AI summary · DOI: 10.64898/2026.10.27.26366008 · medRxiv: Psychiatry and Clinical Psychology
Familial factors inflate the estimated effects of genetic liability to ADHD on behavioural outcomes
The essentials
Within-family Mendelian randomization attenuated many population-based estimates linking ADHD genetic liability to adverse outcomes, suggesting familial confounding, particularly for depressive symptoms and age at first child.
Question
Do associations between genetic liability to ADHD and adverse health, behavioural and social outcomes reflect an individual’s own liability or familial and social confounding?
Method
The authors compared population-based and sibling-based two-sample Mendelian randomization across 16 outcomes, using 21–22 ADHD-associated variants from a European GWAS of 38,691 cases and 186,843 controls. Within-family outcome data covered 18 European cohorts and up to 164,220 siblings. Primary inverse-variance weighted analyses were supplemented with pleiotropy-robust estimators, instrument-shrinkage analyses and comparisons between designs; effects were expressed in outcome standard deviations per doubling of genetically predicted ADHD odds.
Findings
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Result
Population-based associations with depressive symptoms and age at first child attenuated toward zero within families, with nominal between-design differences of p=0.048 and p=0.034, respectively.
See the passage in the paper
In family-based analyses, these estimates were attenuated for most outcomes and exhibited a trend of differing from the population-based estimates, e.g. for depressive symptoms (p=0·048) and age at first child (p=0·034), cigarettes smoked per day (p=0·051), cognitive performance (p=0·054) and educational attainment (0.064).
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Result
The educational-attainment estimate attenuated within families to −0.033 standard deviations per doubling of genetically predicted ADHD odds, with a 95% confidence interval of −0.061 to −0.005.
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The effect on educational attainment also attenuated (beta:-0.033,95%CI:-0.061,-0.005).
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Result
For BMI, waist-to-hip ratio, glycated haemoglobin and CRP, within-family analyses provided little evidence of effects but did not establish differences from population-based estimates.
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The population-based and family-based estimates were statistically consistent for these outcomes, with their confidence intervals overlapping despite differences in point estimates.
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Result
Sensitivity analyses applying shrinkage to population-derived SNP–ADHD associations left the findings largely unchanged.
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Results were largely unchanged, suggesting that our findings are robust to even substantial inconsistency in the SNP-exposure associations (eFigure 2).
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Authors’ interpretation
The authors interpret some population-based associations as reflecting familial and social context rather than direct effects of an individual’s ADHD liability.
See the passage in the paper
Instead, these estimates may reflect the family and social context in which ADHD occurs, most plausibly through confounding of the population-based estimates by population stratification, assortative mating, and/or dynastic effects[26, 29].
Limitations
- Both designs used population-derived SNP–exposure associations that could retain familial confounding, although shrinkage analyses suggested robustness.
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The SNP–exposure associations were derived from a population-based GWAS and could be influenced by familial factors; however, estimates were essentially unchanged across a wide range of shrinkage parameters, suggesting that inflation of the SNP–ADHD association is unlikely to affect our conclusions.
- Within-family estimates were less precise, limiting the ability to distinguish null effects from population-based estimates for several outcomes.
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Family-based Mendelian randomization is inherently less precise than population-based analysis, because it uses only within-family variation and genotyped relatives remain scarce[26, 27]; this likely explains why we could not detect heterogeneity for some outcomes.
- The estimates include pathways through ADHD treatment and cannot identify treatment effects separately.
See the passage in the paper
Our estimates, including the family-based estimates, therefore reflect the total effect of genetic liability to ADHD, including any pathways acting through treatment, and cannot isolate the effect of treatment itself.
Why it matters
The authors argue that familial data are needed to distinguish direct effects of ADHD liability from familial confounding. Attributing all associated harms to individual ADHD may overstate what individual treatment can modify, but implications for interventions require further testing.
Written by AI from the paper. Passages are checked word for word against the text we analysed; the rest may contain errors.
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