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Peer-reviewedCC BYCommunications Biology

Identification of moderate effect size genes in autism spectrum disorder through a novel gene pairing approach

  • Madison Caballero1,2
  • F. Kyle Satterstrom3,4,5,6
  • Silvia de Rubeis7,8,9,1,2
  • Joseph D. Buxbaum7,8,10,9,1,11,2
  • Behrang Mahjani12,13,14,15,16,17,18
18 affiliations
  1. 1Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  2. 2Icahn School of Medicine at Mount Sinai
  3. 3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  4. 4Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  5. 5The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  6. 6Broad Institute of MIT and Harvard
  7. 7Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
  8. 8Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  9. 9Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  10. 10Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  11. 11Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  12. 12Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected]
  13. 13Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]
  14. 14Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]
  15. 15Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. [email protected]
  16. 16Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. [email protected]
  17. 17Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]
  18. 18Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
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Abstract

Autism Spectrum Disorder (ASD) arises from complex genetic and environmental factors, with inherited genetic variation playing a substantial role. This study introduces a novel approach to uncover moderate effect size (MES) genes in ASD, which individually do not meet the ASD liability threshold but collectively contribute when paired with specific other MES genes. Analyzing 10,795 families from the SPARK dataset, we identified 97 MES genes forming 50 significant gene pairs, demonstrating a substantial association with ASD when considered in tandem, but not individually. Our method leverages familial inheritance patterns and statistical analyses, refined by comparisons against control cohorts, to elucidate these gene pairs' contribution to ASD liability. Furthermore, expression profile analyses of these genes in brain tissues underscore their relevance to ASD pathology. This study underscores the complexity of ASD's genetic landscape, suggesting that gene combinations, beyond high impact single-gene mutations, significantly contribute to the disorder's etiology and heterogeneity. Our findings pave the way for new avenues in understanding ASD's genetic underpinnings and developing targeted therapeutic strategies.

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Cite

BibTeXRIS
BibTeX
@article{caballero2026identification,
  title = {{Identification of moderate effect size genes in autism spectrum disorder through a novel gene pairing approach}},
  author = {Madison Caballero and F. Kyle Satterstrom and Silvia de Rubeis and Joseph D. Buxbaum and Behrang Mahjani},
  journal = {Communications Biology},
  year = {2026},
  month = may,
  doi = {10.1038/s42003-026-10380-z},
  url = {https://doi.org/10.1038/s42003-026-10380-z},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Identification of moderate effect size genes in autism spectrum disorder through a novel gene pairing approach
AU  - Madison Caballero
AU  - F. Kyle Satterstrom
AU  - Silvia de Rubeis
AU  - Joseph D. Buxbaum
AU  - Behrang Mahjani
PY  - 2026
DA  - 2026/05/30
JO  - Communications Biology
DO  - 10.1038/s42003-026-10380-z
UR  - https://doi.org/10.1038/s42003-026-10380-z
AB  - Autism Spectrum Disorder (ASD) arises from complex genetic and environmental factors, with inherited genetic variation playing a substantial role. This study introduces a novel approach to uncover moderate effect size (MES) genes in ASD, which individually do not meet the ASD liability threshold but collectively contribute when paired with specific other MES genes. Analyzing 10,795 families from the SPARK dataset, we identified 97 MES genes forming 50 significant gene pairs, demonstrating a substantial association with ASD when considered in tandem, but not individually. Our method leverages familial inheritance patterns and statistical analyses, refined by comparisons against control cohorts, to elucidate these gene pairs' contribution to ASD liability. Furthermore, expression profile analyses of these genes in brain tissues underscore their relevance to ASD pathology. This study underscores the complexity of ASD's genetic landscape, suggesting that gene combinations, beyond high impact single-gene mutations, significantly contribute to the disorder's etiology and heterogeneity. Our findings pave the way for new avenues in understanding ASD's genetic underpinnings and developing targeted therapeutic strategies.
SN  - 2399-3642
ER  -