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Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders

Molecular Psychiatry volume 22, pages 1282–1290 (2017)Cite this article

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Abstract

Autism spectrum disorder (ASD) represents a set of complex neurodevelopmental disorders with large degrees of heritability and heterogeneity. We sequenced 136 microcephaly or macrocephaly (Mic–Mac)-related genes and 158 possible ASD-risk genes in 536 Chinese ASD probands and detected 22 damaging de novo mutations (DNMs) in 20 genes, including CHD8 and SCN2A, with recurrent events. Nine of the 20 genes were previously reported to harbor DNMs in ASD patients from other populations, while 11 of them were first identified in present study. We combined genetic variations of the 294 sequenced genes from publicly available whole-exome or whole-genome sequencing studies (4167 probands plus 1786 controls) with our Chinese population (536 cases plus 1457 controls) to optimize the power of candidate-gene prioritization. As a result, we prioritized 67 ASD-candidate genes that exhibited significantly higher probabilities of haploinsufficiency and genic intolerance, and significantly interacted and co-expressed with each another, as well as other known ASD-risk genes. Probands with DNMs or rare inherited mutations in the 67 candidate genes exhibited significantly lower intelligence quotients, supporting their strong functional impact. In addition, we prioritized 39 ASD-related Mic–Mac-risk genes, and showed their interaction and co-expression in a functional network that converged on chromatin remodeling, synapse transmission and cell cycle progression. Genes within the three functional subnetworks exhibited distinct and recognizable spatiotemporal-expression patterns in human brains and laminar-expression profiles in the developing neocortex, highlighting their important roles in brain development. Our results indicate some of Mic–Mac-risk genes are involved in ASD.

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Acknowledgements

We thank the patients and their families for their participation in this study. The project was funded by the National Basic Research Program of China (2012CB517900) and the National Natural Science Foundation of China (31571301, 81330027, 31400919 and 31671114). HG was supported by the Young Talent Lifts Project of CAST.

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  1. Jinchen Li and Lin Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China

    Jinchen Li, Lin Wang, Hui Guo, Meina Tang, Shanshan Dong, Yanling Liu, Tianyun Wang, Zhengmao Hu, Chunyu Liu & Kun Xia

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

    Leisheng Shi, Kun Zhang, Shanshan Hu, Ping Yu & Zhong Sheng Sun

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

    Xin He

  4. Mental Health Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Jinping Zhao

  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

    Zhong Sheng Sun

  7. Key Laboratory of Medical Information Research, Central South University, Changsha, Hunan, China

    Kun Xia

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  1. Jinchen Li
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Li, J., Wang, L., Guo, H. et al. Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Mol Psychiatry 22, 1282–1290 (2017). https://doi.org/10.1038/mp.2017.140

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