Genetically Informative Mediation Modeling Applied to Stressors and Personality-Disorder Traits in Etiology of Alcohol Use Disorder
A statistical mediation model was developed within a twin design to investigate the etiology of alcohol use disorder (AUD). Unlike conventional statistical mediation models, this biometric mediation model can detect unobserved confounding. Using a sample of 1410 pairs of Norwegian twins, we investigated specific hypotheses that DSM-IV personality-disorder (PD) traits mediate effects of childhood stressful life events (SLEs) on AUD, and that adulthood SLEs mediate effects of PDs on AUD. Models including borderline PD traits indicated unobserved confounding in phenotypic path coefficients, whereas models including antisocial and impulsive traits did not. More than half of the observed effects of childhood SLEs on adulthood AUD were mediated by adulthood antisocial and impulsive traits. Effects of PD traits on AUD 5‒10 years later were direct rather than mediated by adulthood SLEs. The results and the general approach contribute to triangulation of developmental origins for complex behavioral disorders.
KeywordsStatistical mediation model Twin study Causality Stressful life events Antisocial personality disorder Borderline personality disorder Substance use
We acknowledge funding from the US National Institutes of Health and National Institute on Drug Abuse (1R01DA037558-01A1), the Research Council of Norway (226985 and 240061), the Norwegian Foundation for Health and Rehabilitation, the Norwegian Council for Mental Health, and the European Commission under the program “Quality of Life and Management of the Living Resources” of the Fifth Framework Program (QLG2-CT-2002-01254). TR had full access to all the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Compliance with ethical standards
Conflict of interest
Tom Rosenström, Nikolai Czajkowski, Eivind Ystrom, Robert Krueger, Steven Aggen, Nathan Gillespie, Espen Eilertsen, Ted Reichborn-Kjennerud, and Fartein Torvik declare that they have no conflict of interest.
Approval was received from The Norwegian Data Inspectorate and the Regional Committee for Medical and Health Research Ethics.
Human and animal rights
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.
A written informed consent was obtained from all participants after a complete description of the study.
- Baryshnikov I, Joffe G, Koivisto M et al (2017) Relationships between self-reported childhood traumatic experiences, attachment style, neuroticism and features of borderline personality disorders in patients with mood disorders. J Affect Disord 210:82–89. https://doi.org/10.1016/j.jad.2016.12.004 CrossRefPubMedGoogle Scholar
- Castellanos-Ryan N, Rubia K, Conrod PJ (2011) Response inhibition and reward response bias mediate the predictive relationships between impulsivity and sensation seeking and common and unique variance in conduct disorder and substance misuse. Alcohol Clin Exp Res 35:140–155. https://doi.org/10.1111/j.1530-0277.2010.01331.x CrossRefPubMedGoogle Scholar
- Little TD, Card NA, Bovaird JA et al (2007) Structural equation modeling of mediation and moderation with contextual factors. In: Little TD, Bovaird JA, Card NA (eds) Modeling contextual effects in longitudinal studies. Lawrence Erlbaum Associates, Mahwah, pp 207–231Google Scholar
- Murray AL, Molenaar D, Johnson W, Krueger RF (2016) Dependence of gene-by-environment interactions (GxE) on scaling: comparing the use of sum scores, transformed sum scores and IRT scores for the phenotype in tests of GxE. Behav Genet 46:552–572. https://doi.org/10.1007/s10519-016-9783-5 CrossRefPubMedGoogle Scholar
- Pfohl B, Blum N, Zimmerman M (1995) Structured interview for DSM-IV personality (SIDP-IV). University of Iowa, Iowa CityGoogle Scholar
- Preacher KJ (2015) Advances in mediation analysis: a survey and synthesis of new developments. Annu Rev Psychol 66:825–852. https://doi.org/10.1146/annurev-psych-010814-015258 CrossRefPubMedGoogle Scholar
- Turkheimer E, Petterson E, Horn EE (2014) A phenotypic null hypothesis for the genetics of personality. Annu Rev Psychol 65:515–540. https://doi.org/10.1146/annurev-psych-113011-143752 CrossRefPubMedGoogle Scholar
- Wittchen HU, Pfister H (1997) DIA-X interview (M-CIDI). Swets & Zeitlinger, FrankfurtGoogle Scholar
- Ystrom E, Kendler KS, Reichborn-Kjennerud T (2014) Early age of alcohol initiation is not the cause of alcohol use disorders in adulthood, but is a major indicator of genetic risk. A population-based twin study. Addiction 109:1824–1832. https://doi.org/10.1111/add.12620 CrossRefPubMedPubMedCentralGoogle Scholar