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 language | English |
|---|---|
| Article number | 100150 |
| Journal | Human Genetics and Genomics Advances |
| Volume | 4 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 12 2023 |
Funding
We acknowledge funding from the Laboratory Directed Research & Development Program of Oak Ridge National Laboratory, managed by UT-Battelle, for the US Department of Energy (DOE). This research used resources of the Oak Ridge Leadership Computing Facility, which is a DOE Office of Science User Facility supported under contract DE-AC05-00OR22725. This research used resources of the Compute and Data Environment for Science (CADES) at the Oak Ridge National Laboratory. This research was supported in part by National Institutes of Health grant RF1 AG053303. Finally, we thank the two anonymous reviewers for their constructive comments and suggestions to improve the manuscript. D.K.: conceptualization, formal analysis, investigation, methodology, validation, visualization, validation, writing – original draft, writing – review & editing; A.T.: conceptualization, supervision, writing – original draft, writing – review & editing; E.T.P.: formal analysis, investigation, visualization, writing – original draft, writing – review & editing; E.A.: formal analysis, investigation, writing – original draft, writing – review & editing; S.C.: conceptualization, supervision, writing – original draft, writing – review & editing; D.J.: funding acquisition, writing – review & editing; M.R.G.: funding acquisition, conceptualization, data curation, formal analysis, supervision, investigation, methodology, software, visualization, validation, writing – original draft, writing – review & editing. M.R.G. is owner of Williwaw Biosciences, LLC, which has filed a patent on the use of non-Mendelian inheritance to detect genomic structural variants. We acknowledge funding from the Laboratory Directed Research & Development Program of Oak Ridge National Laboratory , managed by UT-Battelle, for the US Department of Energy (DOE). This research used resources of the Oak Ridge Leadership Computing Facility , which is a DOE Office of Science User Facility supported under contract DE-AC05-00OR22725. This research used resources of the Compute and Data Environment for Science ( CADES ) at the Oak Ridge National Laboratory. This research was supported in part by National Institutes of Health grant RF1 AG053303 . Finally, we thank the two anonymous reviewers for their constructive comments and suggestions to improve the manuscript.
Keywords
- Genomic structural variation
- Mendelian inheritance
- artificial intelligence
- autism spectrum disorder
- kynurenine pathway
- missing heritability
- precision medicine