Familial factors inflate the estimated effects of genetic liability to ADHD on behavioural outcomes
Auteurs : D. C. P. Crick, N. M. Davies, S. Medland, D. Evans
Résumé scientifique
BackgroundPeople with ADHD have worse health, behavioural and social outcomes, widely interpreted as evidence that ADHD causes these harms, justifying early identification and treatment. But ADHD clusters in families, and conventional studies cannot separate the effect of a persons own ADHD from the family environment in which it arises. We used a family-based genetic design to distinguish the two. MethodsWe used up to 22 genome-wide significant variants associated with ADHD (38,691 cases, 186,843 controls) to estimate effects of genetic liability to ADHD on 16 health and behavioural outcomes. We compared population-based estimates with family-based estimates from within-sibship analyses of up to 164,220 siblings. We tested for heterogeneity between the designs, and applied sensitivity analyses. We involved individuals with lived experience of ADHD in interpreting the findings and shaping how the clinical/public-health implications were described. FindingsPopulation-based analyses implied that greater genetic liability to ADHD increased smoking, alcohol use and depressive symptoms, and reduced educational attainment, age at first child and cognitive performance. In family-based analyses, these effects attenuated. For example, the effect on number of depressive symptoms fell from 0{middle dot}059 SD (95% CI 0{middle dot}039, 0{middle dot}080) to 0{middle dot}002 SD (-0{middle dot}052, 0{middle dot}055), and age at first child increased from -0{middle dot}045 SD (-0{middle dot}058, -0{middle dot}033) to 0{middle dot}003 SD (-0{middle dot}040, 0{middle dot}047), with significant differences between designs (p=0{middle dot}048 and p=0{middle dot}034). Findings were consistent across sensitivity analyses. InterpretationMuch of the excess health and behavioural burden attributed to ADHD may reflect the family and environmental context in which ADHD occurs, rather than an individuals own ADHD. Interventions targeting the individual might not reduce these outcomes as much as expected. Distinguishing such effects requires family-based designs. FundingMedical Research Council, UK Research and Innovation, Research Council of Norway, US National Institute of Mental Health, and Australian National Health and Medical Research Council. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAttention-deficit hyperactivity disorder (ADHD), and higher genetic liability to ADHD, are associated with a wide range of adverse health, behavioural, and social outcomes. A 2024 umbrella review of the impacts of ADHD summarised consistent associations with addiction, mental and physical illness, lower educational attainment, and social difficulties. Earlier reviews of Mendelian randomization studies of ADHD reached similar conclusions, reporting apparent causal effects on smoking, depression, body-mass index, and educational attainment. A broad two-sample Mendelian randomization analysis of ADHD across more than 100 traits corroborated these findings. Almost all of this genetic evidence, however, comes from samples of unrelated individuals, in which estimates can be confounded by population stratification, assortative mating, and dynastic effects. We searched PubMed and Google Scholar from database inception to 20/07/26 using terms related to ADHD, Mendelian randomization, and within-family designs (Supplementary note), without language restrictions. We identified eight relevant studies, however only three used a within-family or trio Mendelian randomization design. None used a large within-family Mendelian randomization design to investigate the effects of genetic liability to ADHD on health or behavioural outcomes while separating individuals liability from familial influences. Added value of this studyTo our knowledge, this is the largest within-family Mendelian randomization study of genetic liability to ADHD, comparing conventional population-based estimates with family-based estimates across 16 outcomes in up to 164,220 siblings. Population-based estimates reproduced previously reported associations, but most attenuated in family-based analyses. For depressive symptoms and age at first child, the two designs significantly differed, indicating that the population-based estimates were inflated by familial factors. Implications of all the available evidenceMuch of the excess health, behavioural, and social burden attributed to ADHD may reflect the family and environmental context in which ADHD arises, rather than an individuals own liability. If so, interventions directed solely at the individual may not reduce these outcomes as much as observational and population-based estimates imply. These findings should be interpreted alongside the broader evidence rather than as a basis for immediate changes in practice, and they underscore the need for larger family-based genetic studies.
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