title: Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database.
abstract: Currently, many studies on neuropsychiatric disorders have utilized massive trio-based whole-exome sequencing (WES) and whole-genome sequencing (WGS) to identify numerous de novo mutations (DNMs). Here, we retrieved 17,104 DNMs from 3555 trios across four neuropsychiatric disorders: autism spectrum disorder, epileptic encephalopathy, intellectual disability and schizophrenia, in addition to unaffected siblings (control), from 36 studies by WES/WGS. After eliminating non-exonic variants, we focused on 3334 exonic DNMs for evaluation of their association with these diseases. Our results revealed a higher prevalence of DNMs in the probands of all four disorders compared with the one in the controls (P<1.3 × 10(-7)). The elevated DNM frequency is dominated by loss-of-function/deleterious single-nucleotide variants and frameshift indels (that is, extreme mutations, P<4.5 × 10(-5)). With extensive annotation of these 'extreme' mutations, we prioritized 764 candidate genes in these four disorders. A combined analysis of Gene Ontology, microRNA targets and transcription factor targets revealed shared biological process and non-coding regulatory elements of candidate genes in the pathology of neuropsychiatric disorders. In addition, weighted gene co-expression network analysis of human laminar-specific neocortical expression data showed that candidate genes are convergent on eight shared modules with specific layer enrichment and biological process features. Furthermore, we identified that 53 candidate genes are associated with more than one disorder (P<0.000001), suggesting a possibly shared genetic etiology underlying these disorders. Particularly, DNMs of the SCN2A gene are frequently occurred across all four disorders. Finally, we constructed a freely available NPdenovo database, which provides a comprehensive catalog of the DNMs identified in neuropsychiatric disorders.
authors: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.|Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.|State Key Laboratory of Medical Genetics, Central South University, Changsha, China.
authors: Jinchen
authors: J
authors: Li
authors: Experimental Medicine Section, NIDCR/NIH, Bethesda, MD, USA.
authors: Tao
authors: T
authors: Cai
authors: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.
authors: Yi
authors: Y
authors: Jiang
authors: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.
authors: Huiqian
authors: H
authors: Chen
authors: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors: Xin
authors: X
authors: He
authors: State Key Laboratory of Medical Genetics, Central South University, Changsha, China.|Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
authors: Chao
authors: C
authors: Chen
authors: State Key Laboratory of Medical Genetics, Central South University, Changsha, China.
authors: Xianfeng
authors: X
authors: Li
authors: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.
authors: Qianzhi
authors: Q
authors: Shao
authors: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.
authors: Xia
authors: X
authors: Ran
authors: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.
authors: Zhongshan
authors: Z
authors: Li
authors: State Key Laboratory of Medical Genetics, Central South University, Changsha, China.
authors: Kun
authors: K
authors: Xia
authors: State Key Laboratory of Medical Genetics, Central South University, Changsha, China.|Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
authors: Chunyu
authors: C
authors: Liu
authors: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.|Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.
authors: Zhong Sheng
authors: ZS
authors: Sun
authors: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.|Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.
authors: Jinyu
authors: J
authors: Wu
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D059472:Exome / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D058027:Neuropsychiatry; D016017:Odds Ratio; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA