Hong Samantha, Koretsky Mathew J, Lichtenberg Jens, Leonard Hampton, Pitz Vanessa
Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, USA.
DataTecnica LLC, Washington DC, USA.
medRxiv. 2024 Dec 17:2024.12.16.24319097. doi: 10.1101/2024.12.16.24319097.
Known pathogenic variants in Parkinson's disease (PD) contribute to disease development but have yet to be fully explored by arrays at scale.
This study evaluated genotyping success of the NeuroBooster array (NBA) and determined the frequencies of pathogenic variants across ancestries.
We analyzed the presence and allele frequency of 34 pathogenic variants in 28,710 PD cases, 9,614 other neurodegenerative disorder cases, and 15,821 controls across 11 ancestries within the Global Parkinson's Genetics Program dataset. Of these, 25 were genotyped on NBA and cluster plots were used to assess their quality.
Genes previously predicted to have high or very high confidence of causing PD tend to have more pathogenic variants and are present across ancestry groups. Twenty-five of the 34 pathogenic variants were typed by the NBA array and classified "good" (n=12), "medium" (n=4), and "bad" (n=9) variants.
Our results confirm the likelihood that established PD genes are pathogenic and highlight the importance of ancestrally diverse research in PD. We also show the usefulness of the NBA as a reliable tool for genotyping of rare variants for PD.
帕金森病（PD）中已知的致病变异有助于疾病发展，但尚未通过大规模阵列进行充分探索。
本研究评估了NeuroBooster阵列（NBA）的基因分型成功率，并确定了不同祖先群体中致病变异的频率。
我们在全球帕金森病遗传学项目数据集中分析了28710例PD病例、9614例其他神经退行性疾病病例和15821例对照中34个致病变异的存在情况和等位基因频率，这些病例来自11个祖先群体。其中，25个变异在NBA上进行了基因分型，并使用聚类图评估其质量。
先前预测导致PD具有高置信度或非常高置信度（的致病变异）往往有更多的致病变异，并且在不同祖先群体中均有存在。34个致病变异中的25个通过NBA阵列分型，并分为“良好”（n = 12）、“中等”（n = 4）和“不良”（n = 9）变异。
我们的结果证实了已确定的PD基因具有致病性的可能性，并强调了PD中不同祖先群体研究的重要性。我们还展示了NBA作为PD罕见变异基因分型可靠工具的实用性。
