Exome-wide rare variant genetic load is associated with cognition, intellectual disability and psychiatric disorders in population-based cohorts
- 1Herasight Research
Abstract
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.
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BibTeX
@misc{ahangari2026exomewide,
title = {{Exome-wide rare variant genetic load is associated with cognition, intellectual disability and psychiatric disorders in population-based cohorts}},
author = {M. Ahangari and S. M. Moore and J. Schleede and J. Anomaly and A. S. Young and T. Wolfram},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.26365349},
url = {https://www.medrxiv.org/content/10.64898/2026.10.13.26365349v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Exome-wide rare variant genetic load is associated with cognition, intellectual disability and psychiatric disorders in population-based cohorts
AU - M. Ahangari
AU - S. M. Moore
AU - J. Schleede
AU - J. Anomaly
AU - A. S. Young
AU - T. Wolfram
PY - 2026
DA - 2026/10/13
PB - medRxiv
DO - 10.64898/2026.10.13.26365349
UR - https://www.medrxiv.org/content/10.64898/2026.10.13.26365349v1
AB - 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.
ER -