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Background: Commercial genome-wide genotyping arrays have historically neglected coverage of genetic variation across populations., Objective: We aimed to create a multi-ancestry genome-wide array that would include a wide range of neuro-specific genetic content to facilitate genetic research in neurological disorders across multiple ancestral groups, fostering diversity and inclusivity in research studies., Methods: We developed the Illumina NeuroBooster Array (NBA), a custom high-throughput and cost-effective platform on a backbone of 1,914,934 variants from the Infinium Global Diversity Array and added custom content comprising 95,273 variants associated with more than 70 neurological conditions or traits, and we further tested its performance on more than 2000 patient samples. This novel platform includes approximately 10,000 tagging variants to facilitate imputation and analyses of neurodegenerative disease-related genome-wide association study loci across diverse populations., Results: In this article, we describe NBA's potential as an efficient means for researchers to assess known and novel disease genetic associations in a multi-ancestry framework. The NBA can identify rare genetic variants and accurately impute more than 15 million common variants across populations. Apart from enabling sample prioritization for further whole-genome sequencing studies, we envisage that NBA will play a pivotal role in recruitment for interventional studies in the precision medicine space., Conclusions: From a broader perspective, the NBA serves as a promising means to foster collaborative research endeavors in the field of neurological disorders worldwide. Ultimately, this carefully designed tool is poised to make a substantial contribution to uncovering the genetic etiology underlying these debilitating conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objectives To evaluate and compare different polygenic risk score (PRS) models in predicting Parkinsons disease (PD) across diverse ancestries, focusing on identifying the most suitable approach for each population and potentially contributing to equitable advancements in precision medicine. Methods We constructed a total of 105 PRS across individual level data from seven diverse ancestries. First, a cross-ancestry conventional PRS comparison was implemented by utilizing the 90 known European risk loci with weighted effects from four independent summary statistics including European, East Asian, Latino/Admixed American, and African/Admixed. These models were adjusted by sex, age, and principal components (28 PRS) and by sex, age, and percentage of admixture (28 PRS) for comparison. Secondly, a novel and refined multi-ancestry best-fit PRS approach was then applied across the seven ancestries by leveraging multi-ancestry meta-analyzed summary statistics and using a p-value thresholding approach (49 PRS) to enhance prediction applicability in a global setting. Results European-based PRS models predicted disease status across all ancestries to differing degrees of accuracy. Ashkenazi Jewish had the highest Odds Ratio (OR): 1.96 (95% CI: 1.69-2.25, p < 0.0001) with an AUC (Area Under the Curve) of 68%. Conversely, the East Asian population, despite having fewer predictive variants (84 out of 90), had an OR of 1.37 (95% CI: 1.32-1.42) and an AUC of 62%, illustrating the cross-ancestry transferability of this model. Lower OR alongside broader confidence intervals were observed in other populations, including Africans (OR =1.38, 95% CI: 1.12-1.63, p=0.001). Adjustment by percentage of admixture did not outperform principal components. Multi-ancestry best-fit PRS models improved risk prediction in European, Ashkenazi Jewish, and African ancestries, yet didn't surpass conventional PRS in admixed populations such as Latino/American admixed and African admixed populations. Interpretation The present study represents a novel and comprehensive assessment of PRS performance across seven ancestries in PD, highlighting the inadequacy of a 'one size fits all' approach in genetic risk prediction. We demonstrated that European based PD PRS models are partially transferable to other ancestries and could be improved by a novel best-fit multi-ancestry PRS, especially in non-admixed populations.

Background: Identifying hereditary parkinsonism is valuable for diagnosis, genetic counseling, patient prioritization in trials, and studying the disease for personalized therapies. However, most studies were conducted in Europeans, and limited data exist on admixed populations like those from Latin America., Objectives: This study aims to assess the frequency and distribution of genetic parkinsonism in Latin America., Methods: We conducted a systematic review and meta-analysis of the frequency of parkinsonian syndromes associated with genetic pathogenic variants in Latin America. We defined hereditary parkinsonism as those caused by the genes outlined by the MDS Nomenclature of Genetic Movement Disorders and heterozygous carriers of GBA1 pathogenic variants. A systematic search was conducted in PubMed, Web of Science, Embase, and LILACS in August 2022. Researchers reviewed titles and abstracts, and disagreements were resolved by a third researcher. After this screening, five researchers reanalyzed the selection criteria and extracted information based on the full paper. The frequency for each parkinsonism-related gene was determined by the presence of pathogenic/likely pathogenic variants among screened patients. Cochran's Q and I 2 tests were used to quantify heterogeneity. Meta-regression, publication bias tests, and sensitivity analysis regarding study quality were also used for LRRK2-, PRKN-, and GBA1-related papers., Results: We included 73 studies involving 3014 screened studies from 16 countries. Among 7668 Latin American patients, pathogenic variants were found in 19 different genes. The frequency of the pathogenic variants in LRRK2 was 1.38% (95% confidence interval [CI]: 0.52-2.57), PRKN was 1.16% (95% CI: 0.08-3.05), and GBA1 was 4.17% (95% CI: 2.57-6.08). For all meta-analysis, heterogeneity was high and publication bias tests were negative, except for PRKN, which was contradictory. Information on the number of pathogenic variants in the other genes is further presented in the text., Conclusions: This study provides insights into hereditary and GBA1-related parkinsonism in Latin America. Lower GBA1 frequencies compared to European/North American cohorts may result from limited access to gene sequencing. Further research is vital for regional prevalence understanding, enabling personalized care and therapies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Genome-wide genotyping platforms have the capacity to capture genetic variation across different populations, but there have been disparities in the representation of population-dependent genetic diversity. The motivation for pursuing this endeavor was to create a comprehensive genome-wide array capable of encompassing a wide range of neuro-specific content for the Global Parkinson's Genetics Program (GP2) and the Center for Alzheimer's and Related Dementias (CARD). CARD aims to increase diversity in genetic studies, using this array as a tool to foster inclusivity. GP2 is the first supported resource project of the Aligning Science Across Parkinson's (ASAP) initiative that aims to support a collaborative global effort aimed at significantly accelerating the discovery of genetic factors contributing to Parkinson's disease and atypical parkinsonism by generating genome-wide data for over 200,000 individuals in a multi-ancestry context. Here, we present the Illumina NeuroBooster array (NBA), a novel, high-throughput and cost-effective custom-designed content platform to screen for genetic variation in neurological disorders across diverse populations. The NBA contains a backbone of 1,914,934 variants (Infinium Global Diversity Array) complemented with custom content of 95,273 variants implicated in over 70 neurological conditions or traits with potential neurological complications. Furthermore, the platform includes over 10,000 tagging variants to facilitate imputation and analyses of neurodegenerative disease-related GWAS loci across diverse populations. The NBA can identify low frequency variants and accurately impute over 15 million common variants from the latest release of the TOPMed Imputation Server as of August 2023 (reference of over 300 million variants and 90,000 participants). We envisage this valuable tool will standardize genetic studies in neurological disorders across different ancestral groups, allowing researchers to perform genetic research inclusively and at a global scale., Competing Interests: Competing Interests: DV, FF, HLL HI, KSL, and MAN declare that they are consultants employed by Data Tecnica International, whose participation in this is part of a consulting agreement between the US National Institutes of Health and said company. MAN also an advisor to Neuron23 Inc and Character Biosciences. SWS serves on the Scientific Advisory Council of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. S.W.S. and B.J.T. receive research support from Cerevel Therapeutics. HRM is employed by UCL. In the last 12 months he reports paid consultancy from Roche, Aprinoia, AI Therapeutics and Amylyx ; lecture fees/honoraria - BMJ, Kyowa Kirin, Movement Disorders Society. Research Grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, Medical Research Council, Michael J Fox Foundation. Dr Morris is a co-applicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). Dr. Christine Klein is a Medical Advisor to Centogene and Retromer Therapeutics and Speakers’ honoraria from Desitin and Bial.

Background: Ataxia can be classified as genetic, sporadic or acquired., Aim: To report the clinical features of a group of patients with ataxia., Material and Methods: Review of medical records of patients consulting in a specialized center in movement disorders. Those records in which the diagnosis of "ataxia" or "ataxic syndrome" appeared, were selected for the review., Results: Of 4,282 records surveyed, the diagnosis of ataxia appeared in 95. After eliminating repeated or incomplete records, 63 were reviewed., Results: Ataxia was sporadic, genetic and acquired in 27, 22 and 14 patients, respectively. The mean age at presentation for genetic, acquired and sporadic ataxia was 24, 46 and 53 years respectively. All autosomal dominant ataxias were type 3 spinocerebellar ataxia (SCA). Friedrich's ataxia was the most common recessive form. Most sporadic forms of ataxia were multiple system atrophy with predominant cerebellar ataxia (MSA-C) subtype., Conclusions: Considering the heterogeneity of patients with ataxia, we propose a method to approach them.