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 3,487 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.

Tobacco and cannabis use in college students are predicted by sex‐dimorphic interactions between MAOA genotype and child abuse

“…First, the study was conducted on 500 college students of predominantly Caucasian ethnic background. In consideration of the conceptual and methodological limitations of current research on G × E interactions in psychiatry, these findings should be confirmed by further studies with larger, more ethnically diverse cohorts, which may increase their robustness and ascertain their generalizability. Second, the 3‐way interactions examined in this study do not reflect the full complexity of either genetic or environmental mechanisms in substance use.…”

The dopamine transporter VNTR polymorphism moderates the relationship between acute response to alcohol and future alcohol use disorder symptoms

“…Several factors limit interpretation of these findings. First, given the low replication rates for candidate gene studies in addiction, caution is warranted without a replication sample. The lab‐based measures and longitudinal assessment of the CSDP sample offer a unique opportunity to evaluate genetic risk for AUD, but candidate genetic influences on other lab‐assessed drug response measures have suffered from low replication rates .…”

The utility of twins in developmental cognitive neuroscience research: How twins strengthen the ABCD research design

“…The four sites in the Twin Hub each have over 25 years of experience studying behavioral development in twins, adoptees, and nuclear families, with a focus on the genetic contributions to substance use (SU). Twin study findings from member sites have addressed a wide range of substantive topics, including reports that have examined how specific and generalized risk are associated with the development of adolescent SU (Krueger et al, 2002; Maes et al, 2004; Palmer et al, 2012, 2013b, 2009; Young et al, 2006, 2000), the strong relationship of antisocial behavior to alcohol and drug use (Button et al, 2006, 2007, 2009; Hicks et al, 2013; Hopfer et al, 2013), insights into G–E interplay in adolescent SUD development (Hicks et al, 2010, 2012, 2014; Irons et al, 2012; Maes et al, 2017; Vrieze et al, 2012), the relationship between SU and brain integrity (Anokhin and Golosheykin, 2016; Botteron et al, 2002; Carlson et al, 2002, 2004a, b, 2007; Gustavson et al, 2017; Harper et al, 2016; Isen et al, 2014; Malone et al, 2014a; Pagliaccio et al, 2015; Palmer et al, 2013a; Perlman et al, 2009; Prom-Wormley et al, 2015; Sparks et al, 2014; Wilson et al, 2015; Yoon et al, 2015; Young et al, 2009), and the molecular genetic bases of SUDs (Agrawal et al, 2012; Clark et al, 2017; Derringer et al, 2015; Maes et al, 2016; McGue et al, 2013; Samek et al, 2016) and associated endophenotypes (Iacono, 2014; Iacono et al, 2014a, b; Liu et al, 2017; Malone et al, 2016, 2014b; Vaidyanathan et al, 2014a, b; Vaidyanathan et al, 2014c; Vrieze et al, 2014). Member sites have also led the field in the development of methods for the analysis of data from twins (Neale and Cardon, 1992c; Neale et al, 2006), and pioneered research on the human gut microbiome (Faith et al, 2013; Turnbaugh et al, 2009), including human-to-mouse gut microbiota transplantation studies (Ridaura et al, 2013).…”