Recent ultra-rare inherited variants implicate new autism candidate risk genes

Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission...

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Bibliographic Details
Published in:	Nature genetics Vol. 53; no. 8; pp. 1125 - 1134
Main Authors:	Wilfert, Amy B., Turner, Tychele N., Murali, Shwetha C., Hsieh, PingHsun, Sulovari, Arvis, Wang, Tianyun, Coe, Bradley P., Guo, Hui, Hoekzema, Kendra, Bakken, Trygve E., Winterkorn, Lara H., Evani, Uday S., Byrska-Bishop, Marta, Earl, Rachel K., Bernier, Raphael A., Zody, Michael C., Eichler, Evan E.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-08-2021 Nature Publishing Group
Subjects:	631/208 631/208/366 631/208/366/1373 Agriculture Animal Genetics and Genomics Autism Autism Spectrum Disorder - genetics Autistic Disorder - genetics Biomedical and Life Sciences Biomedicine Cancer Research Children & youth Evolution, Molecular Families & family life Gene Dosage Gene Function Gene sequencing Genes Genetic aspects Genetic Predisposition to Disease Genetic research Genetic variation Genomes Genomics Haplotypes Human Genetics Humans Intracellular signalling Linkage Disequilibrium Models, Genetic Mutation Pedigree Polymorphism, Single Nucleotide Population Protein Interaction Maps - genetics Protein transport Proteins Proteins - genetics Risk Risk factors Siblings Ubiquitin Ubiquitin-protein ligase Whole Genome Sequencing X chromosomes United States
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Summary:	Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin–protein ligase complex, intracellular transport and Erb signaling protein networks. We estimate that these variants are approximately 2.5 generations old and significantly younger than other variants of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and appear to act on a distinct set of genes not yet associated with autism. Analysis of whole-genome sequence data from 3,474 families finds an excess of private, likely gene-disrupting variants in individuals with autism. These variants are under purifying selection and suggest candidate genes not previously associated with autism.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1061-4036 1546-1718
DOI:	10.1038/s41588-021-00899-8