A Test-Replicate Approach to Candidate Gene Research on Addiction and Externalizing Disorders: A Collaboration Across Five Longitudinal Studies

Abstract

This study presents results from a collaboration across five longitudinal studies seeking to test and replicate models of gene–environment interplay in the development of substance use and externalizing disorders (SUDs, EXT). We describe an overview of our conceptual models, plan for gene–environment interplay analyses, and present main effects results evaluating six candidate genes potentially relevant to SUDs and EXT (MAOA, 5-HTTLPR, COMT, DRD2, DAT1, and DRD4). All samples included rich longitudinal and phenotypic measurements from childhood/adolescence (ages 5–13) through early adulthood (ages 25–33); sample sizes ranged from 3487 in the test sample, to ~600–1000 in the replication samples. Phenotypes included lifetime symptom counts of SUDs (nicotine, alcohol and cannabis), adult antisocial behavior, and an aggregate externalizing disorder composite. Covariates included the first 10 ancestral principal components computed using all autosomal markers in subjects across the data sets, and age at the most recent assessment. Sex, ancestry, and exposure effects were thoroughly evaluated. After correcting for multiple testing, only one significant main effect was found in the test sample, but it was not replicated. Implications for subsequent gene–environment interplay analyses are discussed.

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Fig. 1

Notes

  1. 1.

    We checked to see whether normalizing the genetic risk score (calculated by dividing by the number of assessed risk alleles in each person) impacted results in the test sample (MCTFR). The correlation between the original genetic risk score and the normalized genetic risk score was nearly perfect (r = .98, p < .001), suggesting limited impact. We also checked whether the pattern of results changed as a result of using the normalized variable in the test sample and found essentially identical results.

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Acknowledgments

Authors Ken C. Winters and Susanne Lee would like to thank Dr.’s George Realmuto and Irv Gottesman for their help consulting with the genetic portion of their study.

Funding

This research was supported by Grants DA024417, DA05147, DA13240, DA012995, DA024411-01-06, DA009679, DA036216, DA008093-15-18, and DA037280 (to S. W.) from the National Institute on Drug Abuse and Grant AA09367, and Grant AA11886 from the National Institute of Alcohol Abuse and Alcoholism. The first author (D. R. S.) was also supported by the USDA National Institute of Food and Agriculture, Hatch project 1006129. The content is solely the responsibility of the authors and does not necessarily represent the official views of the aforementioned funding agencies.

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Correspondence to Diana R. Samek.

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Conflict of Interest

Diana R. Samek, Jennifer Bailey, Karl G. Hill, Sylia Wilson, Susanne Lee, Margaret A. Keyes, Marina Epstein, Andrew Smolen, Michael Miller, Ken C. Winters, J. David Hawkins, Richard F. Catalano, William G. Iacono, and Matt McGue declare that they have no conflict of interest.

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This article does not contain any studies with animals performed by any of the authors. Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Edited by Valerie Knopik.

Ken C. Winters is now affiliated with the Winters Consulting Group, Minneapolis, MN, USA.

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Samek, D.R., Bailey, J., Hill, K.G. et al. A Test-Replicate Approach to Candidate Gene Research on Addiction and Externalizing Disorders: A Collaboration Across Five Longitudinal Studies. Behav Genet 46, 608–626 (2016). https://doi.org/10.1007/s10519-016-9800-8

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Keywords

  • Addiction
  • Alcohol
  • Candidate gene studies
  • Cannabis
  • Externalizing disorders
  • Nicotine
  • Replication studies
  • Substance use disorders