Structural variants identified using non-Mendelian inheritance patterns advance the mechanistic understanding of autism spectrum disorder

David Kainer, Alan R. Templeton, Erica T. Prates, Daniel Jacboson, Euan R.O. Allan, Sharlee Climer, Michael R. Garvin

Research output: Contribution to journalArticlepeer-review

Abstract

The heritability of autism spectrum disorder (ASD), based on 680,000 families and five countries, is estimated to be nearly 80%, yet heritability reported from SNP-based studies are consistently lower, and few significant loci have been identified with genome-wide association studies. This gap in genomic information may reside in rare variants, interaction among variants (epistasis), or cryptic structural variation (SV) and may provide mechanisms that underlie ASD. Here we use a method to identify potential SVs based on non-Mendelian inheritance patterns in pedigrees using parent-child genotypes from ASD families and demonstrate that they are enriched in ASD-risk genes. Most are in non-coding genic space and are over-represented in expression quantitative trait loci, suggesting that they affect gene regulation, which we confirm with their overlap of differentially expressed genes in postmortem brain tissue of ASD individuals. We then identify an SV in the GRIK2 gene that alters RNA splicing and a regulatory region of the ACMSD gene in the kynurenine pathway as significantly associated with a non-verbal ASD phenotype, supporting our hypothesis that these currently excluded loci can provide a clearer mechanistic understanding of ASD. Finally, we use an explainable artificial intelligence approach to define subgroups demonstrating their use in the context of precision medicine.

Original languageEnglish
Article number100150
JournalHuman Genetics and Genomics Advances
Volume4
Issue number1
DOIs
StatePublished - 12 Jan 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 Oak Ridge National Laboratory, The Author(s)

Keywords

  • Genomic structural variation
  • Mendelian inheritance
  • artificial intelligence
  • autism spectrum disorder
  • kynurenine pathway
  • missing heritability
  • precision medicine

ASJC Scopus subject areas

  • Genetics(clinical)
  • Molecular Medicine

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