Abstract
Increasing evidence suggests that the circadian and stress regulatory systems contribute to alcohol use disorder (AUD) risk, which may partially arise through effects on reward-related neural function. The C allele of the PER1 rs3027172 single nucleotide polymorphism (SNP) reduces PER1 expression in cells incubated with cortisol and has been associated with increased risk for adult AUD and problematic drinking among adolescents exposed to high levels of familial psychosocial adversity. Using data from undergraduate students who completed the ongoing Duke Neurogenetics Study (DNS) (n = 665), we tested whether exposure to early life stress (ELS; Childhood Trauma Questionnaire) moderates the association between rs3027172 genotype and later problematic alcohol use (Alcohol Use Disorders Identification Test) as well as ventral striatum (VS) reactivity to reward (card-guessing task while functional magnetic resonance imaging data were acquired). Initial analyses found that PER1 rs3027172 genotype interacted with ELS to predict both problematic drinking and VS reactivity; minor C allele carriers, who were also exposed to elevated ELS reported greater problematic drinking and exhibited greater ventral striatum reactivity to reward-related stimuli. When gene × covariate and environment × covariate interactions were controlled for, the interaction predicting problematic alcohol use remained significant (p < 0.05, corrected) while the interaction predicting VS reactivity was no longer significant. These results extend our understanding of relationships between PER1 genotype, ELS, and problematic alcohol use, and serve as a cautionary tale on the importance of controlling for potential confounders in studies of moderation including gene × environment interactions.
Highlights
Observable psychiatric symptoms and biological rhythm perturbation have been linked to variability in circadian rhythm function (Nader et al, 2009; Wulff et al, 2009; Chong et al, 2012; Wirth et al, 2013)
period 1 gene (PER1) rs3027172 genotype groups differed by ethnicity, wherein the minor allele carrier group had a higher percentage of Caucasian and a lower percentage of Asian1 and Asian2 participants (Supplemental Table 5; Supplemental Figure 1)
Consistent with a prior report (Dong et al, 2011), PER1 rs3027172 genotype groups differed according to Alcohol Use Disorders Identification Test (AUDIT) scores such that C allele carriers reported higher levels of problematic drinking (Supplemental Table 5); notably, this effect did not remain after controlling for covariates
Summary
Observable psychiatric symptoms (e.g., insomnia/hypersomnia) and biological rhythm perturbation (e.g., dysregulated diurnal cortisol) have been linked to variability in circadian rhythm function (Nader et al, 2009; Wulff et al, 2009; Chong et al, 2012; Wirth et al, 2013). The circadian system is governed by a system of transcriptional repressors (i.e., Period genes: PER1, PER2, PER3; Cryptochrome genes: CRY1, CRY2) and enhancers (i.e., CLOCK and BMAL1) that influence numerous downstream clock-responsive genes to maintain a 24-h biochemical (e.g., hormone production), physiological (e.g., brain function, body temperature), and behavioral (e.g., sleep, eating) cycle (Sarkar, 2012) The maintenance of this daily oscillation is disrupted by stress (Meerlo et al, 2002) with intriguing evidence that mutual interactions among the circadian system and HPA axis may mediate these effects (Nader et al, 2010) and importantly contribute to problematic alcohol use (Dong et al, 2011; Blomeyer et al, 2013). Highlighting the potential etiologic role of stress and the HPA axis in this relationship, these mice display stress-induced (social defeat, swim stress, or foot shock) increases in ethanol consumption (Dong et al, 2011) and impaired glucocorticoid rhythmicity (Dallmann et al, 2006)
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