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.

现有的神经质遗传学研究在很大程度上仅限于常见变异。在这里，我们对来自英国生物样本库的英国白人个体进行了大规模的外显子组分析，揭示了编码变异在神经质中的作用。对于罕见的变异，坍塌分析发现了 14 个神经质相关基因。其中，12 （PTPRE、BCL10、TRIM32、ANKRD12、ADGRB2、MON2、HIF1A、ITGB2、STK39、CAPNS2、OGFOD1 和 KDM4B）是新的，其余 （MADD 和 TRPC4AP） 显示出与常见变异的趋同证据。神经质的罕见编码变异的遗传力估计高达 7.3%。对于常见变异，我们确定了 78 个显著关联，涉及 6 个未报道的基因。随后，我们通过对来自英国生物样本库的其他四个祖先的荟萃分析和来自 23andMe 样本的摘要数据来复制这些变异。此外，这些变异对神经精神疾病、认知能力和大脑结构产生了广泛的影响。我们的研究结果加深了对神经质遗传结构的理解，并为未来的机制研究提供了潜在的靶点。