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 () and Jin-Tai Yu ()
Additional contact information
Yue-Ting Deng: Fudan University
Bang-Sheng Wu: Fudan University
Liu Yang: Fudan University
Xiao-Yu He: Fudan University
Ju-Jiao Kang: Fudan University
Wei-Shi Liu: Fudan University
Ze-Yu Li: Fudan University
Xin-Rui Wu: Fudan University
Ya-Ru Zhang: Fudan University
Shi-Dong Chen: Fudan University
Yi-Jun Ge: Fudan University
Yu-Yuan Huang: Fudan University
Jian-Feng Feng: Fudan University
Ying Zhu: Fudan University
Qiang Dong: Fudan University
Ying Mao: Huashan Hospital Fudan University
Wei Cheng: Fudan University
Jin-Tai Yu: Fudan University

Nature Human Behaviour, 2024, vol. 8, issue 6, 1194-1208

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41562-024-01861-4

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