Journal article
Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes
Nature genetics, Vol.54(9), pp.1305-1319
08/18/2022
DOI: 10.1038/s41588-022-01148-2
PMCID: PMC9470534
PMID: 35982159
Abstract
To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10−6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10−6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.
Details
- Title: Subtitle
- Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes
- Creators
- Xueya Zhou - Columbia University Irving Medical CenterPamela Feliciano - Simons FoundationChang Shu - Columbia University Irving Medical CenterTianyun Wang - University of WashingtonIrina Astrovskaya - Simons FoundationJacob B Hall - Simons FoundationJoseph U Obiajulu - Columbia University Irving Medical CenterJessica R Wright - Simons FoundationShwetha C Murali - University of WashingtonSimon Xuming Xu - Simons FoundationLeo Brueggeman - Roy J. and Lucille A. Carver College of MedicineTaylor R Thomas - Roy J. and Lucille A. Carver College of MedicineOlena Marchenko - Simons FoundationChristopher Fleisch - Simons FoundationSarah D Barns - Simons FoundationLeeAnne Green Snyder - Simons FoundationBing Han - Simons FoundationTimothy S Chang - University of California, Los AngelesTychele N Turner - Washington University in St. LouisWilliam T Harvey - University of WashingtonAndrew Nishida - Oregon Health & Science UniversityBrian J O'Roak - Oregon Health & Science UniversityDaniel H Geschwind - University of California, Los AngelesJacob J Michaelson - Roy J. and Lucille A. Carver College of MedicineNatalia Volfovsky - Simons FoundationEvan E Eichler - University of WashingtonYufeng Shen - Columbia University Irving Medical CenterWendy K Chung - Columbia University Irving Medical Center
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.54(9), pp.1305-1319
- DOI
- 10.1038/s41588-022-01148-2
- PMID
- 35982159
- PMCID
- PMC9470534
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Language
- English
- Date published
- 08/18/2022
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Communication Sciences and Disorders; Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984296206202771
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