Large-scale whole-exome sequencing of neuropsychiatric diseases and traits in 350,770 adults

Yue-Ting Deng; Bang-Sheng Wu; Liu Yang; Xiao-Yu He; Ju-Jiao Kang; Wei-Shi Liu; Ze-Yu Li; Xin-Rui Wu; Ya-Ru Zhang; Shi-Dong Chen; Yi-Jun Ge; Yu-Yuan Huang; Jian-Feng Feng; Ying Zhu; Qiang Dong; Ying Mao; Wei Cheng; Jin-Tai Yu

doi:10.1038/s41562-024-01861-4

Large-scale whole-exome sequencing of neuropsychiatric diseases and traits in 350,770 adults

Nat Hum Behav. 2024 Apr 8. doi: 10.1038/s41562-024-01861-4. Online ahead of print.

Authors

Yue-Ting Deng^#¹, Bang-Sheng Wu^#¹, Liu Yang^#¹, Xiao-Yu He^#¹, Ju-Jiao Kang^{2

3}, Wei-Shi Liu¹, Ze-Yu Li^{2

3}, Xin-Rui Wu¹, Ya-Ru Zhang¹, Shi-Dong Chen¹, Yi-Jun Ge¹, Yu-Yuan Huang¹, Jian-Feng Feng^{2

3

4}, Ying Zhu⁵, Qiang Dong¹, Ying Mao⁶, Wei Cheng^{7

8

9

10}, Jin-Tai Yu¹¹

Affiliations

¹ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
² Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.
³ Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China.
⁴ Department of Computer Science, University of Warwick, Coventry, UK.
⁵ Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
⁶ Department of Neurosurgery, Huashan Hospital Fudan University, Shanghai, China.
⁷ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China. wcheng@fudan.edu.cn.
⁸ Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China. wcheng@fudan.edu.cn.
⁹ Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China. wcheng@fudan.edu.cn.
¹⁰ Fudan ISTBI-ZJNU Algorithm Centre for Brain-inspired Intelligence, Zhejiang Normal University, Zhejiang, China. wcheng@fudan.edu.cn.
¹¹ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China. jintai_yu@fudan.edu.cn.

^# Contributed equally.

PMID: 38589703
DOI: 10.1038/s41562-024-01861-4

Abstract

While numerous genomic loci have been identified for neuropsychiatric conditions, the contribution of protein-coding variants has yet to be determined. Here we conducted a large-scale whole-exome-sequencing study to interrogate the impact of protein-coding variants on 46 neuropsychiatric diseases and 23 traits in 350,770 adults from the UK Biobank. Twenty new genes were associated with neuropsychiatric diseases through coding variants, among which 16 genes had impacts on the longitudinal risks of diseases. Thirty new genes were associated with neuropsychiatric traits, with SYNGAP1 showing pleiotropic effects across cognitive function domains. Pairwise estimation of genetic correlations at the coding-variant level highlighted shared genetic associations among pairs of neurodegenerative diseases and mental disorders. Lastly, a comprehensive multi-omics analysis suggested that alterations in brain structures, blood proteins and inflammation potentially contribute to the gene-phenotype linkages. Overall, our findings characterized a compendium of protein-coding variants for future research on the biology and therapeutics of neuropsychiatric phenotypes.

Abstract

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