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2. Genome-wide case-only analysis of gene-gene interactions with known Parkinson’s disease risk variants reveals link between LRRK2 and SYT10

Author

Aleknonytė-Resch, Milda, Trinh, Joanne, Leonard, Hampton, Delcambre, Sylvie, Leitão, Elsa, Lai, Dongbing, Smajić, Semra, Orr-Urtreger, Avi, Thaler, Avner, Blauwendraat, Cornelis, Sharma, Arunabh, Makarious, Mary B., Kim, Jonggeol Jeff, Lake, Julie, Rahmati, Pegah, Freitag-Wolf, Sandra, Seibler, Philip, Foroud, Tatiana, Singleton, Andrew B., Grünewald, Anne, Kaiser, Frank, Klein, Christine, Krawczak, Michael, and Dempfle, Astrid

Published
2023
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3. Decreased expression of B cell related genes in leukocytes of women with Parkinson's disease

Author

Giladi Nir, Gurevich Tanya, Bar-Shira Anat, Kedmi Merav, and Orr-Urtreger Avi

Subjects
Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Background Parkinson's disease (PD) is a complex disorder caused by genetic, environmental and age-related factors, and it is more prevalent in men. We aimed to identify differentially expressed genes in peripheral blood leukocytes (PBLs) that might be involved in PD pathogenesis. Transcriptomes of 30 female PD-patients and 29 age- and sex-matched controls were profiled using GeneChip Human Exon 1.0 ST Arrays. Samples were from unrelated Ashkenazi individuals, non-carriers of LRRK2 G2019S or GBA founder mutations. Results Differential expression was detected in 115 genes (206 exons), with over-representation of immune response annotations. Thirty genes were related to B cell functions, including the uniquely B cell-expressed IGHM and IGHD, the B cell surface molecules CD19, CD22 and CD79A, and the B cell gene regulator, PAX5. Quantitative-RT-PCR confirmation of these 6 genes in 79 individuals demonstrated decreased expression, mainly in women patients, independent of PD-pharmacotherapy status. Conclusions Our results suggest that the down regulation of genes related to B cell activity reflect the involvement of these cells in PD in Ashkenazi individuals and represents a molecular aspect of gender-specificity in PD.

Published
2011
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5. Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients

Author

Alcalay, Roy N, Wolf, Pavlina, Chiang, Ming Sum Ruby, Helesicova, Karolina, Zhang, Xiaokui Kate, Merchant, Kalpana, Hutten, Samantha J, Scherzer, Clemens, Caspell‐Garcia, Chelsea, Blauwendraat, Cornelis, Foroud, Tatiana, Nudelman, Kelly, Gan‐Or, Ziv, Simuni, Tanya, Chahine, Lana M, Levy, Oren, Zheng, Dandi, Li, Sardi, Sergio Pablo, Marek, Kenneth, Siderowf, Andrew, Seibyl, John, Coffey, Christopher, Tanner, Caroline, Tosun‐Turgut, Duygu, Shaw, Leslie M, Trojanowski, John Q, Singleton, Andrew, Kieburtz, Karl, Toga, Arthur, Mollenhauer, Brit, Galasko, Douglas, Poewe, Werner, Poston, Kathleen, Bressman, Susan, Reimer, Alyssa, Arnedo, Vanessa, Clark, Adrienne, Frasier, Mark, Kopil, Catherine, Chowdhury, Sohini, Sherer, Todd, Casaceli, Cynthia, Dorsey, Ray, Wilson, Renee, Mahes, Sugi, Salerno, Christina, Crawford, Karen, Casalin, Paola, Malferrari, Giulia, Weisz, Mali Gani, Orr‐Urtreger, Avi, Montine, Thomas, Baglieri, Chris, Christini, Amanda, Russell, David, Dahodwala, Nabila, Giladi, Nir, Factor, Stewart, Hogarth, Penelope, Standaert, David, Hauser, Robert, Jankovic, Joseph, Saint‐Hilaire, Marie, Richard, Irene, Shprecher, David, Fernandez, Hubert, Brockmann, Katrina, Rosenthal, Liana, Barone, Paolo, Espay, Alberto, Rowe, Dominic, Marder, Karen, Santiago, Anthony, Hu, Shu‐Ching, Isaacson, Stuart, Martinez, Javiar Ruiz, Tolosa, Eduardo, Tai, Yen, Politis, Marios, Smejdir, Debra, Rees, Linda, Williams, Karen, Kausar, Farah, Richardson, Whitney, Willeke, Diana, Peacock, Shawnees, Sommerfeld, Barbara, Freed, Alison, Wakeman, Katrina, Blair, Courtney, Guthrie, Stephanie, Harrell, Leigh, Hunter, Christine, Thomas, Cathi‐Ann, James, Raymond, Zimmerman, Grace, Brown, Victoria, and Mule, Jennifer

Subjects
Clinical and Health Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Human Genome, Parkinson's Disease, Neurodegenerative, Brain Disorders, Aging, Genetics, Neurological, Adult, Dementia, Disease Progression, Female, Genotype, Glucosylceramidase, Heterozygote, Humans, Male, Mental Status and Dementia Tests, Middle Aged, Mutation, Parkinson Disease, Phenotype, Parkinson’s Progression Markers Initiative, Clinical Sciences, Clinical and health psychology
Abstract

ObjectiveReduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson's disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson's Progression Markers Initiative (PPMI) cohort.MethodsWe measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, n = 392; controls, n = 175) were fully sequenced for GBA variants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing.ResultsFifty-two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n = 20; controls, n = 5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/L/h vs. 11.68 µmol/L/h, P = 0.035). Glucocerebrosidase activity was moderately (r = 0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson's Disease Rating Scale motor score in the "off" medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time.InterpretationGCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation.

Published
2020

6. Feasibility and safety of lumbar puncture in the Parkinson's disease research participants: Parkinson's Progression Marker Initiative (PPMI)

Author

Prakash, Neha, Caspell-Garcia, Chelsea, Coffey, Christopher, Siderowf, Andrew, Tanner, Caroline M, Kieburtz, Karl, Mollenhauer, Brit, Galasko, Douglas, Merchant, Kalpana, Foroud, Tatiana, Chahine, Lana M, Weintraub, Daniel, Casaceli, Cindy, Dorsey, Ray, Wilson, Renee, Herzog, Margaret, Daegele, Nichole, Arnedo, Vanessa, Frasier, Mark, Sherer, Todd, Marek, Ken, Frank, Samuel, Jennings, Danna, Simuni, Tanya, Marek, Kenneth, Seibyl, John, Tanner, Caroline, Tosun-Turgut, Duygu, Shaw, Leslie, Trojanowski, John, Singleton, Andrew, Toga, Arthur, Poewe, Werner, Poston, Kathleen, Chowdhury, Sohini, Kopil, Catherine, Casaceli, Cynthia, Mahes, Sugi, Salerno, Christina, Crawford, Karen, Casalin, Paola, Malferrari, Giulia, Weisz, Mali Gani, Orr-Urtreger, Avi, Montine, Thomas, Russell, David, Dahodwala, Nabila, Giladi, Nir, Factor, Stewart, Hogarth, Penelope, Standaert, David, Hauser, Robert, Jankovic, Joseph, Saint-Hilaire, Marie, Richard, Irene, Shprecher, David, Fernandez, Hubert, Brockmann, Katrina, Rosenthal, Liana, Barone, Paolo, Espay, Alberto, Rowe, Dominic, Marder, Karen, Santiago, Anthony, Bressman, Susan, Hu, Shu-Ching, Isaacson, Stuart, Corvol, Jean-Christophe, Martinez, Javiar Ruiz, and Tolosa, Eduardo

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Parkinson's Disease, Prevention, Clinical Research, Brain Disorders, Neurodegenerative, Aging, Neurosciences, Neurological, Aged, Biomarkers, Cohort Studies, Disease Progression, Feasibility Studies, Female, Humans, Longitudinal Studies, Male, Middle Aged, Parkinson Disease, Post-Dural Puncture Headache, Spinal Puncture, Tinnitus, Parkinson's disease, Lumbar puncture, Safety, Adverse events, Parkinson's Progression Markers InitiativeSteering Committee, Study Cores, Site Investigators, Coordinators, Industry and Scientific Advisory Board, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

ObjectiveTo determine the feasibility, safety and tolerability of lumbar punctures (LPs) in research participants with early Parkinson disease (PD), subjects without evidence of dopaminergic deficiency (SWEDDs) and healthy volunteers (HC).BackgroundCerebrospinal fluid (CSF) analysis is becoming an essential part of the biomarkers discovery effort in PD with still limited data on safety and feasibility of serial LPs in PD participants.Design/methodsParkinson's Progression Marker Initiative (PPMI) is a longitudinal observation study designed to identify PD progression biomarkers. All PPMI participants undergo LP at baseline, 6, 12 months and yearly thereafter. CSF collection is performed by a trained investigator using predominantly atraumatic needles. Adverse events (AEs) are monitored by phone one week after LP completion. We analyzed safety data from baseline LPs.ResultsPPMI enrolled 683 participants (423 PD/196 HC/64 SWEDDs) from 23 study sites. CSF was collected at baseline in 97.5% of participants, of whom 5.4% underwent collection under fluoroscopy. 23% participants reported any related AEs, 68% of all AE were mild while 5.6% were severe. The most common AEs were headaches (13%) and low back pain (6.5%) and both occurred more commonly in HC and SWEDDs compared to PD participants. Factors associated with higher incidence of AEs across the cohorts included female gender, younger age and use of traumatic needles with larger diameter. AEs largely did not impact compliance with the future LPs.ConclusionsLPs are safe and feasible in PD research participants. Specific LP techniques (needle type and gauge) may reduce the overall incidence of AEs.

Published
2019

9. Estimation of Genetic Risk Function with Covariates in the Presence of Missing Genotypes

Author

Lee, Annie J., Marder, Karen, Mejia-Santana, Helen, Orr-Urtreger, Avi, Giladi, Nir, Bressman, Susan, and Wang, Yuanjia

Subjects
Statistics - Methodology
Abstract

In genetic epidemiological studies, family history data are collected on relatives of study participants and used to estimate the age-specific risk of disease for individuals who carry a causal mutation. However, a family member's genotype data may not be collected due to the high cost of in-person interview to obtain blood sample or death of a relative. Previously, efficient nonparametric genotype-specific risk estimation in censored mixture data has been proposed without considering covariates. With multiple predictive risk factors available, risk estimation requires a multivariate model to account for additional covariates that may affect disease risk simultaneously. Therefore, it is important to consider the role of covariates in the genotype-specific distribution estimation using family history data. We propose an estimation method that permits more precise risk prediction by controlling for individual characteristics and incorporating interaction effects with missing genotypes in relatives, and thus gene-gene interactions and gene-environment interactions can be handled within the framework of a single model. We examine performance of the proposed methods by simulations and apply them to estimate the age-specific cumulative risk of Parkinson's disease (PD) in carriers of LRRK2 G2019S mutation using first-degree relatives who are at genetic risk for PD. The utility of estimated carrier risk is demonstrated through designing a future clinical trial under various assumptions. Such sample size estimation is seen in the Huntington's disease literature using the length of abnormal expansion of a CAG repeat in the HTT gene, but is less common in the PD literature., Comment: 16 pages, 5 tables, 4 figures (7 Supplementary pages, 4 Supplementary tables, 13 Supplementary figures)

Published
2017

10. Validity of the Short Weekly Calendar Planning Activity in patients with Parkinson disease and nonmanifesting LRRK2 and GBA carriers

Author

Schejter‐Margalit, Tamara, primary, Binyamin, Noam Ben, additional, Thaler, Avner, additional, Maidan, Inbal, additional, Cedarbaum, Jesse M., additional, Orr‐Urtreger, Avi, additional, Gana Weisz, Mali, additional, Goldstein, Orly, additional, Giladi, Nir, additional, Mirelman, Anat, additional, and Kizony, Rachel, additional

Published
2024
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12. Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study

Author

Arnedo, Vanessa, Clark, Adrienne, Fraiser, Mark, Kopil, Catherine, Chowdhury, Sohini, Sherer, Todd, Daegele, Nichole, Casaceli, Cynthia, Dorsey, Ray, Wilson, Renee, Mahes, Sugi, Salerno, Christina, Crawford, Karen, Casalin, Paola, Malferrari, Giulia, Weisz, Mali Gani, Orr-Urtreger, Avi, Montine, Thomas, Baglieri, Chris, Christini, Amanda, Russell, David, Dahodwala, Nabila, Giladi, Nir, Factor, Stewart, Hogarth, Penelope, Standaert, David, Hauser, Robert, Jankovic, Joseph, Saint-Hilaire, Marie, Richard, Irene, Shprecher, David, Fernandez, Hubert, Brockmann, Katrina, Rosenthal, Liana, Barone, Paolo, Espay, Alberto, Rowe, Dominic, Marder, Karen, Santiago, Anthony, Hu, Shu-Ching, Isaacson, Stuart, Corvol, Jean-Christophe, Ruiz Martinez, Javiar, Tolosa, Eduardo, Tai, Yen, Politis, Marios, Smejdir, Debra, Rees, Linda, Williams, Karen, Kausar, Farah, Richardson, Whitney, Willeke, Diana, Peacock, Shawnees, Sommerfeld, Barbara, Freed, Alison, Wakeman, Katrina, Blair, Courtney, Guthrie, Stephanie, Harrell, Leigh, Hunter, Christine, Thomas, Cathi-Ann, James, Raymond, Zimmerman, Grace, Brown, Victoria, Mule, Jennifer, Hilt, Ella, Ribb, Kori, Ainscough, Susan, Wethington, Misty, Ranola, Madelaine, Mejia Santana, Helen, Moreno, Juliana, Raymond, Deborah, Speketer, Krista, Carvajal, Lisbeth, Carvalo, Stephanie, Croitoru, Ioana, Garrido, Alicia, Payne, Laura Marie, Viswanth, Veena, Severt, Lawrence, Facheris, Maurizio, Soares, Holly, Mintun, Mark A., Cedarbaum, Jesse, Taylor, Peggy, Biglan, Kevin, Vandenbroucke, Emily, Haider Sheikh, Zulfiqar, Bingol, Baris, Fischer, Tanya, Sardi, Pablo, Forrat, Remi, Reith, Alastair, Egebjerg, Jan, Ahlberg Hillert, Gabrielle, Saba, Barbara, Min, Chris, Umek, Robert, Mather, Joe, De Santi, Susan, Post, Anke, Boess, Frank, Taylor, Kirsten, Grachev, Igor, Avbersek, Andreja, Muglia, Pierandrea, Merchant, Kaplana, Tauscher, Johannes, Simuni, Tanya, Uribe, Liz, Cho, Hyunkeun Ryan, Caspell-Garcia, Chelsea, Coffey, Christopher S, Siderowf, Andrew, Trojanowski, John Q, Shaw, Leslie M, Seibyl, John, Singleton, Andrew, Toga, Arthur W, Galasko, Doug, Foroud, Tatiana, Tosun, Duygu, Poston, Kathleen, Weintraub, Daniel, Mollenhauer, Brit, Tanner, Caroline M, Kieburtz, Karl, Chahine, Lana M, Reimer, Alyssa, Hutten, Samantha J, Bressman, Susan, and Marek, Kenneth

Published
2020
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15. Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Author

Marder, Karen, Wang, Yuanjia, Alcalay, Roy N, Mejia-Santana, Helen, Tang, Ming-Xin, Lee, Annie, Raymond, Deborah, Mirelman, Anat, Saunders-Pullman, Rachel, Clark, Lorraine, Ozelius, Laurie, Orr-Urtreger, Avi, Giladi, Nir, and Bressman, Susan

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Parkinson's Disease, Clinical Research, Aging, Brain Disorders, Genetics, Neurodegenerative, Age Factors, Aged, Cohort Studies, Female, Humans, Jews, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Parkinson Disease, Penetrance, Protein Serine-Threonine Kinases, LRRK2 Ashkenazi Jewish Consortium, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveEstimates of the penetrance of LRRK2 G2019S vary widely (24%-100%), reflective of differences in ascertainment, age, sex, ethnic group, and genetic and environmental modifiers.MethodsThe kin-cohort method was used to predict penetrance in 2,270 relatives of 474 Ashkenazi Jewish (AJ) Parkinson disease (PD) probands in the Michael J. Fox LRRK2 AJ Consortium in New York and Tel Aviv, Israel. Patients with PD were genotyped for the LRRK2 G2019S mutation and at least 7 founder GBA mutations. GBA mutation carriers were excluded. A validated family history interview, including age at onset of PD and current age or age at death for each first-degree relative, was administered. Neurologic examination and LRRK2 genotype of relatives were included when available.ResultsRisk of PD in relatives predicted to carry an LRRK2 G2019S mutation was 0.26 (95% confidence interval [CI] 0.18-0.36) to age 80 years, and was almost 3-fold higher than in relatives predicted to be noncarriers (hazard ratio [HR] 2.89, 95% CI 1.73-4.55, p < 0.001). The risk among predicted G2019S carrier male relatives (0.22, 95% CI 0.10-0.37) was similar to predicted carrier female relatives (0.29, 95% CI 0.18-0.40; HR male to female: 0.74, 95% CI 0.27-1.63, p = 0.44). In contrast, predicted noncarrier male relatives had a higher risk (0.15, 95% CI 0.11-0.20) than predicted noncarrier female relatives (0.07, 95% CI 0.04-0.10; HR male to female: 2.40, 95% CI 1.50-4.15, p < 0.001).ConclusionPenetrance of LRRK2 G2019S in AJ is only 26% and lower than reported in other ethnic groups. Further study of the genetic and environmental risk factors that influence G2019S penetrance is warranted.

Published
2015

16. Higher Frequency of Certain Cancers in LRRK2 G2019S Mutation Carriers With Parkinson Disease: A Pooled Analysis

Author

Agalliu, Ilir, San Luciano, Marta, Mirelman, Anat, Giladi, Nir, Waro, Bjorg, Aasly, Jan, Inzelberg, Rivka, Hassin-Baer, Sharon, Friedman, Eitan, Ruiz-Martinez, Javier, Marti-Masso, Jose Felix, Orr-Urtreger, Avi, Bressman, Susan, and Saunders-Pullman, Rachel

Subjects
Breast Cancer, Neurodegenerative, Brain Disorders, Cancer, Genetics, Aging, Parkinson's Disease, Neurosciences, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Europe, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Glycine, Humans, Israel, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Mutation, Neoplasms, Odds Ratio, Parkinson Disease, Protein Serine-Threonine Kinases, Sensitivity and Specificity, Sex Factors, United States, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ImportancePatients with Parkinson disease (PD) who harbor LRRK2 G2019S mutations may have increased risks of nonskin cancers. However, the results have been inconsistent across studies.ObjectivesTo analyze pooled data from 5 centers to further examine the association between LRRK2 G2019S mutation and cancer among patients with PD and to explore factors that could explain discrepancies.Design, setting, and participantsClinical, demographic, and genotyping data as well as cancer outcomes were pooled from 1549 patients with PD recruited across 5 movement disorders clinics located in Europe, Israel, and the United States. Associations between LRRK2 G2019S mutation and the outcomes were examined using mixed-effects logistic regression models to estimate odds ratios (ORs) and 95% CIs. Models were adjusted for age and ethnicity (Ashkenazi Jewish vs others) as fixed effects and study center as a random effect.Main outcomes and measuresAll cancers combined, nonskin cancers, smoking-related cancers, hormone-related cancers, and other types of cancer.ResultsThe overall prevalence of the LRRK2 G2019S mutation was 11.4% among all patients with PD. Mutation carriers were younger at PD diagnosis and more likely to be women (53.1%) and of Ashkenazi Jewish descent (76.8%) in comparison with individuals who were not mutation carriers. The LRRK2 G2019S mutation carriers had statistically significant increased risks for nonskin cancers (OR, 1.62; 95% CI, 1.04-2.52), hormone-related cancers (OR, 1.87; 95% CI, 1.07-3.26) and breast cancer (OR, 2.34; 95% CI, 1.05-5.22) in comparison with noncarriers. There were no associations with other cancers. There were no major statistically significant differences in the results when the data were stratified by Ashkenazi Jewish ethnicity; however, there was some evidence of heterogeneity across centers.Conclusions and relevanceThis multinational study from 5 centers demonstrates that LRRK2 G2019S mutation carriers have an overall increased risk of cancer, especially for hormone-related cancer and breast cancer in women. Larger prospective cohorts or family-based studies investigating associations between LRRK2 mutations and cancer among patients with PD are warranted to better understand the underlying genetic susceptibility between PD and hormone-related cancers.

Published
2015

20. Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma

Author

Ledergor, Guy, Weiner, Assaf, Zada, Mor, Wang, Shuang-Yin, Cohen, Yael C., Gatt, Moshe E., Snir, Nimrod, Magen, Hila, Koren-Michowitz, Maya, Herzog-Tzarfati, Katrin, Keren-Shaul, Hadas, Bornstein, Chamutal, Rotkopf, Ron, Yofe, Ido, David, Eyal, Yellapantula, Venkata, Kay, Sigalit, Salai, Moshe, Ben Yehuda, Dina, Nagler, Arnon, Shvidel, Lev, Orr-Urtreger, Avi, Halpern, Keren Bahar, Itzkovitz, Shalev, Landgren, Ola, San-Miguel, Jesus, Paiva, Bruno, Keats, Jonathan J., Papaemmanuil, Elli, Avivi, Irit, Barbash, Gabriel I., Tanay, Amos, and Amit, Ido

Published
2018
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24. MAPT Locus in Parkinson's Disease Patients of Ashkenazi Origin: A Stratified Analysis.

Author

Shani, Shachar, Gana-Weisz, Mali, Bar-Shira, Anat, Thaler, Avner, Gurevich, Tanya, Mirelman, Anat, Giladi, Nir, Alcalay, Roy N., Goldstein, Orly, and Orr-Urtreger, Avi

Subjects
GENE expression, PARKINSON'S disease, LOCUS (Genetics), MISSENSE mutation, GENETIC variation, WHOLE genome sequencing
Abstract

Introduction: MAPT locus is associated with Parkinson's disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk allele carrier status, and to further characterize genetic alterations that might contribute to its effect. Methods: LD analysis was performed using whole-genome sequencing data of 202 unrelated Ashkenazi Jewish (AJ) PDs. A haplotype-divergent variant was genotyped in a cohort of 1200 consecutively recruited AJ-PDs. The odd ratios were calculated using AJ-non-neuro cases from the gnomAD database as the controls in an un-stratified and a stratified manner according to the mutation carrier status, and the effect on the Age at Motor Symptom Onset (AMSO) was examined. Expression and splicing quantitative trait locus (eQTL and sQTL) analyses were carried out using brain tissues from a database. Results: The H2 haplotype exhibited significant association with PD protection, with a similar effect size in GBA1 carriers, LRRK2-G2019S carriers, and non-carriers (OR = 0.77, 0.69, and 0.82, respectively), and there was no effect on AMSO. The LD interval was narrowed to approximately 1.2 Mb. The H2 haplotype carried potential variants in candidate genes (MAPT and SPPL2C); structural deletions and segmental duplication (KANSL1); and variants affecting gene expression and intron excision ratio in brain tissues (LRRC37A/2). Conclusions: Our results demonstrate that H2 is associated with PD and its protective effect is not influenced by the GBA1/LRRK2 risk allele carrier status. This effect may be genetically complex, resulting from different levels of variations such as missense mutations in relevant genes, structural variations, epigenetic modifications, and RNA expression changes, which may operate independently or in synergy. [ABSTRACT FROM AUTHOR]

Published
2024
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26. Central role of alpha7 nicotinic receptor in differentiation of the stratified squamous epithelium.

Author

Arredondo, Juan, Nguyen, Vu Thuong, Chernyavsky, Alexander I, Bercovich, Dani, Orr-Urtreger, Avi, Kummer, Wolfgang, Lips, Katrin, Vetter, Douglas E, and Grando, Sergei A

Subjects
Epidermis, Cells, Cultured, Keratinocytes, Animals, Mice, Knockout, Humans, Mice, Calcium, Receptors, Nicotinic, Oligodeoxyribonucleotides, Excitatory Amino Acid Antagonists, Bungarotoxins, Signal Transduction, Cell Cycle, Cell Differentiation, Gene Expression, alpha7 Nicotinic Acetylcholine Receptor, Epidermal Cells, cell cycle, differentiation, alpha 7 acetylcholine receptor, epidermis, knockout mouse, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Several ganglionic nicotinic acetylcholine receptor (nAChR) types are abundantly expressed in nonneuronal locations, but their functions remain unknown. We found that keratinocyte alpha7 nAChR controls homeostasis and terminal differentiation of epidermal keratinocytes required for formation of the skin barrier. The effects of functional inactivation of alpha7 nAChR on keratinocyte cell cycle progression, differentiation, and apoptosis were studied in cell monolayers treated with alpha-bungarotoxin or antisense oligonucleotides and in the skin of Acra7 homozygous mice lacking alpha7 nAChR channels. Elimination of the alpha7 signaling pathway blocked nicotine-induced influx of 45Ca2+ and also inhibited terminal differentiation of these cells at the transcriptional and/or translational level. On the other hand, inhibition of the alpha7 nAChR pathway favored cell cycle progression. In the epidermis of alpha7-/- mice, the abnormalities in keratinocyte gene expression were associated with phenotypic changes characteristic of delayed epidermal turnover. The lack of alpha7 was associated with up-regulated expression of the alpha3 containing nAChR channels that lack alpha5 subunit, and both homomeric alpha9- and heteromeric alpha9alpha10-made nAChRs. Thus, this study demonstrates that ACh signaling through alpha7 nAChR channels controls late stages of keratinocyte development in the epidermis by regulating expression of the cell cycle progression, apoptosis, and terminal differentiation genes and that these effects are mediated, at least in part, by alterations in transmembrane Ca2+ influx.

Published
2002

28. The influence of GBA and LRRK2 on mood disorders in Parkinson's Disease

Author

DeBroff, Jake, primary, Omer, Nurit, additional, Cohen, Batsheva, additional, Giladi, Nir, additional, Kestenbaum, Meir, additional, Shirvan, Julia C., additional, Cedarbaum, Jesse M., additional, Gana‐Weisz, Mali, additional, Goldstein, Orly, additional, Orr‐Urtreger, Avi, additional, Mirelman, Anat, additional, and Thaler, Avner, additional

Published
2023
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29. Linkage of a Neurophysiological Deficit in Schizophrenia to a Chromosome 15 Locus

Author

Freedman, Robert, Coon, Hilary, Myles-Worsley, Marina, Orr-Urtreger, Avi, Olincy, Ann, Davis, Ashley, Polymeropoulos, Mihael, Holik, John, Hopkins, Jan, Hoff, Mark, Rosenthal, Judy, Waldo, Merilyne C., Reimherr, Fred, Wender, Paul, Yaw, Jeffrey, Young, David A., Breese, Charles R., Adams, Catherine, Patterson, David, Adler, Lawrence E., Kruglyak, Leonid, Leonard, Sherry, and Byerley, William

Published
1997

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

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], MJFF [sponsor], H2020 (Orchestra) [sponsor], Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Karen, Marder, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramirez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Gregor, Kuhlenbäumer, Kühn, Andrea A., Borngräber, Friederike, de Michele, Giuseppe, De Rosa, Anna, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Jolanta, Dorszewska, Carr, Jonathan, Ferese, Rosangela, Stefano, Gambardella, Chase, Bruce, Markopoulou, Katerina, Wataru, Satake, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Gen c, Gen Cer, de Carvalho Aguiar, Patricia, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, van de Warrenburg, Bart, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Joong, Kim Yun, Winkelmann, Juliane, Sue, Carolyn M., Eng-King, Tan, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Parimal, Das, Mollenhauer, Brit, Gatto, Emilia M., Skaalum, Petersen Maria, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, N, Alcalay Roy, Thaler, Avner, Farrer, Matthew J., Kathrin, Brockmann, Corvol, Jean-Christophe, Klein, Christine, Albanese, Alberto, Alcalay, Roy N., Aldakheel, Amaal, Alkhairallah, Thamer, Bashayer, Al-Mubarak, Al-Tassan, Nada, Paolo, Amami, Araujo, Leite Marco Antonio, Ferraz, Henrique Ballalai, Bardien, Soraya, Melinda, Barkhuizen, Barrett, Matthew J., Ba sak, A. Nazl I, Bilgic, Basar, Bloem, Bastiaan R., Bonifati, Vincenzo, Brockmann, Kathrin, Cesarini, Martin Emiliano, Ju, Chung Sun, Guedes, Leonor Correia, Lorraine, Clark, Dieguez, Elena, Dorszewska, Jolanta, Fung, Victor S. C., Pilar, Gómez-Garre, Hattori, Nobutaka, Faycel, Hentati, Januario, Cristina, Maestre, Silvia Jesús, Kaasinen, Valtteri, Hiroshi, Kataoka, Kievit, Anneke A., Kim, Yun Joong, Christine, Klein, Kuhlenbäumer, Gregor, Lim, Jia Lun, Timothy, Lynch, Marder, Karen, May, Patrick, McCarthy, Allan, Briceno, Hugo Morales, Morris, Huw, Mosejova, Alexandra, Cakmak, Özgür Öztop, Orr-Urtreger, Avi, Pachchek, Sinthuja, Periñ\'an, Maria Teresa, Procopio, Radha, Ruiz-Martinez, Javier, Pereira, João Santos, Satake, Wataru, Soto-Beasley, Alexandra I., Sousa, Mário, Tan, Eng-King, Tepge c, Fatih, Uyguner, Oya, Walton, Ronald L., H, Williams-Gray Caroline, Isabel, Wurster, Bao-Rong, Zhang, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], MJFF [sponsor], H2020 (Orchestra) [sponsor], Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Karen, Marder, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramirez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Gregor, Kuhlenbäumer, Kühn, Andrea A., Borngräber, Friederike, de Michele, Giuseppe, De Rosa, Anna, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Jolanta, Dorszewska, Carr, Jonathan, Ferese, Rosangela, Stefano, Gambardella, Chase, Bruce, Markopoulou, Katerina, Wataru, Satake, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Gen c, Gen Cer, de Carvalho Aguiar, Patricia, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, van de Warrenburg, Bart, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Joong, Kim Yun, Winkelmann, Juliane, Sue, Carolyn M., Eng-King, Tan, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Parimal, Das, Mollenhauer, Brit, Gatto, Emilia M., Skaalum, Petersen Maria, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, N, Alcalay Roy, Thaler, Avner, Farrer, Matthew J., Kathrin, Brockmann, Corvol, Jean-Christophe, Klein, Christine, Albanese, Alberto, Alcalay, Roy N., Aldakheel, Amaal, Alkhairallah, Thamer, Bashayer, Al-Mubarak, Al-Tassan, Nada, Paolo, Amami, Araujo, Leite Marco Antonio, Ferraz, Henrique Ballalai, Bardien, Soraya, Melinda, Barkhuizen, Barrett, Matthew J., Ba sak, A. Nazl I, Bilgic, Basar, Bloem, Bastiaan R., Bonifati, Vincenzo, Brockmann, Kathrin, Cesarini, Martin Emiliano, Ju, Chung Sun, Guedes, Leonor Correia, Lorraine, Clark, Dieguez, Elena, Dorszewska, Jolanta, Fung, Victor S. C., Pilar, Gómez-Garre, Hattori, Nobutaka, Faycel, Hentati, Januario, Cristina, Maestre, Silvia Jesús, Kaasinen, Valtteri, Hiroshi, Kataoka, Kievit, Anneke A., Kim, Yun Joong, Christine, Klein, Kuhlenbäumer, Gregor, Lim, Jia Lun, Timothy, Lynch, Marder, Karen, May, Patrick, McCarthy, Allan, Briceno, Hugo Morales, Morris, Huw, Mosejova, Alexandra, Cakmak, Özgür Öztop, Orr-Urtreger, Avi, Pachchek, Sinthuja, Periñ\'an, Maria Teresa, Procopio, Radha, Ruiz-Martinez, Javier, Pereira, João Santos, Satake, Wataru, Soto-Beasley, Alexandra I., Sousa, Mário, Tan, Eng-King, Tepge c, Fatih, Uyguner, Oya, Walton, Ronald L., H, Williams-Gray Caroline, Isabel, Wurster, and Bao-Rong, Zhang

Abstract

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 cl

Published
2023

31. Novel variants in genes related to vesicle-mediated-transport modify Parkinson's disease risk

Author

Goldstein, Orly, Gana-Weisz, Mali, Banfi, Sandro, Nigro, Vincenzo, Bar-Shira, Anat, Thaler, Avner, Gurevich, Tanya, Mirelman, Anat, Giladi, Nir, Alcalay, Roy N, Orr-Urtreger, Avi, Goldstein, Orly, Gana-Weisz, Mali, Banfi, Sandro, Nigro, Vincenzo, Bar-Shira, Anat, Thaler, Avner, Gurevich, Tanya, Mirelman, Anat, Giladi, Nir, Alcalay, Roy N, and Orr-Urtreger, Avi

Subjects
Disease risk, Endocrinology, Genetic, Whole-genome-sequencing, Parkinson's disease, Endocrinology, Diabetes and Metabolism, Genetics, Vacuolar protein sorting (VPS), Molecular Biology, Biochemistry
Abstract

Objectives: VPS35 and VPS13 have been associated with Parkinson's disease (PD), and their shared phenotype in yeast when reduced in function is abnormal vacuolar transport. We aim to test if additional potentially deleterious variants in other genes that share this phenotype can modify the risk for PD. Methods: 77 VPS and VPS-related genes were analyzed using whole-genome-sequencing data from 202 PD patients of Ashkenazi Jewish (AJ) ancestry. Filtering was done based on quality and functionality scores. Ten variants in nine genes were further genotyped in 1200 consecutively recruited unrelated AJ-PD patients, and allele frequencies and odds ratio calculated compared to gnomAD-AJ-non-neuro database, in un-stratified (n=1200) and stratified manner (LRRK2-G2019S-PD patients (n=145), GBA-PD patients (n=235), and non-carriers of these mutations (NC, n=787)). Results: Five variants in PIK3C3, VPS11, AP1G2, HGS and VPS13D were significantly associated with PD-risk. PIK3C3-R768W showed a significant association in an un-stratified (all PDs) analysis, as well as in stratified (LRRK2, GBA, and NC) analyses (Odds ratios=2.71, 5.32, 3.26. and 2.19 with p=0.0015, 0.002, 0.0287, and 0.0447, respectively). AP1G2-R563W was significantly associated in LRRK2-carriers (OR=3.69, p=0.006) while VPS13D-D2932N was significantly associated in GBA-carriers (OR=5.45, p=0.0027). VPS11-C846G and HGS-S243Y were significantly associated in NC (OR=2.48 and 2.06, with p=0.022 and 0.0163, respectively). Conclusions: Variants in genes involved in vesicle-mediated protein transport and recycling pathways, including autophagy and mitophagy, may differentially modify PD-risk in LRRK2-carriers, GBA carriers, or NC. Specifically, PIK3C3-R768W is a PD-risk allele, with the highest effect size in LRRK2-G2019S carriers. These results suggest oligogenic effect that may depends on the genetic background of the patient. An unbiased burden of mutations approach in these genes should be evaluated in additional PD and control groups. The mechanisms by which these novel variants interact and increase PD-risk should be researched in depth for better tailoring therapeutic intervention for PD prevention or slowing disease progression.

Published
2023

35. Genetic markers of Restless Legs Syndrome in Parkinson disease

Author

Gan-Or, Ziv, Alcalay, Roy N., Bar-Shira, Anat, Leblond, Claire S., Postuma, Ronald B., Ben-Shachar, Shay, Waters, Cheryl, Johnson, Amelie, Levy, Oren, Mirelman, Anat, Gana-Weisz, Mali, Dupré, Nicolas, Montplaisir, Jacques, Giladi, Nir, Fahn, Stanley, Xiong, Lan, Dion, Patrick A., Orr-Urtreger, Avi, and Rouleau, Guy A.

Published
2015
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37. Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Author

Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Karen, Marder, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramirez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Gregor, Kuhlenbäumer, Kühn, Andrea A., Borngräber, Friederike, de Michele, Giuseppe, De Rosa, Anna, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Jolanta, Dorszewska, Carr, Jonathan, Ferese, Rosangela, Stefano, Gambardella, Chase, Bruce, Markopoulou, Katerina, Wataru, Satake, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Gen c, Gen Cer, de Carvalho Aguiar, Patricia, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, van de Warrenburg, Bart, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Joong, Kim Yun, Winkelmann, Juliane, Sue, Carolyn M., Eng-King, Tan, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Parimal, Das, Mollenhauer, Brit, Gatto, Emilia M., Skaalum, Petersen Maria, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, N, Alcalay Roy, Thaler, Avner, Farrer, Matthew J., Kathrin, Brockmann, Corvol, Jean-Christophe, Klein, Christine, Albanese, Alberto, Alcalay, Roy N., Aldakheel, Amaal, Alkhairallah, Thamer, Bashayer, Al-Mubarak, Al-Tassan, Nada, Paolo, Amami, Araujo, Leite Marco Antonio, Ferraz, Henrique Ballalai, Bardien, Soraya, Melinda, Barkhuizen, Barrett, Matthew J., Ba sak, A. Nazl I, Bilgic, Basar, Bloem, Bastiaan R., Bonifati, Vincenzo, Brockmann, Kathrin, Cesarini, Martin Emiliano, Ju, Chung Sun, Guedes, Leonor Correia, Lorraine, Clark, Dieguez, Elena, Dorszewska, Jolanta, Fung, Victor S. C., Pilar, Gómez-Garre, Hattori, Nobutaka, Faycel, Hentati, Januario, Cristina, Maestre, Silvia Jesús, Kaasinen, Valtteri, Hiroshi, Kataoka, Kievit, Anneke A., Kim, Yun Joong, Christine, Klein, Kuhlenbäumer, Gregor, Lim, Jia Lun, Timothy, Lynch, Marder, Karen, May, Patrick, McCarthy, Allan, Briceno, Hugo Morales, Morris, Huw, Mosejova, Alexandra, Cakmak, Özgür Öztop, Orr-Urtreger, Avi, Pachchek, Sinthuja, Periñ\'an, Maria Teresa, Procopio, Radha, Ruiz-Martinez, Javier, Pereira, João Santos, Satake, Wataru, Soto-Beasley, Alexandra I., Sousa, Mário, Tan, Eng-King, Tepge c, Fatih, Uyguner, Oya, Walton, Ronald L., H, Williams-Gray Caroline, Isabel, Wurster, Bao-Rong, Zhang, Fonds National de la Recherche - FnR [sponsor], MJFF [sponsor], H2020 (Orchestra) [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Neurologie [D14] [Sciences de la santé humaine], Neurology [D14] [Human health sciences], Genetics & genetic processes [F10] [Life sciences], Parkinson's disease, monogenic PD, Génétique & processus génétiques [F10] [Sciences du vivant]
Abstract

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.

Published
2023

47. Glucocerebrosidase Activity Is Not Associated with Parkinson's Disease Risk or Severity

Author

Omer, Nurit, primary, Giladi, Nir, additional, Gurevich, Tanya, additional, Bar‐Shira, Anat, additional, Gana‐Weisz, Mali, additional, Glinka, Tal, additional, Goldstein, Orly, additional, Kestenbaum, Meir, additional, Cedarbaum, Jesse M., additional, Mabrouk, Omar S., additional, Fraser, Kyle B., additional, Shirvan, Julia C., additional, Orr‐Urtreger, Avi, additional, Mirelman, Anat, additional, and Thaler, Avner, additional

Published
2022
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50. C9orf72-G4C2 Intermediate Repeats and Parkinson’s Disease

Author

Kobo, Hila, Goldstein, Orly, Gana-Weisz, Mali, Bar-Shira, Anat, Gurevich, Tanya, Thaler, Avner, Mirelman, Anat, Giladi, Nir, and Orr-Urtreger, Avi

Subjects
hexanucleotide expansions, C9orf72, mental disorders, intermediate repeats, nutritional and metabolic diseases, Parkinson’s disease (PD), nervous system diseases
Abstract

Pathogenic C9orf72-G4C2 repeat expansions are associated with ALS/FTD, but not with Parkinson’s disease (PD), yet the possible link between intermediate repeat lengths and PD remains inconclusive. We aim to study the potential involvement of these repeats in PD. The number of C9orf72-repeats were determined by flanking and repeat-primed PCR assays, and the risk-haplotype was determined by SNP-array. Their association with PD was assessed in a stratified manner: in PD-patients-carriers of mutations in LRRK2, GBA, or SMPD1 genes (n = 388), and in PD-non-carriers (NC, n = 718). Allelic distribution was significantly different only in PD-NC compared to 600 controls when looking both at the allele with higher repeat’s size (p = 0.034) and at the combined number of repeats from both alleles (p = 0.023). Intermediate repeats (20–60 repeats) were associated with PD in PD-NC patients (p = 0.041, OR = 3.684 (CI 1.05–13.0)) but not in PD-carriers (p = 0.684). The C9orf72 risk-haplotype, determined in a subgroup of 588 PDs and 126 controls, was observed in higher frequency in PD-NC (dominant model, OR = 1.71, CI 1.04–2.81, p = 0.0356). All 19 alleles within the risk-haplotype were associated with higher C9orf72 RNA levels according to the GTEx database. Based on our data, we suggest a model in which intermediate repeats are a risk factor for PD in non-carriers, driven not only by the number of repeats but also by the variants’ genotypes within the risk-haplotype. Further studies are needed to elucidate this possible role of C9orf72 in PD pathogenesis.

Published
2021
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