Mooney Michael A, Ryabinin Peter, Nousen Elizabeth, Tipsord Jessica, Dieckmann Nathan F, Karalunas Sarah L, Herting Megan M, Nikolas Molly, Nigg Joel T, Faraone Stephen V
Department of Psychiatry, Oregon Health & Science University, Portland, Oregon, USA.
Center for Mental Health Innovation, Oregon Health & Science University, Portland, Oregon, USA.
medRxiv. 2025 Jun 17:2025.06.16.25329516. doi: 10.1101/2025.06.16.25329516.
Numerous 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.
Using 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.
For 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.
The 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.
众多研究报告了环境暴露与注意力缺陷多动障碍（ADHD）之间的关联。然而，环境影响是因果关系还是由于与其他家族因素（如遗传风险）混淆所致，仍不清楚。更全面地了解哪些环境风险因素具有因果关系仍然至关重要。
我们使用一个总体人群（ABCD队列，N = 11646）和一个病例对照队列（俄勒冈ADHD - 1000，N = 744），进行了全队列分析和同胞对照分析（ABCD队列和俄勒冈ADHD - 1000中分别有770个和152个家庭），以评估家庭环境和围产期风险因素与ADHD症状的关联。将家庭内部效应与全队列中估计的效应进行比较。我们还使用儿童多基因风险评分和母亲心理健康指标评估了基因 - 环境相关性的影响。
对于两个队列，全队列分析得出儿童ADHD症状与家庭冲突、围产期健康因素和母乳喂养持续时间之间存在显著关联（p值<0.001）。在暴露不一致的同胞对照分析中，在考虑家庭层面的混杂因素（如遗传风险和共享家庭环境）后，这些关联不显著。在全队列中，在调整儿童ADHD多基因风险和与母亲心理健康相关的指标后，效应大小大幅降低（ABCD队列中所有测试暴露的效应大小平均降低43.7%；俄勒冈ADHD - 1000中平均降低47.6%）。
儿童ADHD症状与环境风险之间的全队列关联证实了先前研究的关联，但当前研究结果并未表明存在直接因果效应。相反，观察到的许多或所有风险似乎是由于与家庭层面因素的混杂所致，可能包括遗传因素。我们的结果强调了通过使用多种研究设计来考虑可能混淆行为特征与环境暴露之间关系的家族风险因素的重要性。
