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A comparative study of the genetic components of three subcategories of autism spectrum disorder

Molecular Psychiatry volume 24, pages 1720–1731 (2019)Cite this article

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Abstract

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) controversially combined previously distinct subcategories of autism spectrum disorder (ASD) into a single diagnostic category. However, genetic convergences and divergences between different ASD subcategories are unclear. By retrieving 1725 exonic de novo mutations (DNMs) from 1628 subjects with autistic disorder (AD), 1873 from 1564 subjects with pervasive developmental disorder not otherwise specified (PDD-NOS), 276 from 247 subjects with Asperger’s syndrome (AS), and 2077 from 2299 controls, we found that rates of putative functional DNMs (loss-of-function, predicted deleterious missense, and frameshift) in all three subcategories were significantly higher than those in control. We then investigated the convergences and divergences of the three ASD subcategories based on four genetic aspects: whether any two ASD subcategories (1) shared significantly more genes with functional DNMs, (2) exhibited similar spatio-temporal expression patterns, (3) shared significantly more candidate genes, and (4) shared some ASD-associated functional pathways. It is revealed that AD and PDD-NOS were broadly convergent in terms of all four genetic aspects, suggesting these two ASD subcategories may be genetically combined. AS was divergent to AD and PDD-NOS for aspects of functional DNMs and expression patterns, whereas AS and AD/PDD-NOS were convergent for aspects of candidate genes and functional pathways. Our results indicated that the three ASD subcategories present more genetic convergences than divergences, favouring DSM-5’s new classification. This study suggests that specifically defined genotypes and their corresponding phenotypes should be integrated analyzed for precise diagnosis of complex disorders, such as ASD.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (31571301) and National Basic Research Program of China (973 Program) (2012CB517900).

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  1. These authors contributed equally: Jinchen Li, Shanshan Hu

Authors and Affiliations

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

    Jinchen Li, Shanshan Hu, Kun Zhang, Leisheng Shi, Yi Zhang, Tingting Zhao & Zhongsheng Sun

  2. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China

    Jinchen Li, Lin Wang, Kun Xia & Chunyu Liu

  3. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Jinchen Li

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

    Xin He

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

    Chunyu Liu

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

    Zhongsheng Sun

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Li, J., Hu, S., Zhang, K. et al. A comparative study of the genetic components of three subcategories of autism spectrum disorder. Mol Psychiatry 24, 1720–1731 (2019). https://doi.org/10.1038/s41380-018-0081-x

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