Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population (n = 485,930). We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population.

令人信服的证据表明，人类的认知功能受到遗传学的强烈影响。在这里，我们进行了一项大规模的外显子组研究，以检查罕见的蛋白质编码变异是否影响成年人群的认知功能（n  = 485,930）。我们确定了八个基因（ADGRB2、KDM5B、GIGYF1、ANKRD12、SLC8A1、RC3H2、CACNA1A和BCAS3），它们通过具有重大影响的罕见编码变异与成人认知功能相关。认知功能的罕见遗传结构与神经发育障碍的部分重叠。KDM5B的情况我们展示了这些基因之一的遗传剂量如何决定小鼠和人类认知、行为和分子特征的变异性。我们进一步提供证据表明，罕见和常见的变异在关联信号中重叠，并对认知功能有附加贡献。我们的研究介绍了罕见编码变异与认知功能的相关性，并揭示了对认知功能如何在正常成年人群中分布的高影响单基因贡献。