use. Pooling multiple longitudinal samples (N~6000), we will conduct a genome wide association study on a novel measure of pre-morbid risk for substance abuse to identify specific risk genes.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Scientist Development Award - Research & Training (K01)
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Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Weinberg, Naimah Z
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Wilson, S; Hicks, B M; Foster, K T et al. (2015) Age of onset and course of major depressive disorder: associations with psychosocial functioning outcomes in adulthood. Psychol Med 45:505-14
Samek, D R; Hicks, B M; Keyes, M A et al. (2015) Gene-environment interplay between parent-child relationship problems and externalizing disorders in adolescence and young adulthood. Psychol Med 45:333-44
Durbin, C Emily; Hicks, Brian M (2014) Personality and Psychopathology: A Stagnant Field in Need of Development. Eur J Pers 28:362-386
Samek, Diana R; Hicks, Brian M (2014) Externalizing Disorders and Environmental Risk: Mechanisms of Gene-Environment Interplay and Strategies for Intervention. Clin Pract (Lond) 11:537-547
Foster, Katherine T; Hicks, Brian M; Iacono, William G et al. (2014) Alcohol use disorder in women: Risks and consequences of an adolescent onset and persistent course. Psychol Addict Behav 28:322-35
Hicks, Brian M; Iacono, William G; McGue, Matt (2014) Identifying childhood characteristics that underlie premorbid risk for substance use disorders: socialization and boldness. Dev Psychopathol 26:141-57
Vrieze, Scott I; Vaidyanathan, Uma; Hicks, Brian M et al. (2014) The role of constraint in the development of nicotine, marijuana, and alcohol dependence in young adulthood. Behav Genet 44:14-24
Bornovalova, Marina A; Hicks, Brian M; Iacono, William G et al. (2013) Longitudinal twin study of borderline personality disorder traits and substance use in adolescence: developmental change, reciprocal effects, and genetic and environmental influences. Personal Disord 4:23-32
Vrieze, Scott I; McGue, Matt; Miller, Michael B et al. (2013) Three mutually informative ways to understand the genetic relationships among behavioral disinhibition, alcohol use, drug use, nicotine use/dependence, and their co-occurrence: twin biometry, GCTA, and genome-wide scoring. Behav Genet 43:97-107
Bornovalova, Marina A; Huibregtse, Brooke M; Hicks, Brian M et al. (2013) Tests of a direct effect of childhood abuse on adult borderline personality disorder traits: a longitudinal discordant twin design. J Abnorm Psychol 122:180-94

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