دورية أكاديمية
Recent ultra-rare inherited variants implicate new autism candidate risk genes.
| العنوان: | Recent ultra-rare inherited variants implicate new autism candidate risk genes. |
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| المؤلفون: | Wilfert AB; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA., Turner TN; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA., Murali SC; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.; Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA., Hsieh P; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA., Sulovari A; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA., Wang T; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA., Coe BP; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA., Guo H; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.; Center for Medical Genetic & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China., Hoekzema K; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA., Bakken TE; Allen Institute for Brain Science, Seattle, WA, USA., Winterkorn LH; New York Genome Center, New York, NY, USA., Evani US; New York Genome Center, New York, NY, USA., Byrska-Bishop M; New York Genome Center, New York, NY, USA., Earl RK; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA., Bernier RA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA., Zody MC; New York Genome Center, New York, NY, USA., Eichler EE; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA. eee@gs.washington.edu.; Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. eee@gs.washington.edu. |
| مؤلفون مشاركون: | SPARK Consortium |
| المصدر: | Nature genetics [Nat Genet] 2021 Aug; Vol. 53 (8), pp. 1125-1134. Date of Electronic Publication: 2021 Jul 26. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Pub. Co Country of Publication: United States NLM ID: 9216904 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1718 (Electronic) Linking ISSN: 10614036 NLM ISO Abbreviation: Nat Genet Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Nature Pub. Co., c1992- |
| مواضيع طبية MeSH: | Genetic Predisposition to Disease*, Autism Spectrum Disorder/*genetics , Proteins/*genetics, Autistic Disorder/genetics ; Evolution, Molecular ; Gene Dosage ; Haplotypes ; Humans ; Linkage Disequilibrium ; Models, Genetic ; Mutation ; Pedigree ; Polymorphism, Single Nucleotide ; Protein Interaction Maps/genetics ; Siblings ; Whole Genome Sequencing |
| مستخلص: | 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. (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.) |
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| معلومات مُعتمدة: | United States HHMI Howard Hughes Medical Institute; UM1 HG008901 United States HG NHGRI NIH HHS; K99 MH117165 United States MH NIMH NIH HHS; R00 MH117165 United States MH NIMH NIH HHS; K99 HG011041 United States HG NHGRI NIH HHS; U24 MH081810 United States MH NIMH NIH HHS; K99HG011041 U.S. Department of Health & Human Services | National Institutes of Health (NIH); R01 MH100047 United States MH NIMH NIH HHS; U24 HG008956 United States HG NHGRI NIH HHS; R01 MH101221 United States MH NIMH NIH HHS |
| فهرسة مساهمة: | Investigator: X Zhou; P Feliciano; J Hall; I Astrovskaya; S Xu; C Shu; J Obiajulu; L Brueggeman; J Wright; O Marchenko; C Fleisch; TS Chang; LG Snyder; SD Barns; B Han; W Harvey; A Nishida; R Doan; A Soucy; BJ O'Roak; TW Yu; D Geschwind; J Michaelson; N Volfovsky; Y Shen; WK Chung |
| المشرفين على المادة: | 0 (Proteins) |
| تواريخ الأحداث: | Date Created: 20210727 Date Completed: 20210910 Latest Revision: 20221019 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8459613 |
| DOI: | 10.1038/s41588-021-00899-8 |
| PMID: | 34312540 |
| قاعدة البيانات: | MEDLINE |
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| DOI: | 10.1038/s41588-021-00899-8 |