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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 t...
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... Ion AmpliSeq™ Neurological Research panel and the Ion AmpliSeq™ Library Kit 2.0 (Thermo Scientific, Waltham, Massachusetts, USA) were used for multiplex PCR amplification of 751 genes (Additional file 2: Table S2). The intronic regions incorporated as part of the exon targets are listed separately in Additional file 3: Table S3. ...Context 2
... individual S43_059 carried galactosylceramidase (GALC) T445S (rs34134328) and TSC complex subunit 2 (TSC2) S1092 L (rs148527903) variants; while S94_069 carried arylsulfatase A (ARSA) N442S (rs6151427) and prickle planar cell polarity protein 2 (PRICKLE2) Q274P (rs564701683) variants. All of the variants had a high certainty of being predicted to be deleterious (pathogenicity score > 0.8) ( Table 2). The GALC variant was excluded based on its high MAF in GnomAD African controls (MAF = 0.016) but all of the other variants are rare (MAF < 0.01) ( [32]; Table 2) and are therefore potential candidates. ...Context 3
... of the variants had a high certainty of being predicted to be deleterious (pathogenicity score > 0.8) ( Table 2). The GALC variant was excluded based on its high MAF in GnomAD African controls (MAF = 0.016) but all of the other variants are rare (MAF < 0.01) ( [32]; Table 2) and are therefore potential candidates. Notably, the PC R732G variant that they both share was not found in any of the other patients screened. ...Context 4
... attempted to prioritise one possible pathogenic variant per patient based on MAF (< 0.01), pathogenicity prediction scores (> 0.8) and evidence of prior association of the gene/protein with PD or Parkinsonism (Table 2; Additional file 10: Table S6). In some cases, the MAF of the variant in African controls in GnomAD was ≥0.01, similar to the frequency observed in the patients (Table 2), and those variants were therefore excluded. ...Context 5
... attempted to prioritise one possible pathogenic variant per patient based on MAF (< 0.01), pathogenicity prediction scores (> 0.8) and evidence of prior association of the gene/protein with PD or Parkinsonism (Table 2; Additional file 10: Table S6). In some cases, the MAF of the variant in African controls in GnomAD was ≥0.01, similar to the frequency observed in the patients (Table 2), and those variants were therefore excluded. The prioritised variants are shown in bold and in green font in Table 3. ...Citations
... An eroded cerebral cortex is linked to various neurodegenerative disorders due to neuronal cell loss [42]. Neuronal phenotypic genes that coordinate the cerebral cortex functions and sizes have been previously studied in neurodegenerative disorders like Parkinson's disease (PD) [43]. ...
Causal mutations in the MCPH1 gene have been associated with disorders like microcephaly, and recently congenital hearing impairment. This study examined the MCPH1 DNA repair machinery and identified genetic variations of interest in gnomAD database to discuss the biological roles and effects of rare variants in MCPH1-related diseases. Notably, MCPH1 coordinates two of the seven known mechanisms of DNA repair which confirmed its roles in neurogenesis and chromatin condensation. A pathogenic missense variant in MCPH1 p.Gly753Arg, and two pathogenic frameshifts MCPH1 p.Asn189LysfsTer15 and p.Cys624Ter identified in this study, already had entries in ClinVar and were associated with microcephaly. A pathogenic frameshift in MCPH1 p.Val10SerfsTer5 with a loss-of-function flag and a pathogenic stop gained p.Ser571Ter variants with ultra-rare allele frequency (MAF ≤ 0.001) were identified but have not been linked to any phenotype. The predicted pathogenic ultra-rare variants identified in this study, warranty phenotypic discovery, and also positioned these variants or nearby deleterious variants candidate for screening in MCPH1-associated rare diseases.
... Missense mutations can result in both LOF and non-LOF consequences. To properly stratify LOF/non-LOF mutations, we assessed all of the missense mutations using prediction scores MetaLR and MetaSVM for mutation pathogenicity analysis [38]. MetaLR and MetaSVM are ensemble models based on 10 component scores (SIFT, PolyPhen-2 HDIV, PolyPhen-2 HVAR, GERP + + , MutationTaster, Mutation Assessor, FATHMM, LRT, SiPhy, and PhyloP) and the maximum frequency observed in the 1000 genomes populations. ...
Abstract Background Genes related to the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex are frequently mutated across cancers. SWI/SNF-mutant tumors are vulnerable to synthetic lethal inhibitors. However, the landscape of SWI/SNF mutations and their associations with tumor mutational burden (TMB), microsatellite instability (MSI) status, and response to immune checkpoint inhibitors (ICIs) have not been elucidated in large real-world Chinese patient cohorts. Methods The mutational rates and variation types of six SWI/SNF complex genes (ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, and PBRM1) were analyzed retrospectively by integrating next-generation sequencing data of 4591 cases covering 18 cancer types. Thereafter, characteristics of SWI/SNF mutations were depicted and the TMB and MSI status and therapeutic effects of ICIs in the SWI/SNF-mutant and SWI/SNF-non-mutant groups were compared. Results SWI/SNF mutations were observed in 21.8% of tumors. Endometrial (54.1%), gallbladder and biliary tract (43.4%), and gastric (33.9%) cancers exhibited remarkably higher SWI/SNF mutational rates than other malignancies. Further, ARID1A was the most frequently mutated SWI/SNF gene, and ARID1A D1850fs was identified as relatively crucial. The TMB value, TMB-high (TMB-H), and MSI-high (MSI-H) proportions corresponding to SWI/SNF-mutant cancers were significantly higher than those corresponding to SWI/SNF-non-mutant cancers (25.8 vs. 5.6 mutations/Mb, 44.3% vs. 10.3%, and 16.0% vs. 0.9%, respectively; all p
... For example, Keyser et al. (2011) identified two novel MAPT variants in South African individuals with PD (A91V and V635I), although these were predicted to be benign (Keyser et al., 2011). Similarly, Oluwole et al. (2020) identified an additional seven novel MAPT variants in black South African and Nigerian individuals that may be associated with PD risk, with unknown functional effects (Oluwole et al., 2020). While these data indicate the presence of ancestry-specific variants of MAPT, the association with PD risk is less convincing; this is unsurprising given that the GWAS association in European populations spans a ∼1 Mb region, which incorporates numerous genes other than MAPT. ...
... For example, Keyser et al. (2011) identified two novel MAPT variants in South African individuals with PD (A91V and V635I), although these were predicted to be benign (Keyser et al., 2011). Similarly, Oluwole et al. (2020) identified an additional seven novel MAPT variants in black South African and Nigerian individuals that may be associated with PD risk, with unknown functional effects (Oluwole et al., 2020). While these data indicate the presence of ancestry-specific variants of MAPT, the association with PD risk is less convincing; this is unsurprising given that the GWAS association in European populations spans a ∼1 Mb region, which incorporates numerous genes other than MAPT. ...
Advances in genomic research over the last two decades have greatly enhanced our knowledge concerning the genetic landscape and pathophysiological processes involved in multiple neurodegenerative diseases. However, current insights arise almost exclusively from studies on individuals of European ancestry. Despite this, studies have revealed that genetic variation differentially impacts risk for, and clinical presentation of neurodegenerative disease in non-European populations, conveying the importance of ancestry in predicting disease risk and understanding the biological mechanisms contributing to neurodegeneration. We review the genetic influence of two important disease-associated loci, 17q21.31 (the “ MAPT locus”) and APOE , to neurodegenerative disease risk in non-European populations, touching on global population differences and evolutionary genetics by ancestry that may underlie some of these differences. We conclude there is a need to increase representation of non-European ancestry individuals in genome-wide association studies (GWAS) and biomarker analyses in order to help resolve existing disparities in understanding risk for, diagnosis of, and treatment for neurodegenerative diseases in diverse populations.
... Any predicting method or the consensus of multiple methods can serve this supporting role. Few examples are variants causing FARS2 deficiency (Almannai et al. 2018), ANO5 variants causing Gnathodiaphyseal Dysplasia (Otaify et al. 2018), DHCR24 variants causing Desmosterolosis(Schaaf et al. 2011), variants in multiple genes causing ALS(Gibson et al. 2017;Kenna et al. 2016), Parkinson's disease(Oluwole et al. 2020), and Alzheimer's disease(Vardarajan et al. 2015). Similar analyses for somatic mutations in tumors revealed strong selection patterns, either on numerous candidate genes(Bailey et al. 2018) or on specific genes such as in PTPN12(Nair et al. 2018), BAP1(Sharma et al. 2019), and TP53 ...
Estimating the effects of variants found in disease driver genes opens the door to personalized therapeutic opportunities. Clinical associations and laboratory experiments can only characterize a tiny fraction of all the available variants, leaving the majority as variants of unknown significance (VUS). In silico methods bridge this gap by providing instant estimates on a large scale, most often based on the numerous genetic differences between species. Despite concerns that these methods may lack reliability in individual subjects, their numerous practical applications over cohorts suggest they are already helpful and have a role to play in genome interpretation when used at the proper scale and context. In this review, we aim to gain insights into the training and validation of these variant effect predicting methods and illustrate representative types of experimental and clinical applications. Objective performance assessments using various datasets that are not yet published indicate the strengths and limitations of each method. These show that cautious use of in silico variant impact predictors is essential for addressing genome interpretation challenges.
... At the end of the pole test, mice were anaesthetised via intraperitoneal injection with sodium pentobarbital (100 mg/kg), and were then euthanised using cervical dislocation. The caecum content (0.5 g per sample) was quickly removed, and the gut microbiota was analysed using next gene sequencing (25). 16S rRNA gene amplification was evaluated using the Illumina MiSeq platform by a standardized experimental procedure that provided by Illumina (Illumina, Inc.) (26). ...
The composition of the intestinal flora of patients with Parkinson's disease (PD) can change. However, whether reshaping the gut microbial composition can treat PD remains to be seen. The present study evaluated the effect of intestinal flora in the treatment of PD in a C57BL/6 mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Chronic, low-dose, MPTP-treated mice exhibited upregulated gene expression levels of TNF-α and IL-1β in the substantia nigra (SN) of the mice, and induced intestinal microbial disorders. This indicated that the chronic low-dose MPTP model could be used to evaluate the progress of early intestinal pathology and intestinal flora imbalance in PD. After transplantation of faecal bacteria to MPTP-induced PD mice, the level of inflammation in the SN of the mice was reduced, and motor dysfunction was alleviated. Notably, faecal microbiota transplantation (FMT) upregulated the abundance of Blautia but downregulated Anaerostipes, Bifidobacterium, ASF356 and Ruminococcus in the gut of PD mice. In addition, FMT reduced the activation of microglia and astrocytes in the SN and reduced the expression levels of GSK3β, IL-1β, inducible nitric oxide synthase and phosphorylated PTEN in the SN. Overall, the present study demonstrated that gut microbial dysfunction is associated with the pathogenesis of PD, and that FMT can protect PD mice by inhibiting neuroinflammation.
... Fourteen Nigerian patients with PD were screened for 16 genes associated with PD. However exon dosage and SNCA multiplications analysis were never performed in this population (11). ...
Introduction: Nigeria is one of the most populated countries in the world; however, there is a scarcity of studies in patients with age-related neurodegenerative diseases, such as Parkinson disease (PD). The aim of this study was to screen patients with PD including a small cohort of early-onset PD (EOPD) cases from Nigeria for PRKN, PINK1, DJ1, SNCA multiplication, and LRRK2 p.G2019S.
Methods: We assembled a cohort of 109 Nigerian patients with PD from the four main Nigerian tribes: Yoruba, Igbo, Edo, and Hausa. Fifteen cases [14 from the Yoruba tribe (93.3%)] had EOPD (defined as age-at-onset <50 years). All patients with EOPD were sequenced for the coding regions of PRKN, PINK1, and DJ1. Exon dosage analysis was performed with a multiplex ligation-dependent probe amplification assay, which also included a SNCA probe and LRRK2 p.G2019S. We screened for LRRK2 p.G2019S in the entire PD cohort using a genotyping assay. The PINK1 p.R501Q functional analysis was conducted.
Results: In 15 patients with EOPD, 22 variants were observed [PRKN, 9 (40.9%); PINK1, 10 (45.5%); and DJ1, 3 (13.6%)]. Three (13.6%) rare, nonsynonymous variants were identified, but no homozygous or compound heterozygous carriers were found. No exonic rearrangements were present in the three genes, and no carriers of SNCA genomic multiplications or LRRK2 p.G2019S were identified. The PINK1 p.R501Q functional analysis revealed pathogenic loss of function.
Conclusion: More studies on age-related neurodegenerative diseases are needed in sub-Saharan African countries, including Nigeria. Population-specific variation may provide insight into the genes involved in PD in the local population but may also contribute to larger studiesperformed in White and Asian populations.
... However, a large number of PD cases still remains genetically unexplained, since no common mutations have been detected in the key genes responsible for PD in this population, while target sequencing permitted the identification of rare sequence variants. As a consequence, the limited number of variations in these patients suggests that the well-known PD genes may play a minor role in causing the disorder in these populations and that other genes are likely to be involved [98,99]. ...
Life expectancy has gradually grown over the last century. This has deeply affected healthcare costs, since the growth of an aging population is correlated to the increasing burden of chronic diseases. This represents the interesting challenge of how to manage patients with chronic diseases in order to improve health care budgets. Effective primary prevention could represent a promising route. To this end, precision, together with personalized medicine, are useful instruments in order to investigate pathological processes before the appearance of clinical symptoms and to guide physicians to choose a targeted therapy to manage the patient. Cardiovascular and neurodegenerative diseases represent suitable models for taking full advantage of precision medicine technologies applied to all stages of disease development. The availability of high technology incorporating artificial intelligence and advancement progress made in the field of biomedical research have been substantial to understand how genes, epigenetic modifications, aging, nutrition, drugs, microbiome and other environmental factors can impact health and chronic disorders. The aim of the present review is to address how precision and personalized medicine can bring greater clarity to the clinical and biological complexity of these types of disorders associated with high mortality, involving tremendous health care costs, by describing in detail the methods that can be applied. This might offer precious tools for preventive strategies and possible clues on the evolution of the disease and could help in predicting morbidity, mortality and detecting chronic disease indicators much earlier in the disease course. This, of course, will have a major effect on both improving the quality of care and quality of life of the patients and reducing time efforts and healthcare costs.
... A few studies including two from our group in Nigeria, one in Zambia, one in Ghana and several in South Africa have investigated the LRRK2 PD pathogenic variants in Sub-Saharan Africa. (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) In the present report, we expand on our previous enquiry which focused only on LRRK2 p.gly2019ser in Nigeria, to explore the frequency of 12 pathogenic rare PD-associated LRRK2 variants including the p.gly2019ser in a new cohort of 92 Nigerians with PD and 210 ethnically matched controls. ...
Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are the most commonly identified genetic variants in familial and sporadic Parkinson disease (PD). Over three hundred LRRK2 variants have been described in the literature, of which at least 17 have a confirmed or probable pathogenic role in PD. The distribution of these rare pathogenic variants has been shown to be different among ethnic groups including Caucasians, Latin Americans and East and South Asians. However, to date no PD-related LRRK2 pathogenic variant has been described in persons of black African ancestry within or outside Africa. We previously reported that the LRRK2 p.gly2019ser mutation was not found in 126 PD patients and 55 controls from Nigeria. Using Kompetitive Allele-Specific Polymerase chain reaction (KASP), we screened a new cohort of 92 Nigerians with PD and 210 healthy ethnically matched controls for 12 rare LRRK2 variants (which have been shown to be pathogenic in other ethnic populations) including: p.gly2019ser, p.Arg1441His, p.Gly2385Arg, p.Ala419Val, p.Arg1628Pro, p.Pro755Leu, p.Ile2020Thr and Tyr1699Cys. All 12 rare variants were absent in PD patients and controls from this cohort. These results endorse our previous findings and confirm that rare LRRK2 pathogenic variants reported in Caucasians, Asians and persons of mixed ancestry are absent in West Africans. Applying next generation sequencing technologies in future studies is necessary to explore possible novel LRRK2 variants indigenous to black Africans.
... On the African continent, most of the work has been done on patients from North African Arabic countries where the frequency of the LRRK2 G2019S mutation was reported to be as high as 41% of patients (44) due to the presence of genetic founder effects. A number of studies have been conducted in South Africa but the mutation detection rate has been low (32,40,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). The other studies have been done in Nigeria (30)(31)(32), Tanzania (12), Zambia (56), and Ghana (57) but for the vast majority of the countries in Africa, no genetic studies have been reported. ...
... A number of studies have been conducted in South Africa but the mutation detection rate has been low (32,40,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). The other studies have been done in Nigeria (30)(31)(32), Tanzania (12), Zambia (56), and Ghana (57) but for the vast majority of the countries in Africa, no genetic studies have been reported. This is a striking omission since African populations have the oldest genomes and the greatest genetic diversity in the world, and are therefore likely to reveal novel insights into disease mechanisms and pathways underlying PD (58). ...
The burden of Parkinson's disease (PD) is becoming increasingly important in the context of an aging African population. Although PD has been extensively investigated with respect to its environmental and genetic etiology in various populations across the globe, studies on the African continent remain limited. In this Perspective article, we review some of the obstacles that are limiting research and creating barriers for future studies. We summarize what research is being done in four sub-Saharan countries and what the key elements are that are needed to take research to the next level. We note that there is large variation in neurological and genetic research capacity across the continent, and many opportunities for unexplored areas in African PD research. Only a handful of countries possess appropriate infrastructure and personnel, whereas the majority have yet to develop such capacity. Resource-constrained environments strongly determines the possibilities of performing research locally, and unidirectional export of biological samples and genetic data remains a concern. Local-regional partnerships, in collaboration with global PD consortia, should form an ethically appropriate solution, which will lead to a reduction in inequality and promote capacity building on the African continent.
Background: Parkinson's disease (PD) has become a global public health challenge as disability and death due to the disease are growing rapidly in comparison to other neurological disorders. There are no up-to-date comprehensive reviews on the epidemiology, environmental and genetic risk factors, phenotypic characterization, and patient-reported outcomes of PD in Africa. This data is crucial to understanding the current and future burden and suggesting actionable and/or researchable gaps aimed at improving disease outcomes.
Methodology: We conducted a systematic literature search using the electronic databases of Cochrane Central Register of Controlled Trials (CCRT), EMBASE, Medline, PsychINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), African Journals (AJOL) and other unpublished literature. We included all studies providing data on people with PD in Africa from the start of each database till February 2023. Studies were not restricted based on diagnostic criteria or language. Outcomes of interest were summarised based on epidemiology, genetics, environmental risk factors, clinical characteristics, patient-reported outcomes (experience and quality of life), disease management and outcomes, access to care, patient support, and healthcare workforce training.
We also investigated collaboration between African countries (internal) and across continents/world regions (external) and journal impact factors.
Results: A total of 4,855 articles were identified, of which 180 were included in this review. The majority were published from North Africa (mainly from Tunisia, and involved collaboration with investigators from France, the United Kingdom, and the United States of America). West Africa (Nigeria), Southern Africa (South Africa) and East Africa (mainly Tanzania) also had a relatively high number of publications. Methodological design varied across studies. Based on the pre-determined outcomes, articles identified were genetics (67), clinical features (65), environmental risk factors (16), epidemiology (14), patient experience and quality of life (10), management and access to care (5) and education and training (3).
Conclusions: The main hubs of PD-related research output in Africa are the Northern, Western and Southern regions of Africa (although with limited involvement of countries within these regions). External collaboration (outside the continent) currently predominates. There are considerable actionable and researchable gaps across all outcomes of interest, with a dearth of published information on health workforce capacity building, disease management and access to care, patient and caregiver engagement, and quality of life of people with PD in Africa. We recommend strengthening existing and emerging intercontinental networks for research, education, training and policy formulation and funding, leveraging on more recent developments such as the International Parkinson's Disease Genomics Consortium-Africa (IPDGC-Africa), the International Parkinson and Movement Disorder Society Africa Section (MDS-AS), World Health Organisation (WHO) and initiatives with similar objectives.
