Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa.
Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
BMC Med Genet. 2020 Feb 4;21(1):23. doi: 10.1186/s12881-020-0953-1.
The prevalence of Parkinson's disease (PD) is increasing in sub-Saharan Africa, but little is known about the genetics of PD in these populations. Due to their unique ancestry and diversity, sub-Saharan African populations have the potential to reveal novel insights into the pathobiology of PD. In this study, we aimed to characterise the genetic variation in known and novel PD genes in a group of Black South African and Nigerian patients.
We recruited 33 Black South African and 14 Nigerian PD patients, and screened them for sequence variants in 751 genes using an Ion AmpliSeq™ Neurological Research panel. We used bcftools to filter variants and annovar software for the annotation. Rare variants were prioritised using MetaLR and MetaSVM prediction scores. The effect of a variant on ATP13A2's protein structure was investigated by molecular modelling.
We identified 14,655 rare variants with a minor allele frequency ≤ 0.01, which included 2448 missense variants. Notably, no common pathogenic mutations were identified in these patients. Also, none of the known PD-associated mutations were found highlighting the need for more studies in African populations. Altogether, 54 rare variants in 42 genes were considered deleterious and were prioritized, based on MetaLR and MetaSVM scores, for follow-up studies. Protein modelling showed that the S1004R variant in ATP13A2 possibly alters the conformation of the protein.
We identified several rare variants predicted to be deleterious in sub-Saharan Africa PD patients; however, further studies are required to determine the biological effects of these variants and their possible role in PD. Studies such as these are important to elucidate the genetic aetiology of this disorder in patients of African ancestry.
帕金森病（PD）在撒哈拉以南非洲的发病率正在上升，但人们对这些人群中 PD 的遗传学知之甚少。由于其独特的起源和多样性，撒哈拉以南非洲人群有可能揭示 PD 病理生物学的新见解。在这项研究中，我们旨在描述一组南非黑人患者和尼日利亚 PD 患者中已知和新型 PD 基因的遗传变异。
我们招募了 33 名南非黑人患者和 14 名尼日利亚 PD 患者，并使用 Ion AmpliSeq™神经研究面板对 751 个基因的序列变体进行了筛选。我们使用 bcftools 过滤变体，annovar 软件进行注释。使用 MetaLR 和 MetaSVM 预测评分对稀有变体进行优先级排序。通过分子建模研究变体对 ATP13A2 蛋白结构的影响。
我们确定了 14,655 个罕见变异体，其等位基因频率≤0.01，其中包括 2448 个错义变异体。值得注意的是，这些患者中未发现常见的致病性突变。此外，也未发现已知的 PD 相关突变，这突出表明需要在非洲人群中进行更多的研究。共有 42 个基因中的 54 个罕见变异被认为是有害的，并根据 MetaLR 和 MetaSVM 评分进行了优先排序，以进行后续研究。蛋白建模表明，ATP13A2 中的 S1004R 变异可能改变蛋白的构象。
我们在撒哈拉以南非洲 PD 患者中发现了一些预测为有害的罕见变异；然而，需要进一步研究来确定这些变异的生物学效应及其在 PD 中的可能作用。开展此类研究对于阐明非洲裔患者这种疾病的遗传病因学非常重要。
