Large-scale exome sequencing identified 18 novel genes for neuroticism in 394,005 UK-based individuals

Xin-Rui Wu, Ze-Yu Li, Liu Yang, Ying Liu, Chen-Jie Fei, Yue-Ting Deng, Wei-Shi Liu, Bang-Sheng Wu, Qiang Dong, Jian-Feng Feng, Wei Cheng () and Jin-Tai Yu ()
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Xin-Rui Wu: Fudan University
Ze-Yu Li: Fudan University
Liu Yang: Fudan University
Ying Liu: Fudan University
Chen-Jie Fei: Fudan University
Yue-Ting Deng: Fudan University
Wei-Shi Liu: Fudan University
Bang-Sheng Wu: Fudan University
Qiang Dong: Fudan University
Jian-Feng Feng: Fudan University
Wei Cheng: Fudan University
Jin-Tai Yu: Fudan University

Nature Human Behaviour, 2025, vol. 9, issue 2, 406-419

Abstract: Abstract Existing genetic studies of neuroticism have been largely limited to common variants. Here we performed a large-scale exome analysis of white British individuals from UK Biobank, revealing the role of coding variants in neuroticism. For rare variants, collapsing analysis uncovered 14 neuroticism-associated genes. Among these, 12 (PTPRE, BCL10, TRIM32, ANKRD12, ADGRB2, MON2, HIF1A, ITGB2, STK39, CAPNS2, OGFOD1 and KDM4B) were novel, and the remaining (MADD and TRPC4AP) showed convergent evidence with common variants. Heritability of rare coding variants was estimated to be up to 7.3% for neuroticism. For common variants, we identified 78 significant associations, implicating 6 unreported genes. We subsequently replicated these variants using meta-analysis across other four ancestries from UK Biobank and summary data from 23andMe sample. Furthermore, these variants had widespread impacts on neuropsychiatric disorders, cognitive abilities and brain structure. Our findings deepen the understanding of neuroticism’s genetic architecture and provide potential targets for future mechanistic research.

Date: 2025
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DOI: 10.1038/s41562-024-02045-w

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