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

Genome-wide association study of copy number variations in Parkinson's disease

Objective: Our study investigates the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data, aiming to uncover novel genetic mechanisms and improve the understanding of the role of CNVs in sporadic PD. Methods: We applied a sliding window approach to perform CNV-GWAS and conducted genome-wide burden analyses on CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium. Results: We identified 14 genome-wide significant CNV loci associated with PD, including one deletion and 13 duplications. Among these, duplications in 7q22.1, 11q12.3 and 7q33 displayed the highest effect. Two significant duplications overlapped with PD-related genes SNCA and VPS13C, but none overlapped with recent significant SNP-based GWAS findings. Five duplications included genes associated with neurological disease, and four overlapping genes were dosage-sensitive and intolerant to loss-of-function variants. Enriched pathways included neurodegeneration, steroid hormone biosynthesis, and lipid metabolism. In early-onset cases, four loci were significantly associated with EOPD, including three known duplications and one novel deletion in PRKN. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results. Interpretation: This is the largest CNV-based GWAS in PD identifying novel CNV regions and confirming the significant CNV burden in EOPD, primarily driven by the PRKN gene, warranting further investigation.R-AGR-0382 - INTER/JPND/13/01 COURAGE-PD - BALLING Rudolf3. Good health and well-bein

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

Accumulation processes of trace metals into Arctic sea ice: distribution of Fe, Mn and Cd associated with ice structure

Biogeochemical cycling of trace metals in sea ice is important to the productivity of the Arctic Ocean. Unfortunately, the processes by which trace metals accumulate into sea ice are poorly understood. To gain a clearer understanding of the mechanisms behind trace metal accumulation, dissolved (D, < 0.2 mu m), and labile particulate (LP = Total Dissolvable Dissolved) iron (Fe), manganese (Mn), and cadmium (Cd) concentrations were compared to the structure observed in sea ice. Samples were pre-concentrated via solid-phase extraction on NOBIAS Chelate PA-1 resin and analyzed on a Graphite Furnace Atomic Absorption Spectrometer. Using photographic analysis for the percentage of pore microstructure and delta O-18 analysis, sea ice structure was determined to be snow ice, granular ice (frazil ice), mixed ice (granular and columnar ice) and columnar ice. Salinity and nutrients were low, indicating brine drainage and multi-year ice. High trace metal concentrations in snow ice indicated meteoric snow was a source of trace metals to sea ice. High concentrations of LPFe in granular ice indicated entrainment of suspended particulate trace metals by frazil ice during the formation of the granular ice structure. Whereas the high concentrations of DFe and DMn in granular ice may have been due to reduction from LPFe and LPMn after particle entrainment, indicating chemical transformation processes. Low dissolved and labile particulate trace metal concentrations in mixed and columnar ice indicated a release due to brine drainage. Our study clearly indicates that the differences observed in trace metals among sea ice structures, showed that sea ice formation, chemical reduction and brine release were the processes driving trace metal accumulation and release in the Arctic sea ice

Quantitative analysis of Fe, Mn and Cd from sea ice and seawater in the Chukchi Sea, Arctic Ocean

Sea ice is important for the health of the polar oceans yet its role in the biogeochemical cycling of trace metals is not so clear. To understand the geochemical behaviour of trace metals and their accumulation into sea ice, dissolved (D, < 0.2 mu m), and labile particulate (LP, Total Dissolvable - Dissolved) Fe, Mn, and Cd were examined in sea ice and seawater collected from the Chukchi Sea in the Arctic Ocean. Samples were pre-concentrated utilizing the solid-phase extraction NOBIAS Chelate PA-1 resin (Hitachi High-Technologies Corporation) and analyzed on a Graphite Furnace Atomic Absorption Spectrometer. Chukchi seawater showed high percentage for DMn (71.5%) and DCd (66.3%) with a high percentage of LPFe (94.1%). In seawater, DCd was the only metal to correlate with phosphate (R-2 = 0.78) indicating a biogeochemical cycling source. Chukchi seawater concentrations of Fe and Mn may have been controlled through external sources such as sediments (shelf or river) and/or sediment reductive processes. Trace metal concentrations in Chukchi sea ice were heterogeneous. Sea ice showed high percentages for the LP fraction (99.2% Fe, 63.6% Mn and 71.2% Cd). This data indicated that, regardless of the trace metal behaviour in Chukchi seawater, Chukchi sea ice was observed to have a preference for the LP trace metal fraction

ファローシチョウノジュツゴノサシンキノウ

京都大学0048新制・論文博士医学博士乙第3873号論医博第789号新制||医||260(附属図書館)6114UT51-54-H173(主査)教授 日笠 頼則, 教授 河合 忠一, 教授 奥田 六郎学位規則第5条第2項該当Kyoto UniversityDA