Background: The genetic architecture of Parkinson’s disease (PD) varies considerably across ancestries, yet most genetic studies have focused on individuals of European descent, limiting insights into the genetic landscape of PD at a global scale. Methods: We conducted a large-scale, multi-ancestry investigation of causal and risk variants in PD-related genes. Using genetic datasets from the Global Parkinson’s Genetics Program (GP2), we analyzed sequencing and genotyping data from 105,588 individuals, including 63,837 affected and 41,751 unaffected, from eleven different ancestries. Approximately 29% of individuals included were from underrepresented populations. Findings: Our findings revealed shared and ancestry-specific patterns in the prevalence and variant spectrum. Overall, ∼2% of PD individuals carried a causative variant, with substantial variations across ancestries ranging from ∼0·5% in African to ∼7% in Middle Eastern and >10% Ashkenazi Jewish ancestries. Including disease-associated GBA1 and LRRK2 risk variants raised the yield to 13·6%, largely driven by GBA1 , except in East Asians, where LRRK2 risk variants dominated. GBA1 variants were most frequent globally, albeit with substantial differences in frequencies and variant spectra. While GBA1 variants were identified across all ancestries, frequencies ranged from ∼5% in Middle Eastern and South Asian to ∼52% in African ancestry. Similarly, LRRK2 variants showed ancestry-specific enrichment, with p.G2019S most frequently seen in Middle Eastern and Ashkenazi Jewish populations, and risk variants predominating in East Asians. Notably, clinical trials targeting specific genetic variants are currently primarily based in Europe and North America. Another globally PD-relevant gene was PRKN , with variant carriers identified across almost all ancestries. Interpretation: This large-scale, multi-ancestry assessment offers crucial insights into the population-specific genetic architecture of PD. It underscores the critical need for increased ancestral diversity in PD research to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure equitable development and application of emerging precision therapies. Funding: Aligning Science Across Parkinson’s (ASAP) Global Parkinson’s Genetics Program (GP2)

Our understanding of Parkinson’s disease (PD) has significantly accelerated over the last few years, but predominant advances have been made in developed, Western countries. Little is known about PD in the Central Asian (CA) and Transcaucasian (TC) countries. Here, we review the clinical characteristics, treatments used, epidemiology, and genetics of PD in CA and TC countries via a methodological search in MEDLINE, EMBASE, Scopus, Web of Science, and Google Scholar databases. For the acquisition of PD care-related data, the search was extended to the local web resources. Our findings showed that PD prevalence in the region is averaging 62 per 100,000 population. The mean age of onset is 56.4 ± 2.8 in females and 63.3 ± 3.5 in males. Large-scale national studies on PD prevalence from the region are currently lacking. A limited number of genetic studies with small cohorts and inconclusive results were identified. The G2019S LRRK2 mutation, the commonest mutation in PD worldwide, was found in 5.7% of patients with idiopathic PD and 17.6% of familial cases in 153 Uzbek patients. Our review highlighted systematic deficiencies in PD health care in the region including lacks of neurologists specializing in PD, delays in PD diagnosis, absence of specialized PD nurses and PD rehab services, limited access to PD medications and surgery, and the unavailability of PD infusion therapies. Overall, this article demonstrated the paucity of data on this common neurological disorder in CA and TC countries and identified a number of healthcare areas that require an urgent consideration. We conclude that well-designed large-scale epidemiological, genetic, and clinical studies are desperately needed in this region. Healthcare professionals, local and national institutions, and stakeholders must come together to address deficiencies in PD healthcare systems in CA and TC countries.

Background. LRRK2 mutations have emerged as the most prevalent and potentially treatable determinants of Parkinson’s disease (PD). Peculiar geographic distribution of these mutations has triggered an interest in genotyping PD cohorts of different ethnic backgrounds for LRRK.Objective. Here, we report on the results of LRRK2 screening in the first Central Asian PD cohort.Methods. 246 PD patients were consecutively recruited by movement disorder specialists from four medical centers in Kazakhstan, and clinicodemographic data and genomic DNA from blood were systematically obtained and shipped to the Institute of Neurology University College London together with DNAs from 200 healthy controls. The cohort was genotyped for five LRRK2 mutations (p.Gly2019Ser, p.Arg1441His, p.Tyr1699Cys, p.Ile2020Thr, and p.Asn1437His) and three East Asian disease-associated variants (p.Gly2385Arg, p.Ala419Val, and p.Arg1628Pro) via Kompetitive allele-specific polymerase chain reaction assay analysis.Results. None of the study subjects carried LRRK2 mutations, whereas the following Asian variants were found with insignificant odds ratios (OR): p.Gly2385Arg (1.2%, minor allele frequency (MAF) 0.007, OR 1.25,p=0.8), p.Ala419Val (3.7%, MAF 0.02, OR 1.5,p=0.4), and p.Arg1628Pro was found only in 1% of controls. p.Gly2385Arg was positive in a big family with PD and tremor, although with incomplete segregation. One early-onset PD subject was homozygous for p.Ala419Val who developed fast progression and severe dyskinesias. p.Ala419Val was associated with early-onset PD.Conclusions. We showed that East Asian LRRK variants could be found in Central Asian populations but their pathogenicity remains to be elucidated in larger PD cohorts.