Gibbs Kyle D, Schott Benjamin H, Ko Dennis C
Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, North Carolina, USA; email:
Duke University Program in Genetics and Genomics, Duke University, Durham, North Carolina, USA.
Annu Rev Genet. 2022 Nov 30;56:41-62. doi: 10.1146/annurev-genet-080320-010449. Epub 2022 Jun 13.
Since the identification of sickle cell trait as a heritable form of resistance to malaria, candidate gene studies, linkage analysis paired with sequencing, and genome-wide association (GWA) studies have revealed many examples of genetic resistance and susceptibility to infectious diseases. GWA studies enabled the identification of many common variants associated with small shifts in susceptibility to infectious diseases. This is exemplified by multiple loci associated with leprosy, malaria, HIV, tuberculosis, and coronavirus disease 2019 (COVID-19), which illuminate genetic architecture and implicate pathways underlying pathophysiology. Despite these successes, most of the heritability of infectious diseases remains to be explained. As the field advances, current limitations may be overcome by applying methodological innovations such as cellular GWA studies and phenome-wide association (PheWA) studies as well as by improving methodological rigor with more precise case definitions, deeper phenotyping, increased cohort diversity, and functional validation of candidate loci in the laboratory or human challenge studies.
自从镰状细胞性状被鉴定为一种对疟疾具有遗传性抗性的形式以来，候选基因研究、与测序相结合的连锁分析以及全基因组关联（GWA）研究已经揭示了许多对传染病具有遗传抗性和易感性的例子。GWA研究使得能够识别出许多与传染病易感性微小变化相关的常见变异。与麻风病、疟疾、艾滋病毒、结核病和2019冠状病毒病（COVID-19）相关的多个基因座就是例证，这些基因座阐明了遗传结构，并暗示了病理生理学的潜在途径。尽管取得了这些成功，但传染病的大部分遗传力仍有待解释。随着该领域的发展，当前的局限性可能通过应用细胞GWA研究和全表型组关联（PheWA）研究等方法创新来克服，以及通过采用更精确的病例定义、更深入的表型分析、增加队列多样性以及在实验室或人体激发试验中对候选基因座进行功能验证来提高方法的严谨性。
