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.

虽然已鉴定出许多与神经精神疾病有关的基因组位点，但蛋白质编码变异的贡献尚未确定。在这里，我们进行了一项大规模全外显子组测序研究，以探究蛋白质编码变异对英国生物银行 350,770 名成年人的 46 种神经精神疾病和 23 种特征的影响。 20个新基因通过编码变异与神经精神疾病相关，其中16个基因对疾病的纵向风险有影响。 30 个新基因与神经精神特征相关，其中SYNGAP1在认知功能领域表现出多效性。在编码变异水平上的遗传相关性的成对估计突出了神经退行性疾病和精神障碍对之间共享的遗传关联。最后，全面的多组学分析表明，大脑结构、血液蛋白和炎症的改变可能有助于基因与表型的联系。总的来说，我们的研究结果描述了蛋白质编码变异的概要，用于神经精神表型的生物学和治疗学的未来研究。