Family History of Substance Use and Stressful Life Events Impact Adolescent Maturation of Cerebral White Matter.

Family history (FH) of substance use disorders (SUDs) and stressful life events (SLEs) are known risk factors for SUDs in adolescents and young adults. Cross-sectional studies suggest that FH and SLEs affect adolescent white matter (WM) development and form abnormal WM patterns. Here, we examined the effects of FH, SLEs and their interaction on WM integrity in youths in the Adolescent Cognitive Brain Development (ABCD) study at baseline and 2- and 4-year follow-ups. ABCD youths (N = 8939, age ± SD = 9.9 ± 0.6 years, 4302 female) completed baseline diffusion tensor imaging, of which 5661 repeated the scan at 2-year follow-up (age ± SD = 12.0 ± 0.7 years, 2634 female) and 2177 at 4-year follow-up (age ± SD = 14.1 ± 0.7 years, 1007 female). FH was measured as the weighted sum of biological parents and grandparents with alcohol and/or drug problems. SLEs were measured with parental report of life events. WM integrity was measured with fractional anisotropy (FA) of 23 WM tracts. Linear mixed effect models were used to examine the effects of FH, SLEs and their interaction on FA at baseline and longitudinally, modelling family and study site as random intercepts and correcting for multiple comparisons with false discovery rate (FDR) q = 0.05. At baseline, there were no significant effects of FH, SLEs and their interaction on FA after multiple comparison correction when controlling for race, family income and parental education. From baseline to 4-year follow-up, FH significantly negatively interacted with newly occurred SLEs on FA in 19 out of 23 tracts, so that FA at 4-year was lower in youths with both FH and newly occurred SLEs when controlling for baseline FA (βinteraction = -0.049 - -0.018, pFDR = 6.2 × 10-5 - 4.7 × 10-2). These negative interactions were not significant with shorter time spans (baseline to 2-year follow-up and 2- to 4-year follow-up). In conclusion, we replicated findings from cross-sectional cohorts of the effects of FH and SLEs on lower WM integrity in youths. The study utilized Big Data longitudinal design to show that FH-by-SLE interaction, rather than their independent effects was responsible for developmental WM changes associated with FH of SUDs and life stressors.