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Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database

Molecular Psychiatry volume 21, pages 290–297 (2016)Cite this article

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A Corrigendum to this article was published on 05 May 2015

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.

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Acknowledgements

The project was funded by the National Natural Science Foundation of China (31171236/C060503), the National Basic Research Program of China (No. 2012CB517902 and 2012CB517904), the National ‘12th Five-Year’ scientific and technological support projects (No. 2012BAI03B02) and the Special Funds of National Health and Family Planning Commission of China (No. 201302002). As a disclaimer, Tao Cai represented his own perspective in the article, not NIDCR/NIH.

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  1. Jinchen Li and Tao Cai: These authors contributed equally to this work.

Authors and Affiliations

  1. Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China

    Jinchen Li, Zhong Sheng Sun & Jinyu Wu

  2. Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China

    Jinchen Li, Yi Jiang, Huiqian Chen, Qianzhi Shao, Xia Ran, Zhongshan Li, Zhong Sheng Sun & Jinyu Wu

  3. State Key Laboratory of Medical Genetics, Central South University, Changsha, China

    Jinchen Li, Chao Chen, Xianfeng Li, Kun Xia & Chunyu Liu

  4. Experimental Medicine Section, NIDCR/NIH, Bethesda, MD, USA

    Tao Cai

  5. Department of Human Genetics, University of Chicago, Chicago, IL, USA

    Xin He

  6. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    Chao Chen & Chunyu Liu

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  1. Jinchen Li
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Li, J., Cai, T., Jiang, Y. et al. Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database. Mol Psychiatry 21, 290–297 (2016). https://doi.org/10.1038/mp.2015.40

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