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Background <p>The genetic basis of autism spectrum disorder (ASD) is complicated by high heritability and substantial heterogeneity, in which de novo variants and polygenic burden from common variants have not been comprehensively elucidated. Increasing evidence indicates that aggregates of rare variants can exert additive or synergistic effects that modulate disease risk. Using an approach that considers variant co-occurrence, we aim to detect the contribution of rare variants with modest effect in ASD.</p> Results <p>We analyze large-scale genomic data from individuals of East-Asian and European ancestry and identify disrupted gene pairs affected by co-occurring rare deleterious variants. Candidate genes comprising disrupted gene pairs are enriched in cytoskeletal pathways, and those involving cytoskeletal genes are highly co-expressed in neural precursor cells. Phenotype analysis reveals that affected males with co-occurring rare variants in disrupted gene pairs exhibit increased symptom severity, a pattern not observed in females. Unaffected parents harboring these variants display elevated autistic traits, suggesting potential impacts beyond diagnosed individuals.</p> Conclusions <p>This study employs large-scale, multi-ancestry genomic datasets to identify gene pairs affected by the co-occurrence of rare variants and assess their biological and clinical impact. Our findings highlight the significance of rare variants with modest effects in ASD and offer insights into the complex mechanisms underlying ASD.</p>

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Co-occurrence of rare variants implicates gene pairs in cytoskeletal pathways and is associated with increased severity in autism spectrum disorder

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月23日

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  • Hyeji Lee,
  • Kahee Ko,
  • Seoyeon Kim,
  • Ganghee Lee,
  • Soowhee Kim,
  • Jihae Lee,
  • Da-Yea Song,
  • Guiyoung Bong,
  • Jae Hyun Han,
  • Jeewon Lee,
  • Ye Rim Kim,
  • Yoojeong Lee,
  • Eunjoon Kim,
  • Anders D. Børglum,
  • Jakob Grove,
  • So Hyun Kim,
  • Woong Sun,
  • Hee Jeong Yoo,
  • Joon-Yong An

摘要

Background

The genetic basis of autism spectrum disorder (ASD) is complicated by high heritability and substantial heterogeneity, in which de novo variants and polygenic burden from common variants have not been comprehensively elucidated. Increasing evidence indicates that aggregates of rare variants can exert additive or synergistic effects that modulate disease risk. Using an approach that considers variant co-occurrence, we aim to detect the contribution of rare variants with modest effect in ASD.

Results

We analyze large-scale genomic data from individuals of East-Asian and European ancestry and identify disrupted gene pairs affected by co-occurring rare deleterious variants. Candidate genes comprising disrupted gene pairs are enriched in cytoskeletal pathways, and those involving cytoskeletal genes are highly co-expressed in neural precursor cells. Phenotype analysis reveals that affected males with co-occurring rare variants in disrupted gene pairs exhibit increased symptom severity, a pattern not observed in females. Unaffected parents harboring these variants display elevated autistic traits, suggesting potential impacts beyond diagnosed individuals.

Conclusions

This study employs large-scale, multi-ancestry genomic datasets to identify gene pairs affected by the co-occurrence of rare variants and assess their biological and clinical impact. Our findings highlight the significance of rare variants with modest effects in ASD and offer insights into the complex mechanisms underlying ASD.