Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations:Experience from the MJFF Global Genetic Parkinson's Disease Project

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.</p

Embracing monogenic Parkinson's disease: the MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.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.Michael J. Fox Foundation for Parkinson's Research. Grant Number: ID 15015.02. NIHR Cambridge Biomedical Research Centre. Grant Number: BRC-1215-20014info:eu-repo/semantics/publishedVersio

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.[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.This project was funded by The Michael J. Fox Foundation (ID 15015.02)Peer reviewe

Permo-Carboniferous granitoids with Jurassic high temperature metamorphism in Central Pontides, Northern Turkey

In the northern part of the Central Pontides (N Turkey) there are different metamorphic rocks exposed, notably the Devrekani metamorphic rocks. Here, upper amphibolite-lower granulite facies metamorphic rocks contain predominantly paragneiss, orthogneiss and metacarbonate, and to a lesser extent, amphibolite and quartzite, with cross-cutting aplite, pegmatite and granite veins. This is the first report of these rocks and includes new data on the petrochemistry, geochronology and metamorphic evolution of the Devrekani orthogneisses from the Central Pontides. The orthogneisses show five different mineral parageneses with the characteristic mineral assemblage quartz + K-feldspar + plagioclase + biotite ± hornblende ± opaque (± ilmenite and ± magnetite), and accessory minerals (zircon, sphene and apatite). These metamorphic rocks exhibit generally granoblastic, lepidogranoblastic and nematolepidogranoblastic with locally migmatitic and relic micrographic textures. They have well-developed centimeter-spaced gneissic banding and display gneissose structure with symmetric, asymmetric and irregular folds. The petrographic features, mineralogical assemblages and weak migmatization reflect high temperature conditions. Thermometric calculations in the orthogneisses indicate metamorphic temperatures reached 744 ± 33 °C. Field relations, petrography and petrochemistry suggest that the orthogneisses have predominantly granodioritic and some granitic protoliths, that show features of I-type, medium to high-potassic calc-alkaline volcanic arc granitoids. The orthogneisses have high contents of LILEs and low contents of HFSEs with negative Nb and Ti anomalies, which are typical of subduction-related magmas. The orthogneisses also show significant LREE enrichment relative to HREE with negative Eu anomalies (EuN/Eu* = 0.33–1.07) with LaN/LuN = 6.98–20.47 values. Based on U-Pb zircon dating data, the protoliths are related to Permo-Carboniferous (316–252 Ma) magmatism. It is likely that peak metamorphism took place during the Jurassic as reflected by the U-Pb zircon ages (199–158 Ma) and also 40Ar/39Ar from hornblende/biotite (163–152 Ma). The four biotite 40Ar/39Ar average ages from the rock samples are ca. 156 Ma, suggesting that the metamorphic rocks cooled to 350–400 °C at ca. 156 Ma. Conclusively, the Devrekani metamorphic rocks can be ascribed as products of Permo-Carboniferous continental arc magmatism overprinted by Jurassic metamorphism in the northern Central Pontides

Lutetian arc-type magmatism along the southern Eurasian margin: New U-Pb LA-ICPMS and whole-rock geochemical data from Marmara Island, NW Turkey

The rocks of Turkey, Greece and Syria preserve evidence for the destruction of Tethys, the construction of much of the continental crust of the region and the formation of the Tauride orogenic belt. These events occurred between the Late Cretaceous and Miocene, but the detailed evolution of the southern Eurasian margin during this period of progressive continental accretion is largely unknown. Marmara Island is a basement high lying at a key location in the Cenozoic Turkish tectonic collage, with a Palaeogene suture zone to the south and a deep Eocene sedimentary basin to the north. North-dipping metamorphic thrust sheets make up the island and are interlayered with a major metagranitoid intrusion. We have dated the intrusion by Laser Ablation ICP-MS analysis of U and Pb isotopes on zircon separates to 47.6 ± 2 Ma. We also performed major- and trace-elemental geochemical analysis of 16 samples of the intrusion that revealed that the intrusion is a calc-alkaline, metaluminous granitoid, marked by Nb depletion relative to LREE and LIL-element enrichment when compared to ocean ridge granite (ORG). We interpret the metagranitoid sill as a member of a mid-Eocene magmatic arc, forming a 30 km wide and more than 200 km long arcuate belt in NW Turkey that post-dates suturing along the İzmir-Ankara-Erzincan Suture zone. The arc magmatism was emplaced at the early stages of mountain building, related to collision of Eurasia with the Menderes-Taurus Platform in early Eocene times. Orogenesis and magmatism loaded the crust to the north creating coeval upward-deepening marine basins partially filled by volcanoclastic sediments.P. Ayda Ustaömer, Timur Ustaömer, Alan S. Collins and Jörg Reischpeitsc