Xiao Qingyang, Lauschke Volker M
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
NPJ Genom Med. 2021 Jun 2;6(1):41. doi: 10.1038/s41525-021-00203-x.
Autosomal recessive (AR) disorders pose a significant burden for public health. However, despite their clinical importance, epidemiology and molecular genetics of many AR diseases remain poorly characterized. Here, we analyzed the genetic variability of 508 genes associated with AR disorders based on sequencing data from 141,456 individuals across seven ethnogeographic groups by integrating variants with documented pathogenicity from ClinVar, with stringent functionality predictions for variants with unknown pathogenicity. We first validated our model using 85 diseases for which population-specific prevalence data were available and found that our estimates strongly correlated with the respective clinically observed disease frequencies (r = 0.68; p < 0.0001). We found striking differences in population-specific disease prevalence with 101 AR diseases (27%) being limited to specific populations, while an additional 305 diseases (68%) differed more than tenfold across major ethnogeographic groups. Furthermore, by analyzing genetic AR disease complexity, we confirm founder effects for cystic fibrosis and Stargardt disease, and provide strong evidences for >25 additional population-specific founder mutations. The presented analyses reveal the molecular genetics of AR diseases with unprecedented resolution and provide insights into epidemiology, complexity, and population-specific founder effects. These data can serve as a powerful resource for clinical geneticists to inform population-adjusted genetic screening programs, particularly in otherwise understudied ethnogeographic groups.
常染色体隐性（AR）疾病给公共卫生带来了沉重负担。然而，尽管它们具有临床重要性，但许多AR疾病的流行病学和分子遗传学特征仍不清楚。在此，我们通过整合来自ClinVar的具有已记录致病性的变异，并对致病性未知的变异进行严格的功能预测，基于来自七个种族地理群体的141,456人的测序数据，分析了与AR疾病相关的508个基因的遗传变异性。我们首先使用85种有特定人群患病率数据的疾病验证了我们的模型，发现我们的估计值与各自临床观察到的疾病频率高度相关（r = 0.68；p < 0.0001）。我们发现特定人群疾病患病率存在显著差异，101种AR疾病（27%）仅限于特定人群，而另外305种疾病（68%）在主要种族地理群体中的差异超过十倍。此外，通过分析遗传性AR疾病的复杂性，我们证实了囊性纤维化和斯塔加特病的奠基者效应，并为另外25种以上特定人群的奠基者突变提供了有力证据。所呈现的分析以前所未有的分辨率揭示了AR疾病的分子遗传学，并提供了对流行病学、复杂性和特定人群奠基者效应的见解。这些数据可作为临床遗传学家的有力资源，为人群调整后的基因筛查项目提供信息，特别是在其他研究较少的种族地理群体中。
