Journal article
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
Nature communications, Vol.11(1), pp.4932-4932
10/01/2020
DOI: 10.1038/s41467-020-18723-y
PMCID: PMC7530681
PMID: 33004838
Abstract
Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
Details
- Title: Subtitle
- Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
- Creators
- Tianyun Wang - Department of Genome Sciences, University of Washington, Seattle, WA, USAKendra Hoekzema - Department of Genome Sciences, University of Washington, Seattle, WA, USADavide Vecchio - Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Rome, ItalyHuidan Wu - Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaArvis Sulovari - Department of Genome Sciences, University of Washington, Seattle, WA, USABradley P Coe - Department of Genome Sciences, University of Washington, Seattle, WA, USAMadelyn A Gillentine - Department of Genome Sciences, University of Washington, Seattle, WA, USAAmy B Wilfert - Department of Genome Sciences, University of Washington, Seattle, WA, USALuis A Perez-Jurado - Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM) and CIBERER, Barcelona, SpainMalin Kvarnung - Department of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenYoeri Sleyp - Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, BelgiumRachel K Earl - Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USAJill A Rosenfeld - Baylor Genetics, Houston, TX, USAMadeleine R Geisheker - Department of Genome Sciences, University of Washington, Seattle, WA, USALin Han - Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaBing Du - Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaChris Barnett - Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, AustraliaElizabeth Thompson - Paediatric and Reproductive Genetics unit, Women's and Children's Hospital, Adelaide, SA, AustraliaMarie Shaw - Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, AustraliaRenee Carroll - Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, AustraliaKathryn Friend - Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, AustraliaRachael Catford - Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, AustraliaElizabeth E Palmer - School of Women's and Children's Health, University of New South Wales, Randwick, NSW, AustraliaXiaobing Zou - Children Development Behavior Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, ChinaJianjun Ou - Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, ChinaHonghui Li - Key Laboratory of Developmental Disorders in Children, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, ChinaHui Guo - Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaJennifer Gerdts - Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USAEmanuela Avola - Oasi Research Institute-IRCCS, Troina, ItalyGiuseppe Calabrese - Oasi Research Institute-IRCCS, Troina, ItalyMaurizio Elia - Oasi Research Institute-IRCCS, Troina, ItalyDonatella Greco - Oasi Research Institute-IRCCS, Troina, ItalyAnna Lindstrand - Department of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenAnn Nordgren - Department of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenBritt-Marie Anderlid - Department of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenGeert Vandeweyer - Department of Medical Genetics, University of Antwerp, Antwerp, BelgiumAnke Van Dijck - Department of Medical Genetics, University of Antwerp, Antwerp, BelgiumNathalie Van der Aa - Department of Medical Genetics, University of Antwerp, Antwerp, BelgiumBrooke McKenna - Department of Psychology, Emory University, Atlanta, GA, USAMiroslava Hancarova - Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech RepublicSarka Bendova - Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech RepublicMarketa Havlovicova - Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech RepublicGiovanni Malerba - Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, ItalyBernardo Dalla Bernardina - Child Neuropsychiatry Unit, AOUI, Verona, ItalyPierandrea Muglia - UCB Pharma, Bruxelles, BelgiumArie van Haeringen - Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, NetherlandsMariette J V Hoffer - Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, NetherlandsBarbara Franke - Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, NetherlandsGerarda Cappuccio - Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, ItalyMartin Delatycki - Murdoch Children's Research Institute, Melbourne, AustraliaPaul J Lockhart - Department of Paediatrics, University of Melbourne, Parkville, VIC, AustraliaMelanie A Manning - Department of Pathology, Stanford University, Stanford, CA, USAPengfei Liu - Baylor Genetics, Houston, TX, USAIngrid E Scheffer - The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, AustraliaNicola Brunetti-Pierri - Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, ItalyNanda Rommelse - Karakter Child and Adolescent Psychiatry Center, Nijmegen, NetherlandsDavid G Amaral - Department of Psychiatry and Behavioral Sciences and the MIND Institute, University of California, Davis, Sacramento, CA, USAGijs W E Santen - Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, NetherlandsElisabetta Trabetti - Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, ItalyZdeněk Sedláček - Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech RepublicJacob J Michaelson - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USAKaren Pierce - Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, CA, USAEric Courchesne - Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, CA, USAR Frank Kooy - Department of Medical Genetics, University of Antwerp, Antwerp, BelgiumMagnus Nordenskjöld - Department of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenCorrado Romano - Oasi Research Institute-IRCCS, Troina, ItalyHilde Peeters - Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, BelgiumRaphael A Bernier - Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USAJozef Gecz - Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, AustraliaKun Xia - CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Chinese Academy of Sciences, Shanghai, ChinaEvan E Eichler - Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. eee@gs.washington.edu
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.11(1), pp.4932-4932
- DOI
- 10.1038/s41467-020-18723-y
- PMID
- 33004838
- PMCID
- PMC7530681
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- England
- Grant note
- P50 HD103524 / NICHD NIH HHS Howard Hughes Medical Institute T32 HG000035 / NHGRI NIH HHS R01 MH101221 / NIMH NIH HHS R01 MH109912 / NIMH NIH HHS
- Language
- English
- Date published
- 10/01/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Communication Sciences and Disorders; Psychiatry; Pathology; Iowa Neuroscience Institute
- Record Identifier
- 9984070758902771
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