Genes moderate the association of trait diurnal cortisol and externalizing in boys

The hypothalamus pituitary adrenal (HPA) axis and the human genome are important components of the biological etiology of externalizing disorders. By studying the associations between specific genetic variants, diurnal cortisol, and externalizing symptoms we can begin to unpack this complex etiology. It was hypothesized that genetic variants from the corticotropine releasing hormone receptor 1 (CRHR1), FK506 binding protein 51 (FKBP5), catechol-O-methyl transferase (COMT), and dopamine transporter (DAT1) genes and diurnal cortisol intercepts and slopes would separately predict externalizing symptoms. It was also hypothesized that genetic variants would moderate the association between cortisol and externalizing. Participants were 800 twins (51% boys), 88.5% Caucasian, M=7.93 years (SD=0.87) participating in the Wisconsin Twin Project. Hierarchical Linear Modeling (HLM) was used to separate the variance associated with state and trait cortisol measured across three consecutive days and trait cortisol measures were used. There were no main effects of genes on externalizing symptoms. The evening cortisol intercept, the morning cortisol slope and the evening cortisol slope predicted externalizing, but only in boys, such that boys with higher cortisol and flatter slopes across the day also had more externalizing symptoms. The morning cortisol intercept and CRHR1 rs242924 interacted to predict externalizing in both boys and girls, with GG carriers significantly higher compared to TT carriers at one standard deviation below the mean of morning cortisol. For boys only there was a significant interaction between the DAT1 variable number tandem repeat (VNTR) and the afternoon slope and a significant slope for 9/9 carriers and 9/10 carriers such that when the slope was more steep, boys carrying a nine had fewer externalizing symptoms but when the slope was less steep, they had more. Results confirm a link between diurnal trait cortisol and externalizing in boys, as well as moderation of that association by genetic polymorphisms. This is the first study to empirically examine this association and should encourage further research on the biological etiology of externalizing disorder symptoms.