AI Insight
This study analyzed rare genetic variants in over 300,000 participants and found that protein-truncating variants (PTVs) in constrained genes are associated with lower cognitive performance and increased risk of autism spectrum disorder, schizophrenia, and intellectual disability. Participants carrying these rare variants in highly constrained genes showed up to nine times higher odds of intellectual disability, and while representing only 12% of the population, they accounted for 31% of intellectual disability cases, 20% of schizophrenia cases, and 17% of autism cases. These rare variant effects were largely independent of common genetic variation measured by polygenic scores and showed better cross-ancestry prediction than polygenic scores.
Why it matters
This research demonstrates that rare genetic variants contribute substantially to neuropsychiatric conditions in the general population, not just in clinical settings. The findings suggest that genetic screening for rare variants could potentially identify individuals at elevated risk for cognitive and psychiatric conditions earlier than current methods, and these variants work through different mechanisms than common genetic risk factors.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Rare protein-truncating variants (PTVs) and damaging missense variants in constrained genes are enriched among people with autism spectrum disorder (ASD), schizophrenia and related conditions, but most studies used clinical cohorts. In European-ancestry participants of the Adolescent Brain Cognitive Development Study (ABCD, 3,523 children) and the All of Us Research Program (AoU, 302,421 adults), we summed, separately for rare PTVs and damaging missense variants, the selection coefficients of affected genes into genetic loads (GLs). In ABCD, one additional typical constrained gene with a PTV was associated with 0.22 SD lower cognition and with ASD (odds ratio 1.80). In AoU, it was associated with ASD (1.34), schizophrenia (1.51) and intellectual disability (ID, 2.02). Missense GL showed smaller, concordant associations. Risk rose with gene constraint, to almost ninefold odds of ID in the most constrained genes, and carriers of a constrained PTV (12% of AoU participants) made up 31% of ID, 20% of schizophrenia and 17% of ASD cases. GL was essentially uncorrelated with polygenic scores. In African-ancestry participants, PTV GL retained 71-125% of its European-ancestry effect, versus 23-62% for matched polygenic scores. Constraint-weighted rare variant load contributes measurably to cognitive and neuropsychiatric outcomes in population cohorts.