An exploration of the genetics of the mutant Huntingtin (mHtt) gene in a cohort of patients with chorea from different ethnic groups in sub-Saharan Africa.

BACKGROUND: Africans are underrepresented in Huntington's disease (HD) research. A European ancestor was postulated to have introduced the mutant Huntingtin (mHtt) gene to the continent; however, recent work has shown the existence of a unique Htt haplotype in South-Africa specific to indigenous Africans. OBJECTIVE: We aimed to investigate the CAG trinucleotide repeats expansion in the Htt gene in a geographically diverse cohort of patients with chorea and unaffected controls from sub-Saharan Africa. METHODS: We evaluated 99 participants: 43 patients with chorea, 21 asymptomatic first-degree relatives of subjects with chorea, and 35 healthy controls for the presence of the mHtt. Participants were recruited from 5 African countries. Additional data were collected from patients positive for the mHtt gene; these included demographics, the presence of psychiatric and (or) cognitive symptoms, family history, spoken languages, and ethnic origin. Additionally, their pedigrees were examined to estimate the number of people at risk of developing HD and to trace back the earliest account of the disease in each region. RESULTS: HD cases were identified in all countries. Overall, 53.4% of patients with chorea were carriers for the mHTT; median tract size was 45 CAG repeats. Of the asymptomatic relatives, 28.6% (6/21) were carriers for the mHTT; median tract size was 40 CAG. No homozygous carries were identified. Median CAG tract size in controls was 17 CAG repeats. Men and women were equally affected by HD. All patients with HD-bar three who were juvenile onset of <21 years-were defined as adult onset (median age of onset was 40 years). HD transmission followed an autosomal dominant pattern in 84.2% (16/19) of HD families. In familial cases, maternal transmission was higher 52.6% (10/19) than paternal transmission 36.8% (7/19). The number of asymptomatic individuals at risk of developing HD was estimated at ten times more than the symptomatic patients. HD could be traced back to the early 1900s in most African sites. HD cases spread over seven ethnic groups belonging to two distinct linguistic lineages separated from each other approximately 54-16 kya ago: Nilo-Sahara and Niger-Congo. CONCLUSION: This is the first study examining HD in multiple sites in sub-Saharan Africa. We demonstrated that HD is found in multiple ethnic groups residing in five sub-Saharan African countries including the first genetically confirmed HD cases from Guinea and Kenya. The prevalence of HD in the African continent, its associated socio-economic impact, and genetic origins need further exploration and reappraisal.

A systematic analysis of neurologic manifestations of Long COVID in Nigeria.

Long COVID, also called post-acute sequelae of SARS-CoV-2 infection (PASC) affects millions of people in the world. The neurologic manifestations of PASC (Neuro-PASC) are among the most debilitating but they are largely unreported in Africa. We sought to compare the demographics, symptoms and cognitive profile of post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients in Nigeria. In this cross-sectional study performed at the Lagos University Teaching Hospital, 106/2319 (4.6%) SARS-CoV-2 positive individuals contacted via telephone reported Neuro-PASC symptoms with a higher frequency in PNP than in NNP individuals ((23/200 (11.5%) vs. 83/2119 (3.9%), p = < 0.0001). The predominant neurologic symptoms at any time during the disease course were difficulty remembering / brain fog (63/106; 59.4%), fatigue (59/106; 55.7%), sleep problems (34/106; 32%), headache (33/106; 31%), paresthesia (12/106; 11.3%), and myalgia (10/106; 9.4%). Of 66 participants with Neuro-PASC who underwent in-person neurological evaluation and cognitive screening, all had normal scores on the Intervention for Dementia in Elderly Africans cognition screen, while 11/65 (16.9%) that completed the Montreal Cognitive Assessment had results consistent with mild cognitive impairment (3/16 PNP (18.8%) and 8/49 NNP (16.3%); p = 1.0). Finally, 47/66 (71.2%) had digit span test scores consistent with mild cognitive dysfunction (12/16 PNP (75%) and 35/50 (70%) NNP; p = 1.0). Our findings reveal the previously unrecognized occurrence of Neuro-PASC among COVID-19 survivors in Nigeria and highlight the need for improved screening and diagnosis of Neuro-PASC in our population. Development of cognitive support services for persons suffering from Neuro-PASC in Nigeria is warranted.

GBA1 rs3115534 Is Associated with REM Sleep Behavior Disorder in Parkinson's Disease in Nigerians.

BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) is an early feature of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Damaging coding variants in Glucocerebrosidase (GBA1) are a genetic risk factor for RBD. Recently, a population-specific non-coding risk variant (rs3115534) was found to be associated with PD risk and earlier onset in individuals of African ancestry. OBJECTIVES: We aimed to investigate whether the GBA1 rs3115534 PD risk variant is associated with RBD in persons with PD. METHODS: We studied 709 persons with PD and 776 neurologically healthy controls from Nigeria. All DNA samples were genotyped and imputed, and the GBA1 rs3115534 risk variant was extracted. The RBD screening questionnaire (RBDSQ) was used to assess symptoms of possible RBD. RESULTS: RBD was present in 200 PD (28.2%) and 51 (6.6%) controls. We identified that the non-coding GBA1 rs3115534 risk variant is associated with possible RBD in individuals of Nigerian origin (ß, 0.3640; standard error [SE], 0.103, P = 4.093e-04), as well as in all samples after adjusting for PD status (ß, 0.2542; SE, 0.108; P = 0.019) suggesting that although non-coding, this variant may have the same downstream consequences as GBA1 coding variants. CONCLUSIONS: Our results indicate that the non-coding GBA1 rs3115534 risk variant is associated with an increasing number of RBD symptoms in persons with PD of Nigerian origin. Further research is needed to assess if this variant is also associated with polysomnography-defined RBD and with RBD symptoms in DLB. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Achieving a robust mentoring and research capacity program in a LMIC - the BRAINS faculty development model.

BACKGROUND: A research and training program (RTP) was carried out to build the capacity of faculty and improve the culture of research in the College of Medicine, University of Lagos (CMUL), Nigeria. METHODS: Realist-guided mixed methods evaluation of the BRAINS project was carried out using secondary data generated during the 5-years (2015 - 2020) of project implementation. Capacity building workshops and mentored research activities targeted at faculty in the CMUL were conducted. Overall, 1,418 participants attended the workshops in batches. Among the participants, forty-five faculty received grants and were mentored by senior professionals (local & international) to conduct research. Data were extracted from all project-related documents including coursework biodata, workshop evaluation forms, quarterly project reports, and end- of-project reports, submitted by the mentees, minutes of meetings, and the proposal submitted for funding. It was in the form of continuous variables and prose (sentences & stories). Quantitative data were analysed with IBM SPSS statistics version 20. Mean knowledge score and mean difference was calculated, paired t-test was carried out using p < 0.05 to determine statistical significance. The prose was thematically analysed to generate themes and narratives. Both were subsequently combined for interpretation and used to refine the initial programme theory into an evidence-informed theory. RESULTS: Twelve courses were deployed, and 1,418 participants (47.8% males and 52.2% females) from medical, nursing, and allied medical departments were trained. Eighty participants were trained in Responsible Conduct of Research and eighty-one on Manuscript Writing over three years. A comparison of the pre/post-test knowledge scores showed a positive mean difference. Thematic analysis of workshop data produced three thematic domains representing effectiveness and gains namely: cognitive, reward, and behavioural. 45 trainees were awarded grants and mentored, and analysis of mentee's data generated 4 themes: Achieving a robust mentoring program; Benefits of the mentoring program; Resilience in research; Improving the mentoring program. CONCLUSION: By contributing to the body of knowledge available on RTPs, this evaluation identified key components that contributed to the success of the project and developed a model for achieving a robust training and mentoring program which can be replicated in other LMICs.

Underrepresented Populations in Parkinson's Genetics Research: Current Landscape and Future Directions.

BACKGROUND: Human genetics research lacks diversity; over 80% of genome-wide association studies have been conducted on individuals of European ancestry. In addition to limiting insights regarding disease mechanisms, disproportionate representation can create disparities preventing equitable implementation of personalized medicine. OBJECTIVE: This systematic review provides an overview of research involving Parkinson's disease (PD) genetics in underrepresented populations (URP) and sets a baseline to measure the future impact of current efforts in those populations. METHODS: We searched PubMed and EMBASE until October 2021 using search strings for "PD," "genetics," the main "URP," and and the countries in Latin America, Caribbean, Africa, Asia, and Oceania (excluding Australia and New Zealand). Inclusion criteria were original studies, written in English, reporting genetic results on PD from non-European populations. Two levels of independent reviewers identified and extracted information. RESULTS: We observed imbalances in PD genetic studies among URPs. Asian participants from Greater China were described in the majority of the articles published (57%), but other populations were less well studied; for example, Blacks were represented in just 4.0% of the publications. Also, although idiopathic PD was more studied than monogenic forms of the disease, most studies analyzed a limited number of genetic variants. We identified just nine studies using a genome-wide approach published up to 2021, including URPs. CONCLUSION: This review provides insight into the significant lack of population diversity in PD research highlighting the immediate need for better representation. The Global Parkinson's Genetics Program (GP2) and similar initiatives aim to impact research in URPs, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future. © 2022 International Parkinson and Movement Disorder Society.

The impact of sex on blood pressure and anthropometry trajectories from early adulthood in a Nigerian population: insights into women's cardiovascular disease risk across the lifespan.

BACKGROUND: Sex disparities in blood pressure and anthropometry may account for differences in cardiovascular (CV) risk burden with advancing age; modulated by ethnic variability. We explored trajectories of blood pressures (BPs) and anthropometric indices with age on the basis of sex in an urban Nigerian population. METHODS: We conducted a secondary analysis on data from 5135 participants (aged 16-92 years; 2671(52%) females) from our population-based cross-sectional study of BP profiles. We utilized the WHO STEPS and standardized methods for documenting BPs, body mass index (BMI) and waist circumference (WC). Data was analyzed using Analysis of variance (ANOVA), Spearman correlation analysis and mean difference in variables (with 95% confidence interval). We explored the influence of age and sex on BP profiles and specific anthropometric indices using generalized regression analysis. RESULTS: In those aged 15-44 years, males had significantly higher systolic BP (SBP) and pulse pressure (PP). However, mean SBP and PP rose more steeply in females from 25 to 34 years, intersected with that of males from 45 to 54 years and remained consistently higher. Difference in mean BPs (95% Confidence Interval) (comparing < and > 45 years) was higher in females compared to males for SBP (17.4 (15.8 to 19.0) v. 9.2 (7.7 to 10.7), DBP (9.0 (7.9 to 10.1) v. 7.8 (6.7 to 8.9)), and PP (8.4 (7.3 to 9.5) v. 1.4 (0.3 to 2.5)). Females had significantly higher BMI and WC across all age groups (p < 0.001). Age more significantly correlated with BPs, BMI and WC in females. Interaction models revealed that SBP was significantly predicted by age category in females from (15-54 years), while DBP was only significantly predicted by age in the 15-34-year category (p < 0.01). BMI and WC were significantly predicted by age only in the 25-34-year category in females, (p < 0.01). CONCLUSIONS: Our population demonstrates sex disparity in trajectories of SBP, PP, BMI and WC with age; with steeper rise in females. There is a need to focus on CV risk reduction in females, starting before, or during early adulthood.

Dementia in Africa: Current evidence, knowledge gaps, and future directions.

In tandem with the ever-increasing aging population in low and middle-income countries, the burden of dementia is rising on the African continent. Dementia prevalence varies from 2.3% to 20.0% and incidence rates are 13.3 per 1000 person-years with increasing mortality in parts of rapidly transforming Africa. Differences in nutrition, cardiovascular factors, comorbidities, infections, mortality, and detection likely contribute to lower incidence. Alzheimer's disease, vascular dementia, and human immunodeficiency virus/acquired immunodeficiency syndrome-associated neurocognitive disorders are the most common dementia subtypes. Comprehensive longitudinal studies with robust methodology and regional coverage would provide more reliable information. The apolipoprotein E (APOE) ε4 allele is most studied but has shown differential effects within African ancestry compared to Caucasian. More candidate gene and genome-wide association studies are needed to relate to dementia phenotypes. Validated culture-sensitive cognitive tools not influenced by education and language differences are critically needed for implementation across multidisciplinary groupings such as the proposed African Dementia Consortium.

Availability of Therapies and Services for Parkinson's Disease in Africa: A Continent-Wide Survey.

BACKGROUND: The growing burden of Parkinson's disease (PD) in Africa necessitates the identification of available therapies and services to improve patient care. OBJECTIVE: To investigate the availability, affordability, frequency of usage, and insurance coverage of PD therapies (pharmacological, surgical, physical, and speech therapies) and services including specialized clinics, specialists, and nurses across Africa. METHODS: A comprehensive web-based survey was constructed and distributed to neurologists/physicians with a special interest in PD across Africa. The survey instrument includes components that address availability, affordability, frequency of use, and insurance coverage of different therapies and services. RESULTS: Responses were received from 28 (of 43 contacted) countries. Levodopa-based oral preparations were always available in 13 countries (46.4%) with variable affordability and "partial or no" insurance coverage in 60% of countries. Bromocriptine was the most available (50%) and affordable ergot dopamine agonists (DA), whereas non-ergot DA was always available in only six countries (21.4%). Trihexyphenidyl was the most available and affordable anticholinergic drug (46.4%). Tricyclic antidepressants and selective serotonin reuptake inhibitors were available in most countries (89.3% and 85.7% respectively), with variable affordability. Quetiapine and clozapine were less available. Specialized clinics and nurses were available in 25% and 7.1% of countries surveyed, respectively. Other services were largely unavailable in the countries surveyed. CONCLUSION: PD-specific therapies and services are largely unavailable and unaffordable in most African countries. The data provide a platform for organizing strategies to initiate or scale up existing services and drive policies aimed at improving access to care and tailoring education programs in Africa. © 2021 International Parkinson and Movement Disorder Society.

Global Survey on Telemedicine Utilization for Movement Disorders During the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic restricted usual healthcare management for movement-disorders patients, with a consequent upsurge in telemedicine to bridge the gap. OBJECTIVE: To assess global telemedicine usage in the context of the pandemic. METHODS: The Movement Disorder Society (MDS) Telemedicine Study Group surveyed telemedicine experts from 40 countries across all continents in March-April 2020. Four domains of telemedicine were assessed: legal regulations, reimbursement, clinical use, and barriers; comparing emerging responses to the pandemic versus the baseline scenario. RESULTS: All forms of telemedicine for movement disorders increased globally, irrespective of country income categorization, as an immediate response to the pandemic. This was aided by widespread availability of technology and updated government regulations. However, privacy concerns, lack of reimbursement, limited access, and lack of telemedicine training were barriers highlighted worldwide. CONCLUSIONS: Questions remain about the longevity and extent of changes in regulations and reimbursement regarding telemedicine in the aftermath of the pandemic. © 2020 International Parkinson and Movement Disorder Society.

Addressing Stroke Literacy in Nigeria Through Music: A Qualitative Study of Community Perspectives.

BACKGROUND: The incidence of stroke in Nigeria is unknown, but stroke literacy, defined here as awareness of stroke warning symptoms and risk factors may be poor in high-risk communities. Although there is growing recognition of the use of music as a conduit to promote health literacy, African music is often overlooked as a source of health information. We sought to understand community-level perspectives on using African music to promote acute stroke literacy. METHODS: A purposive sample of education, health and music professionals, high school and university students were recruited to participate in the qualitative study. Study participants completed a brainstorming exercise that elicited their perceptions of potential barriers and facilitators to the use of music to promote acute stroke literacy in Nigeria. Content analysis was used to identify key themes emerging from the brainstorming exercise. RESULTS: A total of 44 individuals, comprising of 25 students with a mean age of 15.9 ± 1.6 years (52% females) and 19 professionals with a mean age of 39 ± 7.7 years (57.9% males) participated in the brainstorming exercise. Facilitators to the use of music to promote acute stroke literacy in Nigeria include the cultural relevance of music, the ubiquity of music, and government involvement. Key barriers include religious beliefs that discourage the use of "secular" music, cost-related barriers, and limited government support. CONCLUSIONS: Findings from this study provide guidance aimed at improving acute stroke literacy in Nigeria, particularly the importance of government involvement in the development and implementation of stroke literacy interventions guided by African music. Future work should consider implementing interventions that leverage the cultural elements of African music and further assess the extent to which these identified facilitators and/or barriers may influence stroke literacy.

Is the knowledge and attitude of physicians in Nigeria adequate for the diagnosis and management of obstructive sleep apnea?

PURPOSE: The knowledge and attitude of doctors in Nigeria towards obstructive sleep apnea is not known. We evaluated the level of knowledge and attitude regarding OSA among resident doctors in Internal Medicine and general practitioners in Nigeria. METHODS: A cross-sectional survey among doctors during continuing medical education programs was conducted. The Obstructive Sleep Apnea Knowledge and Attitude (OSAKA) questionnaire was used to obtain information. RESULTS: Two hundred seventy-three doctors (235 resident doctors and 38 general practitioners) participated in the study. The mean knowledge score was 10.7 ± 2.6 (out of a maximum possible of 18) for all participants corresponding to 59 ± 14.4 % knowledge. There was no significant difference in the mean score of resident doctors (10.8 ± 2.5) compared to general practitioners (10.0 ± 2.8), (t = 2.6, p = 0.10). Over 70 % of the participants wrongly responded that uvuloplasty was an effective treatment and less than 40 % correctly answered that continuous positive airway pressure treatment was first line for severe obstructive sleep apnea. The mean score on the attitude segment was 3.4 ± 0.6 (maximum possible score of 5) for all participants and 3.4 ± 0.6 and 3.3 ± 0.5, respectively, for the residents and the general practitioners (p = 0.47). Increasing age was negatively associated with level of knowledge, while increasing number of years in medical practice and higher level of residency training was positively associated with higher knowledge scores. CONCLUSION: The knowledge of obstructive sleep apnea among resident doctors and general practitioners in Nigeria is inadequate. There is need to improve training on sleep disorders in Nigeria both at continuing medical education programs and during residency training.

Uncovering the genetic basis of Parkinson's disease globally: from discoveries to the clinic.

Knowledge on the genetic basis of Parkinson's disease has grown tremendously since the discovery of the first monogenic form, caused by a mutation in α-synuclein, and with the subsequent identification of multiple other causative genes and associated loci. Genetic studies provide insights into the phenotypic heterogeneity and global distribution of Parkinson's disease. By shedding light on the underlying biological mechanisms, genetics facilitates the identification of new biomarkers and therapeutic targets. Several clinical trials of genetics-informed therapies are ongoing or imminent. International programmes in populations who have been under-represented in Parkinson's disease genetics research are fostering collaboration and capacity-building, and have already generated novel findings. Many challenges remain for genetics research in these populations, but addressing them provides opportunities to obtain a more complete and equitable understanding of Parkinson's disease globally. These advances facilitate the integration of genetics into the clinic, to improve patient management and personalised medicine.

Telemedicine ready or not? A cross-sectional assessment of telemedicine maturity of federally funded tertiary health institutions in Nigeria.

Introduction and objective: Telemedicine has reinforced its position as a means for the continuity of healthcare services and a cost-effective approach to improving health equity as demonstrated during the COVID-19 pandemic. The preparedness of health systems for telemedicine is an indicator of the scalability of their services, especially during catastrophes. We aimed to assess the maturity and preparedness of federally funded tertiary health institutions in Nigeria, to deploy telemedicine as such data are currently lacking and are required to drive improvements in health services delivery. Methods: We conducted a cross-sectional survey of thirty randomly selected federally funded tertiary health institutions in Nigeria using the Pan American Health Organization's tool for assessing the maturity level of health institutions to implement telemedicine between 17 September 2020 and 1 September 2021. Descriptive statistics were used for overall maturity levels and non-parametric tests to compare scores for overall maturity and specific Pan American Health Organization domains per region. The level of significance was set at p-value <0.05. Results: The response rate was 77.4% (24 of 30 randomly polled federally funded tertiary health institutions responded). Overall, the median telemedicine maturity level was 2.0 (1.75) indicating a beginner level. No significant inter-zonal difference in the median overall maturity level (p = 0.87). The median maturity levels for telemedicine readiness in specific domains were organizational readiness - 2.0 (2.0), processes 1.0 (1.0), digital environment 2.0 (3.0), human resources 2.0 (1.0), regulatory issues - 1.5 (1.0) and expertise 2.0 (2.0); mostly at beginner level, with no inter-zonal differences. Most participating institutions had no initiatives in place for domains of processes and regulatory issues. Conclusions: The current telemedicine maturity level of federally funded tertiary health institutions in Nigeria is at the beginner level. This behoves policy-makers to advance the implementation and deployment of telemedicine nationwide as part of digital quality healthcare, to improve health equity and to ensure continuity of healthcare services in the event of another pandemic.

The non-coding GBA1 rs3115534 variant is associated with REM sleep behavior disorder in Nigerians.

Background: Damaging coding variants in GBA1 are a genetic risk factor for rapid eye movement sleep behavior disorder (RBD), which is a known early feature of synucleinopathies. Recently, a population-specific non-coding variant (rs3115534) was found to be associated with PD risk and earlier disease onset in individuals of African ancestry. Objectives: To investigate whether the GBA1 rs3115534 PD risk variant is associated with RBD. Methods: We studied 709 persons with PD and 776 neurologically healthy controls from Nigeria. The GBA1 rs3115534 risk variant status was imputed from previous genotyping for all. Symptoms of RBD were assessed with the RBD screening questionnaire (RBDSQ). Results: The non-coding GBA1 rs3115534 risk variant is associated with possible RBD in individuals of Nigerian origin (Beta = 0.3640, SE = 0.103, P =4.093e-04), as well as after adjusting for PD status (Beta = 0.2542, SE = 0.108, P = 0.019) suggesting that this variant may have the same downstream consequences as GBA1 coding variants. Conclusions: We show that the non-coding GBA1 rs3115534 risk variant is associated with increased RBD symptomatology in Nigerians with PD. Further research is required to assess association with polysomnography-defined RBD.

MAPT allele and haplotype frequencies in Nigerian Africans: Population distribution and association with Parkinson's disease risk and age at onset.

INTRODUCTION: The association between MAPT and PD risk may be subject to ethnic variability even within populations of similar geographical origin. Data on MAPT haplotype frequencies, and its association with PD risk in black Africans are lacking. We aimed to determine the frequencies of MAPT haplotypes and their role as risk factors for PD and age at onset in Nigerians. METHODS: The haplotype and genotype frequencies of MAPT rs1052553 were analysed in 907 individuals with PD and 1022 age-matched healthy controls from the Nigeria Parkinson's Disease Research network cohort. Clinical data related to PD included age at study, age at onset (AAO), and disease duration. RESULTS: The frequency of the H1 haplotype was 98.7% in PD, and 99.1% in controls (p = 0.19). The H2 haplotype was present in - 1.3% of PD and 0.9% of controls (p = 0.24). The most frequent MAPT genotype was H1H1 (PD - 97.5%, controls - 98.2%). The H1 haplotype was not associated with PD risk after accounting for gender and AAO (Odds ratio for H1/H1 vs H1/H2 and H2/H2: 0.68 (95% CI:0.39-1.28); p = 0.23). CONCLUSIONS: Our findings support previous studies that report a low frequency of the MAPT H2 haplotype in black ancestry Africans but document its occurrence in Nigerians. The MAPT H1 haplotype was not associated with an increased risk or age at onset of PD in this cohort.

Evaluating the performance of polygenic risk profiling across diverse ancestry populations in Parkinson's disease.

Objective: This study aims to address disparities in risk prediction by evaluating the performance of polygenic risk score (PRS) models using the 90 risk variants across 78 independent loci previously linked to Parkinson's disease (PD) risk across seven diverse ancestry populations. Methods: We conducted a multi-stage study, testing PRS models in predicting PD status across seven different ancestries applying three approaches: 1) PRS adjusted by gender and age; 2) PRS adjusted by gender, age and principal components (PCs); and 3) PRS adjusted by gender, age and percentage of population admixture. These models were built using the largest four population-specific summary statistics of PD risk to date (base data) and individual level data obtained from the Global Parkinson's Genetics Program (target data). We performed power calculations to estimate the minimum sample size required to conduct these analyses. A total of 91 PRS models were developed to investigate cumulative known genetic variation associated with PD risk and age of onset in a global context. Results: We observed marked heterogeneity in risk estimates across non-European ancestries, including East Asians, Central Asians, Latino/Admixed Americans, Africans, African admixed, and Ashkenazi Jewish populations. Risk allele patterns for the 90 risk variants yielded significant differences in directionality, frequency, and magnitude of effect. PRS did not improve in performance when predicting disease status using similar base and target data across multiple ancestries, demonstrating that cumulative PRS models based on current known risk are inherently biased towards European populations. We found that PRS models adjusted by percentage of admixture outperformed models that adjusted for conventional PCs in highly admixed populations. Overall, the clinical utility of our models in individually predicting PD status is limited in concordance with the estimates observed in European populations. Interpretation: This study represents the first comprehensive assessment of how PRS models predict PD risk and age at onset in a multi-ancestry fashion. Given the heterogeneity and distinct genetic architecture of PD across different populations, our assessment emphasizes the need for larger and diverse study cohorts of individual-level target data and well-powered ancestry-specific summary statistics. Our current understanding of PD status unraveled through GWAS in European populations is not generally applicable to other ancestries. Future studies should integrate clinical and *omics level data to enhance the accuracy and predictive power of PRS across diverse populations.

MAPT allele and haplotype frequencies in Nigerian Africans: population distribution and association with Parkinson's disease risk and age at onset.

Background: The microtubule-associated protein tau ( MAPT ) gene is critical because of its putative role in the causal pathway of neurodegenerative diseases including Parkinson's disease (PD). However, there is a lack of clarity regarding the link between the main H1 haplotype and risk of PD. Inconsistencies in reported association may be driven by genetic variability in the populations studied to date. Data on MAPT haplotype frequencies in the general population and association studies exploring the role of MAPT haplotypes in conferring PD risk in black Africans are lacking. Objectives: To determine the frequencies of MAPT haplotypes and explore the role of the H1 haplotype as a risk factor for PD risk and age at onset in Nigerian Africans. Methods: The haplotype and genotype frequencies of MAPT rs1052553 were analysed using PCR-based KASP™ in 907 individuals with PD and 1,022 age-matched neurologically normal controls from the Nigeria Parkinson's Disease Research (NPDR) network cohort. Clinical data related to PD included age at study, age at onset, and disease duration. Results: The frequency of the main MAPT H1 haplotype in this cohort was 98.7% in individuals with PD, and 99.1% in healthy controls (p=0.19). The H2 haplotype was present in 41/1929 (2.1%) of the cohort (PD - 1.3%; Controls - 0.9%; p=0.24). The most frequent MAPT genotype was H1H1 (PD - 97.5%, controls - 98.2%). The H1 haplotype was not associated with PD risk after accounting for gender and age at onset (Odds ratio for H1/H1 vs H1/H2 and H2/H2: 0.68 (95% CI:0.39-1.28); p=0.23). Conclusions: Our findings support previous studies that report a low frequency of the MAPT H2 haplotype in black ancestry Africans, but document its occurrence in the Nigerian population (2.1%). In this cohort of black Africans with PD, the MAPT H1 haplotype was not associated with an increased risk or age at onset of PD.