美国Biogen Inc公司Heiko Runz研究组阐明了罕见蛋白编码的遗传变异对成人认知功能的影响。相关论文于2023年5月25日发表于国际学术期刊《自然—遗传学》杂志。

研究人员开展了一项大规模的外显子组研究，以探究罕见蛋白质编码变异是否会影响成年人群的认知功能（n=485930）。通过对具有高效罕见编码变体进行分析，研究人员鉴定了与成人认知功能相关的八个基因（ADGRB2、KDM5、GIGYF1、ANKRD12、SLC8A1、RC3H2、CACNA1A和BCAS3）。罕见的认知功能遗传结构与神经发育障碍部分重叠。研究人员以KDM5B为例展示了这些基因的遗传剂量变化如何决定小鼠和人类的认知、行为和分子特征。

研究进一步提供的证据表明罕见和常见变异在关联信号中相重叠，并对认知功能有叠加影响。该研究介绍了罕见编码变异与认知功能的相关性，并揭示了高影响力的单基因突变对正常成年人群认知功能分布的影响。

据介绍，越来越多的证据表明，人类认知功能受到遗传学的强烈影响。

附：英文原文

Title: The impact of rare protein coding genetic variation on adult cognitive function

Author: Chen, Chia-Yen, Tian, Ruoyu, Ge, Tian, Lam, Max, Sanchez-Andrade, Gabriela, Singh, Tarjinder, Urpa, Lea, Liu, Jimmy Z., Sanderson, Mark, Rowley, Christine, Ironfield, Holly, Fang, Terry, Daly, Mark, Palotie, Aarno, Tsai, Ellen A., Huang, Hailiang, Hurles, Matthew E., Gerety, Sebastian S., Lencz, Todd, Runz, Heiko

Issue&Volume: 2023-05-25

Abstract: 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.

DOI: 10.1038/s41588-023-01398-8

Source: https://www.nature.com/articles/s41588-023-01398-8