The 2022 symposium on dementia and brain aging in low- and middle-income countries: Highlights on research, diagnosis, care, and impact.

Two of every three persons living with dementia reside in low- and middle-income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high-income countries (HICs), with dementia research predominantly focusing on HICs. This imbalance necessitates LMIC-focused research to ensure that characterization of dementia accurately reflects the involvement and specificities of diverse populations. Development of effective preventive, diagnostic, and therapeutic approaches for dementia in LMICs requires targeted, personalized, and harmonized efforts. Our article represents timely discussions at the 2022 Symposium on Dementia and Brain Aging in LMICs that identified the foremost opportunities to advance dementia research, differential diagnosis, use of neuropsychometric tools, awareness, and treatment options. We highlight key topics discussed at the meeting and provide future recommendations to foster a more equitable landscape for dementia prevention, diagnosis, care, policy, and management in LMICs. HIGHLIGHTS: Two-thirds of persons with dementia live in LMICs, yet research and costs are skewed toward HICs. LMICs expect dementia prevalence to more than double, accompanied by socioeconomic disparities. The 2022 Symposium on Dementia in LMICs addressed advances in research, diagnosis, prevention, and policy. The Nairobi Declaration urges global action to enhance dementia outcomes in LMICs.

Stroke occurrence by hypertension treatment status in Ghana and Nigeria: A case-control study.

BACKGROUND: Hypertension is preeminent among the vascular risk factors for stroke occurrence. The wide gaps in awareness, detection, treatment, and control rates of hypertension are fueling an epidemic of stroke in sub-Saharan Africa. PURPOSE: To quantify the contribution of untreated, treated but uncontrolled, and controlled hypertension to stroke occurrence in Ghana and Nigeria. METHODS: The Stroke Investigative Research and Educational Network (SIREN) is a case-control study across 16 study sites in Ghana and Nigeria. Cases were acute stroke (n = 3684) with age- and sex-matched stroke-free controls (n = 3684). We evaluated the associations of untreated hypertension, treated but uncontrolled hypertension, and controlled hypertension at BP of <140/90 mmHg with risk of stroke occurrence. We assessed the adjusted odds ratio and population-attributable risk of hypertension treatment control status associated with stroke occurrence. RESULTS: The frequencies of no hypertension, untreated hypertension, treated but uncontrolled hypertension and controlled hypertension among stroke cases were 4.0%, 47.7%, 37.1%, and 9.2% vs 40.7%, 34.9%, 15.9%, and 7.7% respectively among stroke-free controls, p < 0.0001. The aOR and PAR (95% CI) for untreated hypertension were 6.58 (5.15-8.41) and 35.4% (33.4-37.4); treated but uncontrolled hypertension was 9.95 (7.60-13.02) and 35.9% (34.2-37.5); and controlled hypertension 5.37 (3.90-7.41) and 8.5% (7.6-9.5) respectively. Untreated hypertension contributed a PAR of 47.5% to the occurrence of intracerebral hemorrhage vs 29.5% for ischemic stroke. The aOR of untreated hypertension for stroke occurrence was 13.31 (7.64-23.19) for <50 years; 7.14 (4.51-11.31) for 50-64 years; and 3.48 (2.28-5.30) for 65 years or more. CONCLUSION: The contribution of untreated hypertension and treated but uncontrolled hypertension to stroke occurrence among indigenous Africans is substantial. Implementing targeted interventions that address gaps in hypertension prevention and treatment, involving the local population, healthcare providers, and policymakers, can potentially substantially reduce the escalating burden of strokes in Africa.

ACHIEVE conference proceedings: implementing action plans to reduce and control hypertension burden in Africa.

The prevalence of hypertension, the commonest risk factor for preventable disability and premature deaths, is rapidly increasing in Africa. The African Control of Hypertension through Innovative Epidemiology, and a Vibrant Ecosystem [ACHIEVE] conference was convened to discuss and initiate the co-implementation of the strategic solutions to tame this burden toward achieving a target of 80% for awareness, treatment, and control by the year 2030. Experts, including the academia, policymakers, patients, the WHO, and representatives of various hypertension and cardiology societies generated a 12-item communique for implementation by the stakeholders of the ACHIEVE ecosystem at the continental, national, sub-national, and local (primary) healthcare levels.

Novel functional insights into ischemic stroke biology provided by the first genome-wide association study of stroke in indigenous Africans.

BACKGROUND: African ancestry populations have the highest burden of stroke worldwide, yet the genetic basis of stroke in these populations is obscure. The Stroke Investigative Research and Educational Network (SIREN) is a multicenter study involving 16 sites in West Africa. We conducted the first-ever genome-wide association study (GWAS) of stroke in indigenous Africans. METHODS: Cases were consecutively recruited consenting adults (aged > 18 years) with neuroimaging-confirmed ischemic stroke. Stroke-free controls were ascertained using a locally validated Questionnaire for Verifying Stroke-Free Status. DNA genotyping with the H3Africa array was performed, and following initial quality control, GWAS datasets were imputed into the NIH Trans-Omics for Precision Medicine (TOPMed) release2 from BioData Catalyst. Furthermore, we performed fine-mapping, trans-ethnic meta-analysis, and in silico functional characterization to identify likely causal variants with a functional interpretation. RESULTS: We observed genome-wide significant (P-value < 5.0E-8) SNPs associations near AADACL2 and miRNA (MIR5186) genes in chromosome 3 after adjusting for hypertension, diabetes, dyslipidemia, and cardiac status in the base model as covariates. SNPs near the miRNA (MIR4458) gene in chromosome 5 were also associated with stroke (P-value < 1.0E-6). The putative genes near AADACL2, MIR5186, and MIR4458 genes were protective and novel. SNPs associations with stroke in chromosome 2 were more than 77 kb from the closest gene LINC01854 and SNPs in chromosome 7 were more than 116 kb to the closest gene LINC01446 (P-value < 1.0E-6). In addition, we observed SNPs in genes STXBP5-AS1 (chromosome 6), GALTN9 (chromosome 12), FANCA (chromosome 16), and DLGAP1 (chromosome 18) (P-value < 1.0E-6). Both genomic regions near genes AADACL2 and MIR4458 remained significant following fine mapping. CONCLUSIONS: Our findings identify potential roles of regulatory miRNA, intergenic non-coding DNA, and intronic non-coding RNA in the biology of ischemic stroke. These findings reveal new molecular targets that promise to help close the current gaps in accurate African ancestry-based genetic stroke's risk prediction and development of new targeted interventions to prevent or treat stroke.

Dietary patterns associated with hypertension among stroke-free indigenous Africans: insights from the Stroke Investigative Research and Educational Network study.

BACKGROUND: The dietary factors associated with the high burden of hypertension among indigenous Africans remain poorly understood. We assessed the relationship between dietary patterns and hypertension among indigenous Africans. METHOD: In this study, 1550 participants with hypertension matched (for age: ±â€Š5 years, sex and ethnicity) with 1550 participants without hypertension were identified from the stroke-free population in the Stroke Investigative Research and Educational Network study in Ghana and Nigeria. Food consumption was assessed using a food frequency questionnaire, and dietary information was summarized using principal component analysis to identify seven dietary patterns. Conditional logistic regression was applied to compute the odds ratio (OR) and 95% confidence interval (CI) for the risk of hypertension by tertiles of dietary patterns adjusting for age, education, income, smoking, alcohol use, physical inactivity, family history of cardiovascular diseases, obesity and salt intake at a two-sided P less than 0.05. RESULTS: Multivariable-adjusted OR [95% confidence interval (CI)] for risk of hypertension by second and third tertiles [using the lowest (first) tertile as reference] of dietary patterns were 0.62 (0.48-0.80), 0.70 (0.54-0.90) for whole grains and fruit drinks; 0.87 (0.68-1.12), 0.83 (0.64-1.08) for fruits; 0.85 (0.65-1.10), 0.97 (0.75-1.26) for vegetables, legumes and potatoes; 0.78 (0.60-1.00), 0.84 (0.65-1.08) for fried foods and sweetened drinks; 1.13 (0.88-1.45), 0.80 (0.62-1.03) for poultry product and organ meat; 1.11 (0.86-1.43), 0.88 (0.68-1.14) for red meat; and 1.14 (0.88-1.48), 1.09 (0.84-1.43) for processed foods ( P  < 0.05). CONCLUSION: A higher adherence to dietary consumption of whole grains and fruits was inversely associated with low odds of hypertension in this population.

Factors associated with frequency of fruit and vegetable consumption among selected sub-Saharan African populations: evidence from the Cardiovascular H3Africa Innovation Resource Project.

BACKGROUND: Frequent fruit and vegetable consumption is considered a promising dietary behaviour that protects health. However, most existing studies about the factors associated with this phenomenon among Africans are based on single-country reports, apart from one meta-regression combining smaller studies. This study harmonized large datasets and assessed factors associated with the frequency of fruit and vegetable consumption in this population. METHODS: Individual-level data on sociodemographics, lifestyle and diet from 20 443 participants across five African countries (Burkina Faso, Ghana, Kenya, South Africa and Nigeria), from the Stroke Investigative Research and Educational Network (SIREN) and Africa Wits-INDEPTH partnership for Genomic Research (AWI-Gen) studies, were harmonized. Total frequency of fruit and vegetable consumption (in portions/week) was classified as 'low' (≤6), 'moderate' (7-14) and 'high' (≥15). Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of factors associated with the total frequency of fruit and vegetable consumption (using 'low' consumption as the reference) were estimated using multinomial regression models. RESULTS: Mean age of participants was 54.3 ± 11.8 years, 10 641 (52.1%) were female, and the median (interquartile range) frequency of total fruit and vegetable consumption was 10.0 (4.0, 21.0) portions/week. Participants with a family history of cardiovascular disease [moderate (aOR, 0.92; 95% CI, 0.85, 1.00) and high (aOR, 0.85; 95% CI, 0.78, 0.92)], current smokers [moderate (aOR, 0.83; 95% CI, 0.74, 0.94) and high (aOR, 0.78; 95% CI, 0.69, 0.88)], current alcohol users [moderate (aOR, 0.92; 95% CI, 0.85, 1.00) and high (aOR, 0.82; 95% CI, 0.76, 0.89)] and physically inactive participants [moderate (aOR, 0.85; 95% CI, 0.75, 0.96) and high (aOR, 0.80; 95% CI, 0.70, 0.90)] were less likely to consume fruits and vegetables frequently. CONCLUSION: Africans with lifestyle risk factors for cardiovascular disease were less likely to consume fruit and vegetables frequently.

Current perspectives on prevention of vascular cognitive impairment and promotion of vascular brain health.

INTRODUCTION: The true global burden of vascular cognitive impairment (VCI) is unknown. Reducing risk factors for stroke and cardiovascular disease would inevitably curtail VCI. AREAS COVERED: The authors review current diagnosis, epidemiology, and risk factors for VCI. VCI increases in older age and by inheritance of known genetic traits. They emphasize modifiable risk factors identified by the 2020 Lancet Dementia Commission. The most profound risks for VCI also include lower education, cardiometabolic factors, and compromised cognitive reserve. Finally, they discuss pharmacological and non-pharmacological interventions. EXPERT OPINION: By virtue of the high frequencies of stroke and cardiovascular disease the global prevalence of VCI is expectedly higher than prevalent neurodegenerative disorders causing dementia. Since ~ 90% of the global burden of stroke can be attributed to modifiable risk factors, a formidable opportunity arises to reduce the burden of not only stroke but VCI outcomes including progression from mild to the major in form of vascular dementia. Strict control of vascular risk factors and secondary prevention of cerebrovascular disease via pharmacological interventions will impact on burden of VCI. Non-pharmacological measures by adopting healthy diets and encouraging physical and cognitive activities and urging multidomain approaches are important for prevention of VCI and preservation of vascular brain health.

Non-cigarette tobacco use and stroke among West Africans: evidence from the SIREN study.

INTRODUCTION: Non-cigarette tobacco (NCT) represents a form of tobacco use with a misperceived significance in chronic disease events. Whether NCT use is sufficient to promote stroke events, especially among Africans, is yet to be understood. This study assessed the relationship between NCT use and stroke among indigenous Africans. METHODS: A total of 7,617 respondents (NCT users: 41 vs. non-NCT: 7576) from the Stroke Investigation Research and Educational Network study were included in the current analysis. NCT use was defined as self-reported use of smoked (cigars or piper) or smokeless (snuff or chewed) tobacco in the past year preceding stroke events. Stroke was defined based on clinical presentation and confirmed with a cranial CT/MRI. Multivariable-adjusted logistic regression was applied to estimate the odds ratio (OR) and 95% confidence interval (CI) for the relationship between NCT and stroke at p<0.05. RESULTS: Out of the 41 (0.54%) who reported NCT use, 27 (65.9%) reported using smokeless NCT. NCT users were older than non-smokers (62.8±15.7 vs 57.7±14.8 years). Overall, NCT use was associated with first-ever stroke (OR: 2.08; 95%CI: 1.02, 4.23) in the entire sample. Notably, smokeless NCT use was independently associated with higher odds of stroke (OR: 2.74; 95%CI: 1.15, 6.54), but smoked NCT use (OR: 0.16; 95%CI: 0.02, 1.63) presented a statistically insignificant association after adjusting for hypertension and other covariates. CONCLUSIONS: NCT use was associated with higher odds of stroke, and public health interventions targeting NCT use might be promising in reducing the burden of stroke among indigenous Africans. IMPLICATIONS: A detailed understanding of the relationship between NCT use and stroke will likely inform well-articulated policy guidance to promote evidence-based recommendations for public health prevention and management of stroke on the African continent.

Risk Assessment Score and Chi-Square Automatic Interaction Detection Algorithm for Hypertension Among Africans: Models From the SIREN Study.

BACKGROUND: This study aimed to develop a risk-scoring model for hypertension among Africans. METHODS: In this study, 4413 stroke-free controls were used to develop the risk-scoring model for hypertension. Logistic regression models were applied to 13 risk factors. We randomly split the dataset into training and testing data at a ratio of 80:20. Constant and standardized weights were assigned to factors significantly associated with hypertension in the regression model to develop a probability risk score on a scale of 0 to 1 using a logistic regression model. The model accuracy was assessed to estimate the cutoff score for discriminating hypertensives. RESULTS: Mean age was 59.9±13.3 years, 56.0% were hypertensives, and 8 factors, including diabetes, age ≥65 years, higher waist circumference, (BMI) ≥30 kg/m2, lack of formal education, living in urban residence, family history of cardiovascular diseases, and dyslipidemia use were associated with hypertension. Cohen κ was maximal at ≥0.28, and a total probability risk score of ≥0.60 was adopted for both statistical weighting for risk quantification of hypertension in both datasets. The probability risk score presented a good performance-receiver operating characteristic: 64% (95% CI, 61.0-68.0), a sensitivity of 55.1%, specificity of 71.5%, positive predicted value of 70.9%, and negative predicted value of 55.8%, in the test dataset. Similarly, decision tree had a predictive accuracy of 67.7% (95% CI, 66.1-69.3) for the training set and 64.6% (95% CI, 61.0-68.0) for the testing dataset. CONCLUSIONS: The novel risk-scoring model discriminated hypertensives with good accuracy and will be helpful in the early identification of community-based Africans vulnerable to hypertension for its primary prevention.

Research participants' perception of ethical issues in stroke genomics and neurobiobanking research in Africa.

Background: There is a growing interest in stroke genomics and neurobiobanking research in Africa. These raise several ethical issues, such as consent, re-use, data sharing, storage, and incidental result of biological samples. Despite the availability of ethical guidelines developed for research in Africa, there is paucity of information on how the research participants' perspectives could guide the research community on ethical issues in stroke genomics and neurobiobanking research. To explore African research participants' perspectives on these issues, a study was conducted at existing Stroke Investigation Research and Education Network (SIREN) sites in Nigeria and Ghana. Method: Using an exploratory design, twenty-eight Focus Group Discussions (FGDs) sessions were conducted with stroke survivors (n=7), caregivers(n=7), stroke - free controls(n=7), and Community Advisory Board members(n=7). Data were collected using an interview guide. Interviews were conducted in English and indigenous languages of the community, audio recorded, and transcribed verbatim. Data were analyzed using NVivo (March, 2020) Software. Result: Results revealed that stroke genomics and neurobiobanking research in Africa require researchers' direct attention to ethical issues. Concerns were raised about understanding, disclosure and absence of coercion as components of true autonomous decision making in research participation. Participants argued that the risk and benefits attached to participation should be disclosed at the time of recruitment. Fears around data sharing were voiced as adherence to the principle of privacy and confidentiality were of paramount importance to participants. The preference was to receive the results of incidental findings with no stigma attached from society. Conclusion: Research participants' perspectives are a vital aspect of community engagement in stroke genomics and neurobiobanking research. Findings from this study suggest that research participants are interested in these fields of research in Africa if their concerns about ethical issues are appropriately addressed within the research framework.

Extended genome-wide association study employing the African Genome Resources Panel identifies novel susceptibility loci for Alzheimer's Disease in individuals of African ancestry.

INTRODUCTION: Despite a two-fold increased risk, individuals of African ancestry have been significantly underrepresented in Alzheimer's Disease (AD) genomics efforts. METHODS: GWAS of 2,903 AD cases and 6,265 cognitive controls of African ancestry. Within-dataset results were meta-analyzed, followed by gene-based and pathway analyses, and analysis of RNAseq and whole-genome sequencing data. RESULTS: A novel AD risk locus was identified in MPDZ on chromosome 9p23 (rs141610415, MAF=.002, P =3.68×10 -9 ). Two additional novel common and nine novel rare loci approached genome-wide significance at P <9×10 -7 . Comparison of association and LD patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 ( ASCL1 ), suggesting that the association is modulated by regional origin of local African ancestry. DISCUSSION: Increased sample sizes and sample sets from Africa covering as much African genetic diversity as possible will be critical to identify additional disease-associated loci and improve deconvolution of local genetic ancestry effects.

Biomarkers and Risk Assessment of Alzheimer's Disease in Low- and Middle-Income Countries.

Dementia is a chronic syndrome which is common among the elderly and is associated with significant morbidity and mortality for patients and their caregivers. Alzheimer's disease (AD), the most common form of clinical dementia, is biologically characterized by the deposition of amyloid-ß plaques and neurofibrillary tangles in the brain. The onset of AD begins decades before manifestation of symptoms and clinical diagnosis, underlining the need to shift from clinical diagnosis of AD to a more objective diagnosis using biomarkers. Having performed a literature search of original articles and reviews on PubMed and Google Scholar, we present this review detailing the existing biomarkers and risk assessment tools for AD. The prevalence of dementia in low- and middle-income countries (LMICs) is predicted to increase over the next couple of years. Thus, we aimed to identify potential biomarkers that may be appropriate for use in LMICs, considering the following factors: sensitivity, specificity, invasiveness, and affordability of the biomarkers. We also explored risk assessment tools and the potential use of artificial intelligence/machine learning solutions for diagnosing, assessing risks, and monitoring the progression of AD in low-resource settings. Routine use of AD biomarkers has yet to gain sufficient ground in clinical settings. Therefore, clinical diagnosis of AD will remain the mainstay in LMICs for the foreseeable future. Efforts should be made towards the development of low-cost, easily administered risk assessment tools to identify individuals who are at risk of AD in the population. We recommend that stakeholders invest in education, research and development targeted towards effective risk assessment and management.

Organized multi-disciplinary stroke team care improves acute stroke outcomes in resource limited settings; Results of a retrospective study from a Nigerian tertiary hospital.

BACKGROUND: Evidence for the impact of organized stroke multidisciplinary teams (MDTs) on outcomes in Africa is sparse. AIM: To compare stroke outcomes, before and after the establishment (September 16, 2016) of a pioneer MDT at a tertiary hospital in southern Nigeria. METHODS: Using a retrospective, observational study design, the in-patient record of all stroke patients admitted between September 2014 to September 2018 was retrieved and rigorously reviewed. 155 patients seen 2 years before the MDT were compared with 169 stroke patients seen 2 years after the MDT. Stroke severity at admission and functioning at discharge were assessed using the Stroke Levity Scale (SLS) and the modified Rankin scale (mRS). RESULTS: Mean ages (in years) were 60 pre-MDT vs 59.57 post MDT (p = 0.754). There were more males, 51% pre-MDT vs 54.2% post MDT (p = 0.565). SLS and mRS were not significantly different; severe SLS and mRS pre-MDT, 52.9% vs post-MDT, 49.4% (p = 0.727) and pre-MDT 19.4% vs post-MDT 19.5% (p = 0.685) respectively. More post-MDT patients were discharged alive, pre-MDT,56.8% vs 79.2% post MDT (p < 0.001); had swallow tests, pre-MDT 9.23% vs post-MDT 33.5% (p < 0.001); on secondary prevention, pre-MDT 67.7% vs post-MDT 78.9% (p = 0.023); had more clinic visits, pre-MDT,0.7% vs post-MDT 38.3% (p < 0.001). MDT was independently associated with lower in-hospital mortality on multivariable regression, adjusted odds ratio (OR) (95% Confidence interval CI) 0.17 (0.09-0.32). CONCLUSION: Our results suggest that an organized MDT may improve acute outcomes and reduce mortality in resource constrained settings where there may be no stroke units. These findings need further prospective validation.

Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.

BACKGROUND: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations. METHODS: We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity. FINDINGS: We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10-14) and age at onset at the GBA1 locus, rs3115534-G (age at onset ß=-2·00 [SE=0·57], p=0·0005, for African ancestry; and ß=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity. INTERPRETATION: Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease. FUNDING: The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research.

Genes, environment, and African ancestry in cardiometabolic disorders.

The past two decades have been characterized by a substantial global increase in cardiometabolic diseases, but the prevalence and incidence of these diseases and related traits differ across populations. African ancestry populations are among the most affected yet least included in research. Populations of African descent manifest significant genetic and environmental diversity and this under-representation is a missed opportunity for discovery and could exacerbate existing health disparities and curtail equitable implementation of precision medicine. Here, we discuss cardiometabolic diseases and traits in the context of African descent populations, including both genetic and environmental contributors and emphasizing novel discoveries. We also review new initiatives to include more individuals of African descent in genomics to address current gaps in the field.

Genome-wide Association Identifies Novel Etiological Insights Associated with Parkinson's Disease in African and African Admixed Populations.

Background: Understanding the genetic mechanisms underlying diseases in ancestrally diverse populations is a critical step towards the realization of the global application of precision medicine. The African and African admixed populations enable mapping of complex traits given their greater levels of genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. Methods: Here we perform a comprehensive genome-wide assessment of Parkinson's disease (PD) in 197,918 individuals (1,488 cases; 196,430 controls) of African and African admixed ancestry, characterizing population-specific risk, differential haplotype structure and admixture, coding and structural genetic variation and polygenic risk profiling. Findings: We identified a novel common risk factor for PD and age at onset at the GBA1 locus (risk, rs3115534-G; OR=1.58, 95% CI = 1.37 - 1.80, P=2.397E-14; age at onset, BETA =-2.004, SE =0.57, P = 0.0005), that was found to be rare in non-African/African admixed populations. Downstream short- and long-read whole genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. However, we identified that this signal mediates PD risk via expression quantitative trait locus (eQTL) mechanisms. While previously identified GBA1 associated disease risk variants are coding mutations, here we suggest a novel functional mechanism consistent with a trend in decreasing glucocerebrosidase activity levels. Given the high population frequency of the underlying signal and the phenotypic characteristics of the homozygous carriers, we hypothesize that this variant may not cause Gaucher disease. Additionally, the prevalence of Gaucher's disease in Africa is low. Interpretation: The present study identifies a novel African-ancestry genetic risk factor in GBA1 as a major mechanistic basis of PD in the African and African admixed populations. This striking result contrasts to previous work in Northern European populations, both in terms of mechanism and attributable risk. This finding highlights the importance of understanding population-specific genetic risk in complex diseases, a particularly crucial point as the field moves toward precision medicine in PD clinical trials and while recognizing the need for equitable inclusion of ancestrally diverse groups in such trials. Given the distinctive genetics of these underrepresented populations, their inclusion represents a valuable step towards insights into novel genetic determinants underlying PD etiology. This opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk. Evidence Before this Study: Our current understanding of Parkinson's disease (PD) is disproportionately based on studying populations of European ancestry, leading to a significant gap in our knowledge about the genetics, clinical characteristics, and pathophysiology in underrepresented populations. This is particularly notable in individuals of African and African admixed ancestries. Over the last two decades, we have witnessed a revolution in the research area of complex genetic diseases. In the PD field, large-scale genome-wide association studies in the European, Asian, and Latin American populations have identified multiple risk loci associated with disease. These include 78 loci and 90 independent signals associated with PD risk in the European population, nine replicated loci and two novel population-specific signals in the Asian population, and a total of 11 novel loci recently nominated through multi-ancestry GWAS efforts.Nevertheless, the African and African admixed populations remain completely unexplored in the context of PD genetics. Added Value of this Study: To address the lack of diversity in our research field, this study aimed to conduct the first genome-wide assessment of PD genetics in the African and African admixed populations. Here, we identified a genetic risk factor linked to PD etiology, dissected African-specific differences in risk and age at onset, characterized known genetic risk factors, and highlighted the utility of the African and African admixed risk haplotype substructure for future fine-mapping efforts. We identified a novel disease mechanism via expression changes consistent with decreased GBA1 activity levels. Future large scale single cell expression studies should investigate the neuronal populations in which expression differences are most prominent. This novel mechanism may hold promise for future efficient RNA-based therapeutic strategies such as antisense oligonucleotides or short interfering RNAs aimed at preventing and decreasing disease risk. We envisage that these data generated under the umbrella of the Global Parkinson's Genetics Program (GP2) will shed light on the molecular mechanisms involved in the disease process and might pave the way for future clinical trials and therapeutic interventions. This work represents a valuable resource in an underserved population, supporting pioneering research within GP2 and beyond. Deciphering causal and genetic risk factors in all these ancestries will help determine whether interventions, potential targets for disease modifying treatment, and prevention strategies that are being studied in the European populations are relevant to the African and African admixed populations. Implications of all the Available Evidence: We nominate a novel signal impacting GBA1 as the major genetic risk factor for PD in the African and African admixed populations. The present study could inform future GBA1 clinical trials, improving patient stratification. In this regard, genetic testing can help to design trials likely to provide meaningful and actionable answers. It is our hope that these findings may ultimately have clinical utility for this underrepresented population.