Sibling Control Analysis of Perinatal Health and Family Environment Factors Related to Childhood ADHD Symptoms

BackgroundNumerous studies have reported associations between environmental exposures and ADHD. However, whether environmental effects are causal or due to confounding with other familial factors, such as genetic risk, is still unclear. A more complete understanding of which environmental risk factors are causal remains crucial. MethodsUsing one population (ABCD cohort, N=11646) and one case-control cohort (Oregon ADHD-1000, N=744), we conducted both full-cohort and sibling-control analyses (770 and 152 families in ABCD and Oregon ADHD-1000, respectively) to assess the association of family environment and perinatal risk factors with ADHD symptoms. Within-family effects were compared to effects estimated in the full cohorts. We also assessed the impact of gene-environment correlation using child polygenic risk scores and measures of maternal mental health. ResultsFor both cohorts, full-cohort analyses yielded significant associations between child ADHD symptoms and family conflict, perinatal health factors, and breastfeeding duration (p-values <0.001). These associations were non-significant after accounting for family-level confounds (e.g., genetic risk and shared family environment) in exposure-discordant sibling-control analyses. In the full cohorts, effect sizes were substantially reduced (an average 43.7% decrease in effect size across all exposures tested in the ABCD cohort; average 47.6% decrease in Oregon ADHD-1000) after adjusting for child ADHD polygenic risk and measures related to maternal mental health. ConclusionsThe full-cohort associations between child ADHD symptoms and environmental risks confirm associations from prior research, but current findings do not indicate direct causal effects. Instead, much or all of the observed risk appears due to confounding with family-level factors, likely including genetic factors. Our results underscore the importance of accounting for familial risk factors that may confound relationships between behavioral traits and environmental exposures by using multiple study designs. Key PointsO_LINumerous environmental risk factors are associated with ADHD, but whether these are important casual associations is insufficiently studied. C_LIO_LISignificant associations between child ADHD symptoms and features of the family environment and perinatal health were replicated in two independent cohorts, confirming prior work. C_LIO_LISibling-control analyses provided no consistent evidence of causal relationships for any of the risk factors studied. Furthermore, accounting for factors related to genetic risk and parental mental health substantially reduced the observed effect sizes in full-cohort analyses. C_LIO_LIFindings are consistent with previous studies on the effects of breastfeeding duration and some substance exposures (e.g., smoking during pregnancy), suggesting associations are largely due to confounding with unmeasured familial factors. C_LIO_LIFurther study is warranted regarding potential sex differences in exposure associations with ADHD symptoms, as well as more complex causal pathways (e.g., gene-environment or environment-environment interaction). C_LI