Journal Article

Targeted next-generation sequencing identifies novel variants in candidate genes for Parkinson’s disease in Black South African and Nigerian patients

Rossouw, Anastasia C., Tromp, Gerard, Oluwole, Oluwafemi G., Fawale, Michael B., Olaogun, Matthew O., Vorster, Alvera A., Sunmonu, Taofiki A., Tabb, David L., Ajose, Abiodun, Ross, Owen A., Kuivaniemi, Helena, Carr, Jonathan, Komolafe, Morenikeji A., van Hillegondsberg, Ludo S., Kenyon, Colin P., Abrahams, Shameemah, van Heerden, Carel J., Haylett, William L., Bardien, Soraya

2020

Overview

Background 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. Methods 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. Results 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. Conclusions 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.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Adult / Aged / Aged, 80 and over / Algorithms / Analysis / Biomedical and Life Sciences / Biomedicine / Black People - genetics / Clinical-Molecular Genetics and Cytogenetics / Cytogenetics / Disease / Diseases / Female / Gene Frequency / Gene Function / Genes / Genetic Association Studies / Genetic diversity / Genetic Predisposition to Disease / Genetics / Genomes / High-Throughput Nucleotide Sequencing / Human Genetics / Humans / Male / Medical research / Middle Aged / Molecular modelling / Molecular Sequence Annotation / Movement disorders / Mutation / Mutation, Missense / Neurodegenerative diseases / Neurological disorders / Neurological research / Neurology / Next-generation sequencing / Nigeria / Nigeria - epidemiology / Novels / Parkinson Disease - epidemiology / Parkinson Disease - genetics / Parkinson Disease - pathology / Parkinson's disease / Point Mutation / Population studies / Protein structure / Proteins / Proton-Translocating ATPases - genetics / Research Article / Scoring of sequence variants / South Africa / South Africa - epidemiology / Studies / Sub-Saharan Africa / Teaching hospitals / West African literature