Kayaalp Barış, Kars Meltem Ece, Itan Yuval, Başak Ayşe Nazlı, Casanova Jean-Laurent, Özçelik Tayfun
Bilkent University.
Icahn School of Medicine at Mount Sinai.
Res Sq. 2025 Mar 10:rs.3.rs-6169692. doi: 10.21203/rs.3.rs-6169692/v1.
Inherited burden for disease predisposition in diverse populations is an open question. American College of Medical Genetics and Genomics (ACMG) guidelines for variant classification, combined with large population variation databases, promise to provide valuable answers. We recently developed a robust ACMG-based automated variant classification tool and categorized the exome sequencing variants of 730,947 individuals from gnomAD.
We leveraged the allele frequency information of variants in 3895 Genomics England PanelApp genes and identified 76,677 pathogenic (P) and 295,356 likely-pathogenic (LP) variants, expanding the ClinVar submissions nearly fivefold.
We found that, on average, an individual is born with 4.31 P or LP variants, of which 1.59 are compatible with a Mendelian condition, 1 in 12 presents with an actionable genotype, and a total of 372 genes are candidates for carrier screening. Furthermore, a genome-first approach revealed that the likelihood of having a genotype compatible with a disease is highest for congenital (1 in 2.24 individuals; 3.37 billion worldwide) followed by nervous (1 in 3.01; 2.39 billion), blood/immune (1 in 3.29; 2.04 billion), musculoskeletal/connective (1 in 3.65; 1.87 billion), skin (1 in 4.46; 1.62 billion), endocrine/metabolic (1 in 4.53; 1.62 billion), circulatory (1 in 7.26; 994 million), eye (1 in 7.62; 961 million), ear (1 in 8.39; 880 million), genitourinary (1 in 10.15; 750 million), neoplasm (1 in 16.01; 410 million), digestive (1 in 18.26; 312 million) and respiratory (1 in 47.72; 155 million) disorders.
Evidence-based genetic epidemiology demonstrates the potential of personalized medicine for the implementation of early preventive measures and incentivization of lifestyle changes to enhance healthspan and lifespan. From a societal standpoint, this research demonstrates the importance of informing the public to decrease discrimination and social stigmatization associated with inherited diseases, as an overwhelming majority of individuals are expected to carry germ-line risk variants on average.
不同人群中疾病易感性的遗传负担仍是一个悬而未决的问题。美国医学遗传学与基因组学学会（ACMG）的变异分类指南，结合大量人群变异数据库，有望提供有价值的答案。我们最近开发了一种基于ACMG的强大自动化变异分类工具，并对gnomAD中730,947个人的外显子组测序变异进行了分类。
我们利用了3895个英国基因组学小组应用程序基因中变异的等位基因频率信息，鉴定出76,677个致病性（P）和295,356个可能致病性（LP）变异，使ClinVar提交的数据增加了近五倍。
我们发现，平均而言，每个人出生时携带4.31个P或LP变异，其中1.59个与孟德尔疾病相符，每12个人中有1人表现出可采取行动的基因型，共有372个基因是携带者筛查的候选基因。此外，一种基因组优先方法显示，患有与疾病相符基因型的可能性在先天性疾病中最高（每2.24个人中有1人；全球33.7亿人），其次是神经系统疾病（每3.01个人中有1人；23.9亿人）、血液/免疫系统疾病（每3.29个人中有1人；20.4亿人）、肌肉骨骼/结缔组织疾病（每3.65个人中有1人；18.7亿人）、皮肤疾病（每4.46个人中有1人；16.2亿人）、内分泌/代谢疾病（每4.53个人中有1人；16.2亿人）、循环系统疾病（每7.26个人中有1人；9.94亿人）、眼部疾病（每7.62个人中有1人；9.61亿人）、耳部疾病（每8.39个人中有1人；8.8亿人）、泌尿生殖系统疾病（每10.15个人中有1人；7.5亿人）、肿瘤疾病（每16.01个人中有1人；4.1亿人）、消化系统疾病（每18.26个人中有1人；3.12亿人）和呼吸系统疾病（每47.72个人中有1人；1.55亿人）。
基于证据的遗传流行病学证明了个性化医疗在实施早期预防措施和激励生活方式改变以延长健康寿命和寿命方面的潜力。从社会角度来看，这项研究表明告知公众减少与遗传疾病相关的歧视和社会污名化的重要性，因为预计绝大多数人平均会携带生殖系风险变异。
