Phenotypic structure and genetic correlates of adolescent psychiatric symptomatology in versus out of autism
- 1Massachusetts General Hospital
Abstract
ObjectiveMental health challenges are highly prevalent in autism, but the degree to which they are similar in experience and etiology to the general population remains unclear. This studys objective was characterization of phenotypic and genetic architectures of psychiatric symptomatology in versus out-of-autism.
MethodsPsychiatric symptoms were evaluated using the Child Behavior Checklist (CBCL) in 22,152 children (8-15 years): 11,111 autistic children with verbal abilities from SPARK and 11,041 non-autistic children from ABCD. The CBCLs canonical, population-wide factor structure and genetic associations were compared between cohorts. In parallel, exploratory factor analysis was conducted in SPARK, with resulting dimensions associated with key clinical phenotypes (cognitive ability, co-occurring neuropsychiatric diagnoses), polygenic scores (PGS) for psychiatric disorders, and de novo burden in autism-associated genes.
ResultsConfirmatory factor analysis supported the canonical structure in ABCD but not in SPARK. Psychiatric PGS associations with canonical CBCL subscales were weaker in SPARK than in ABCD, with the ADHD PGS association to Attention problems lower in SPARK ({beta}=0.05 [CI: 0.04,0.06] than in ABCD ({beta}=0.17 [0.13,0.21]). SPARK exploratory factor analysis replicated canonical internalizing factors while revealing other structural departures, including a distinct Developmental Delays factor and dispersion of social problems across multiple factors. The Developmental Delays factor had the strongest associations with de novo burden and lower cognitive ability but was weakly associated with psychiatric PGS. In contrast, common genetic variation explained larger proportions of variances in somatic and inattentive factors and had stronger PGS associations.
ConclusionsCorrelation structures and genetic architectures of psychiatric symptoms differed in autism compared to the broader population, emphasizing the need for autism-specific approaches in assessment and treatment.
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BibTeX
@misc{thomas2026phenotypic,
title = {{Phenotypic structure and genetic correlates of adolescent psychiatric symptomatology in versus out of autism}},
author = {T. R. Thomas and S. S. Kuo and C. H. Lefebvre and J. Zhang and R. Havkin and F. K. Satterstrom and J. M. Fu and C. Auwerx and C. van der Merwe and K. W. Choi and M. E. Talkowski and G. Joshi and E. B. Robinson},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.26365562},
url = {https://www.medrxiv.org/content/10.64898/2026.10.15.26365562v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Phenotypic structure and genetic correlates of adolescent psychiatric symptomatology in versus out of autism
AU - T. R. Thomas
AU - S. S. Kuo
AU - C. H. Lefebvre
AU - J. Zhang
AU - R. Havkin
AU - F. K. Satterstrom
AU - J. M. Fu
AU - C. Auwerx
AU - C. van der Merwe
AU - K. W. Choi
AU - M. E. Talkowski
AU - G. Joshi
AU - E. B. Robinson
PY - 2026
DA - 2026/10/15
PB - medRxiv
DO - 10.64898/2026.10.15.26365562
UR - https://www.medrxiv.org/content/10.64898/2026.10.15.26365562v1
AB - ObjectiveMental health challenges are highly prevalent in autism, but the degree to which they are similar in experience and etiology to the general population remains unclear. This studys objective was characterization of phenotypic and genetic architectures of psychiatric symptomatology in versus out-of-autism. MethodsPsychiatric symptoms were evaluated using the Child Behavior Checklist (CBCL) in 22,152 children (8-15 years): 11,111 autistic children with verbal abilities from SPARK and 11,041 non-autistic children from ABCD. The CBCLs canonical, population-wide factor structure and genetic associations were compared between cohorts. In parallel, exploratory factor analysis was conducted in SPARK, with resulting dimensions associated with key clinical phenotypes (cognitive ability, co-occurring neuropsychiatric diagnoses), polygenic scores (PGS) for psychiatric disorders, and de novo burden in autism-associated genes. ResultsConfirmatory factor analysis supported the canonical structure in ABCD but not in SPARK. Psychiatric PGS associations with canonical CBCL subscales were weaker in SPARK than in ABCD, with the ADHD PGS association to Attention problems lower in SPARK ({beta}=0.05 [CI: 0.04,0.06] than in ABCD ({beta}=0.17 [0.13,0.21]). SPARK exploratory factor analysis replicated canonical internalizing factors while revealing other structural departures, including a distinct Developmental Delays factor and dispersion of social problems across multiple factors. The Developmental Delays factor had the strongest associations with de novo burden and lower cognitive ability but was weakly associated with psychiatric PGS. In contrast, common genetic variation explained larger proportions of variances in somatic and inattentive factors and had stronger PGS associations. ConclusionsCorrelation structures and genetic architectures of psychiatric symptoms differed in autism compared to the broader population, emphasizing the need for autism-specific approaches in assessment and treatment.
ER -