<b><i>Introduction:</i></b> Dynamic relations between genetic, hormone, and pre- and postnatal environments are theorized as critically important for adolescent substance use but are rarely tested in multifactorial models. This study assessed the impact of interactions of genetic risk and cortisol reactivity with prenatal and parenting influences on both any and frequency of adolescent substance use. <b><i>Methods:</i></b> Data are from the TRacking Adolescents' Individual Lives Survey (TRAILS), a prospective longitudinal, multi-rater study of 2,230 Dutch adolescents. Genetic risk was assessed via 3 substance-specific polygenic scores. Mothers retrospectively reported prenatal risk when adolescents were 11 years old. Adolescents rated their parents' warmth and hostility at age 11. Salivary cortisol reactivity was measured in response to a social stress task at age 16. Adolescents' self-reported cigarette, alcohol, and cannabis use frequency at age 16. <b><i>Results:</i></b> A multivariate hurdle regression model showed that polygenic risk for smoking, alcohol, and cannabis predicted any use of each substance, respectively, but predicted more frequent use only for smoking. Blunted cortisol reactivity predicted any use and more frequent use for all 3 outcomes. There were 2 interactions: blunted cortisol reactivity exacerbated the association of polygenic risk with any smoking and the association of prenatal risk with any alcohol use. <b><i>Conclusion:</i></b> Polygenic risk seems of importance for early use but less so for frequency of use, whereas blunted cortisol reactivity was correlated with both. Blunted cortisol reactivity may also catalyze early risks for substance use, though to a limited degree. Gene-environment interactions play no role in the context of this multifactorial model.
In: Smith , A K , Ratanatharathorn , A , Maihofer , A X , Naviaux , R K , Aiello , A E , Amstadter , A B , Ashley-Koch , A E , Baker , D G , Beckham , J C , Boks , M P , Bromet , E , Dennis , M , Galea , S , Garrett , M E , Geuze , E , Guffanti , G , Hauser , M A , Katrinli , S , Kilaru , V , Kessler , R C , Kimbrel , N A , Koenen , K C , Kuan , P F , Li , K , Logue , M W , Lori , A , Luft , B J , Miller , M W , Naviaux , J C , Nugent , N R , Qin , X , Ressler , K J , Risbrough , V B , Rutten , B P F , Stein , M B , Ursano , R J , Vermetten , E , Vinkers , C H , Wang , L , Youssef , N A , Marx , C , Grant , G , Stein , M , Qin , X J , Jain , S , McAllister , T W , Zafonte , R , Lang , A , Coimbra , R , Andaluz , N , Shutter , L , George , M S , Brancu , M , Calhoun , P S , Dedert , E , Elbogen , E B , Fairbank , J A , Hurley , R A , Kilts , J D , Kirby , A , Marx , C E , McDonald , S D , Moore , S D , Morey , R A , Naylor , J C , Rowland , J A , Swinkels , C , Szabo , S T , Taber , K H , Tupler , L A , Van Voorhees , E E , Yoash-Gantz , R E , Basu , A , Brick , L A , Dalvie , S , Daskalakis , N P , Ensink , J B M , Hemmings , S M J , Herringa , R , Ikiyo , S , Koen , N , Kuan , P F , Montalvo-Ortiz , J , Nispeling , D , Pfeiffer , J , Qin , X J , Ressler , K J , Schijven , D , Seedat , S , Shinozaki , G , Sumner , J A , Swart , P , Tyrka , A , Van Zuiden , M , Wani , A , Wolf , E J , Zannas , A , Uddin , M , Nievergelt , C M , INTRuST Clinical Consortium , VA Mid-Atlantic MIRECC Workgroup & PGC PTSD Epigenetics Workgroup 2020 , ' Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR ' , Nature Communications , vol. 11 , no. 1 , 5965 . https://doi.org/10.1038/s41467-020-19615-x
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.