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The Genetic Architecture of Parkinson's Disease in the AfrAbia Population: Current State and Future Perspectives

Mohamed W, Eltantawi MA, Agarwal V, Bandres-Ciga S, Makarious MB, Mecheri Y, et al.

J Integr Neurosci, 2024 Aug 19;23(8):152.
PMID: 39207075 DOI: 10.31083/j.jin2308152

Over 80% of genetic studies in the Parkinson's disease (PD) field have been conducted on individuals of European descent. There is a social and scientific imperative to understand the genetic basis of PD across global populations for therapeutic development and deployment. PD etiology is impacted by genetic and environmental factors that are variable by ancestry and region, emphasising the need for worldwide programs to gather large numbers of patients to identify novel candidate genes and risk loci involved in disease. Only a handful of documented genetic assessments have investigated families with PD in AfrAbia, which comprises the member nations of the Arab League and the African Union, with very limited cohort and case-control studies reported. This review article summarises prior research on PD genetics in AfrAbia, highlighting gaps and challenges. We discuss the etiological risk spectrum in the context of historical interactions, highlighting allele frequencies, penetrance, and the clinical manifestations of known genetic variants in the AfrAbian PD patient community.
Fulltext Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project

Vollstedt EJ, Madoev H, Aasly A, Ahmad-Annuar A, Al-Mubarak B, Alcalay RN, et al.

PLoS One, 2023;18(10):e0292180.
PMID: 37788254 DOI: 10.1371/journal.pone.0292180

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.
Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Vollstedt EJ, Schaake S, Lohmann K, Padmanabhan S, Brice A, Lesage S, et al.

Mov Disord, 2023 Feb;38(2):286-303.
PMID: 36692014 DOI: 10.1002/mds.29288

BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited.
OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.
METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed.
RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.
CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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