A Machine Learning Approach to Predicting Autism Risk Genes: Validation of Known Genes and Discovery of New Candidates

Ying Lin, Shiva Afshar, Anjali M. Rajadhyaksha, James B. Potash, Shizhong Han

Research output: Contribution to journalArticlepeer-review


Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic basis. The role of de novo mutations in ASD has been well established, but the set of genes implicated to date is still far from complete. The current study employs a machine learning-based approach to predict ASD risk genes using features from spatiotemporal gene expression patterns in human brain, gene-level constraint metrics, and other gene variation features. The genes identified through our prediction model were enriched for independent sets of ASD risk genes, and tended to be down-expressed in ASD brains, especially in frontal and parietal cortex. The highest-ranked genes not only included those with strong prior evidence for involvement in ASD (for example, NBEA, HERC1, and TCF20), but also indicated potentially novel candidates, such as, MYCBP2 and CAND1, which are involved in protein ubiquitination. We also showed that our method outperformed state-of-the-art scoring systems for ranking curated ASD candidate genes. Gene ontology enrichment analysis of our predicted risk genes revealed biological processes clearly relevant to ASD, including neuronal signaling, neurogenesis, and chromatin remodeling, but also highlighted other potential mechanisms that might underlie ASD, such as regulation of RNA alternative splicing and ubiquitination pathway related to protein degradation. Our study demonstrates that human brain spatiotemporal gene expression patterns and gene-level constraint metrics can help predict ASD risk genes. Our gene ranking system provides a useful resource for prioritizing ASD candidate genes.

Original languageEnglish (US)
Article number500064
JournalFrontiers in Genetics
StatePublished - Sep 10 2020


  • autism
  • constraint
  • de novo mutation
  • gene expression
  • machine learning

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)


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