Abstract
BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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.
Highlights
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
We removed all variants with minor allele frequency (MAF) > 0.01 in any of the sequencing databases used as reference databases for the study (Additional file 6: Table S4) and were left with 14,655 rare variants
Protein modelling for the S1004R variant in ATPase cation transporting 13A2 (ATP13A2) When the S1004R variant was inserted into the ATP13A2 structure and energy minimized (Kenyon et al unpublished results), we found that the peptide backbone around the cation binding site was displaced, changing the distance between the cation and a coordinating atom from 3.44 to 2.66 Å (Additional file 11: Figure S4)
Summary
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. The neuropathological hallmark of PD is the progressive loss of predominantly dopaminergic neurons of the substantia nigra pars compacta of the midbrain, which regulate voluntary movement The diagnosis of this disorder is largely clinical using criteria such as the UK PD Society Brain Bank criteria (UKPDSBBC) to differentiate ageing related symptoms from PD [2]. Estimates of PD prevalence in sub-Saharan Africa (SSA) vary widely across previous studies and range from 10 to 235/100,000 in urban populations [6, 7]
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