Browsing by Author "Alcalay, Roy N."
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Item A blood-based marker of mitochondrial DNA damage in Parkinson's disease(American Association for the Advancement of Science, 2023) Qi, Rui; Sammler, Esther; Gonzalez-Hunt, Claudia P.; Barraza, Ivana; Pena, Nicholas; Rouanet, Jeremy P.; Naaldijk, Yahaira; Goodson, Steven; Fuzzati, Marie; Blandini, Fabio; Erickson, Kirk I.; Weinstein, Andrea M.; Lutz, Michael W.; Kwok, John B.; Halliday, Glenda M.; Dzamko, Nicolas; Padmanabhan, Shalini; Alcalay, Roy N.; Waters, Cheryl; Hogarth, Penelope; Simuni, Tanya; Smith, Danielle; Marras, Connie; Tonelli, Francesca; Alessi, Dario R.; West, Andrew B.; Shiva, Sruti; Hilfiker, Sabine; Sanders, Laurie H.; Oral and Maxillofacial Surgery and Hospital Dentistry, School of DentistryParkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.Item Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study(Elsevier, 2023) Siderowf, Andrew; Concha-Marambio, Luis; Lafontant, David-Erick; Farris, Carly M.; Ma, Yihua; Urenia, Paula A.; Nguyen, Hieu; Alcalay, Roy N.; Chahine, Lana M.; Foroud, Tatiana; Galasko, Douglas; Kieburtz, Karl; Merchant, Kalpana; Mollenhauer, Brit; Poston, Kathleen L.; Seibyl, John; Simuni, Tanya; Tanner, Caroline M.; Weintraub, Daniel; Videnovic, Aleksandar; Choi, Seung Ho; Kurth, Ryan; Caspell-Garcia, Chelsea; Coffey, Christopher S.; Frasier, Mark; Oliveira, Luis M. A.; Hutten, Samantha J.; Sherer, Todd; Marek, Kenneth; Soto, Claudio; Parkinson's Progression Markers Initiative; Medical and Molecular Genetics, School of MedicineBackground: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups. Methods: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson's disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson's disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex. Findings: This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson's disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson's disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson's disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson's disease (67·5% [59·2-75·8]) and participants with sporadic Parkinson's disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive. Interpretation: This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson's disease. Our results show that the assay classifies people with Parkinson's disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson's disease and to establish biomarker-defined at-risk cohorts.Item Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls(Wiley, 2019-09) Agalliu, llir; Ortega, Roberto A.; San Luciano, Marta; Mirelman, Anat; Pont-Sunyer, Claustre; Brockmann, Kathrin; Vilas, Dolores; Tolosa, Eduardo; Berg, Daniela; Warø, Bjørg; Glickman, Amanda; Raymond, Deborah; Inzelberg, Rivka; Ruiz-Martinez, Javier; Mondragon, Elisabet; Friedman, Eitan; Hassin-Baer, Sharon; Alcalay, Roy N.; Mejia-Santana, Helen; Aasly, Jan; Foroud, Tatiana; Marder, Karen; Giladi, Nir; Bressman, Susan; Saunders-Pullman, Rachel; Medical and Molecular Genetics, School of MedicineBACKGROUND: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. METHODS: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. RESULTS: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. CONCLUSIONS: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.Item Genetic Testing for Parkinson Disease: Are We Ready?(American Academy of Neurology, 2021-02) Cook, Lola; Schulze, Jeanine; Kopil, Catherine; Hastings, Tara; Naito, Anna; Wojcieszek, Joanne; Payne, Katelyn; Alcalay, Roy N.; Klein, Christine; Saunders-Pullman, Rachel; Simuni, Tatyana; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicinePurpose of review: With the advent of precision medicine and demand for genomic testing information, we may question whether it is time to offer genetic testing to our patients with Parkinson disease (PD). This review updates the current genetic landscape of PD, describes what genetic testing may offer, provides strategies for evaluating whom to test, and provides resources for the busy clinician. Recent findings: Patients with PD and their relatives, in various settings, have expressed an interest in learning their PD genetic status; however, physicians may be hesitant to widely offer testing due to the perceived low clinical utility of PD genetic test results. The rise of clinical trials available for patients with gene-specific PD and emerging information on genotype-phenotype correlations are starting to shift this discussion about testing. Summary: By learning more about the various genetic testing options for PD and utility of results for patients and their care, clinicians may become more comfortable with widespread PD genetic testing in the research and clinical setting.Item Genetic Testing in Parkinson's Disease(Wiley, 2023) Pal, Gian; Cook, Lola; Schulze, Jeanine; Verbrugge, Jennifer; Alcalay, Roy N.; Merello, Marcelo; Sue, Carolyn M.; Bardien, Soraya; Bonifati, Vincenzo; Chung, Sun Ju; Foroud, Tatiana; Gatto, Emilia; Hall, Anne; Hattori, Nobutaka; Lynch, Tim; Marder, Karen; Mascalzoni, Deborah; Novaković, Ivana; Thaler, Avner; Raymond, Deborah; Salari, Mehri; Shalash, Ali; Suchowersky, Oksana; Mencacci, Niccolò E.; Simuni, Tanya; Saunders-Pullman, Rachel; Klein, Christine; Medical and Molecular Genetics, School of MedicineGenetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct-to-consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene-targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long-term outcomes of consumer- and research-based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost-benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines.Item Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease(Wiley, 2021-07) Lai, Dongbing; Alipanahi, Babak; Fontanillas, Pierre; Schwantes, Tae-Hwi; Aasly, Jan; Alcalay, Roy N.; Beecham, Gary W.; Berg, Daniela; Bressman, Susan; Brice, Alexis; Brockman, Kathrin; Clark, Lorraine; Cookson, Mark; Das, Sayantan; Van Deerlin, Vivianna; Follett, Jordan; Farrer, Matthew J.; Trinh, Joanne; Gasser, Thomas; Goldwurm, Stefano; Gustavsson, Emil; Klein, Christine; Lang, Anthony E.; Langston, J. William; Latourelle, Jeanne; Lynch, Timothy; Marder, Karen; Marras, Connie; Martin, Eden R.; McLean, Cory Y.; Mejia-Santana, Helen; Molho, Eric; Myers, Richard H.; Nuytemans, Karen; Ozelius, Laurie; Payami, Haydeh; Raymond, Deborah; Rogaeva, Ekaterina; Rogers, Michael P.; Ross, Owen A.; Samii, Ali; Saunders-Pullman, Rachel; Schüle, Birgitt; Schulte, Claudia; Scott, William K.; Tanner, Caroline; Tolosa, Eduardo; Tomkins, James E.; Vilas, Dolores; Trojanowski, John Q.; Uitti, Ryan; Vance, Jeffery M.; Visanji, Naomi P.; Wszolek, Zbigniew K.; Zabetian, Cyrus P.; Mirelman, Anat; Giladi, Nir; Urtreger, Avi Orr; Cannon, Paul; Fiske, Brian; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicineObjective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.Item International Genetic Testing and Counseling Practices for Parkinson's Disease(Wiley, 2023) Saunders-Pullman, Rachel; Raymond, Deborah; Ortega, Roberto A.; Shalash, Ali; Gatto, Emilia; Salari, Mehri; Markgraf, Maggie; Alcalay, Roy N.; Mascalzoni, Deborah; Mencacci, Niccolò E.; Bonifati, Vincenzo; Merello, Marcelo; Chung, Sun Ju; Novakovic, Ivana; Bardien, Soraya; Pal, Gian; Hall, Anne; Hattori, Nobutaka; Lynch, Timothy; Thaler, Avner; Sue, Carolyn M.; Foroud, Tatiana; Verbrugge, Jennifer; Schulze, Jeanine; Cook, Lola; Marder, Karen; Suchowersky, Oksana; Klein, Christine; Simuni, Tatyana; Medical and Molecular Genetics, School of MedicineBackground: There is growing clinical and research utilization of genetic testing in Parkinson's disease (PD), including direct-to-consumer testing. Objectives: The aim is to determine the international landscape of genetic testing in PD to inform future worldwide recommendations. Methods: A web-based survey assessing current practices, concerns, and barriers to genetic testing and counseling was administered to the International Parkinson and Movement Disorders Society membership. Results: Common hurdles across sites included cost and access to genetic testing, and counseling, as well as education on genetic counseling. Region-dependent differences in access to and availability of testing and counseling were most notable in Africa. High-income countries also demonstrated heterogeneity, with European nations more likely to have genetic testing covered through insurance than Pan-American and Asian countries. Conclusions: This survey highlights not only diversity of barriers in different regions but also the shared and highly actionable needs for improved education and access to genetic counseling and testing for PD worldwide. © 2023 International Parkinson and Movement Disorder Society.Item Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort(Springer, 2022-10-22) Simuni, Tanya; Merchant, Kalpana; Brumm, Michael C.; Cho, Hyunkeun; Caspell-Garcia, Chelsea; Coffey, Christopher S.; Chahine, Lana M.; Alcalay, Roy N.; Nudelman, Kelly; Foroud, Tatiana; Mollenhauer, Brit; Siderowf, Andrew; Tanner, Caroline; Iwaki, Hirotaka; Sherer, Todd; Marek, Kenneth; Parkinson’s Progression Marker Initiative Authors; Medical and Molecular Genetics, School of MedicineWe examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 11% had hyposmia (defined as ≤15th percentile for age and sex). Only 5 of 176 LRRK2 NMCs developed PD during follow-up. Although NMCs scored significantly worse on numerous clinical scales at baseline than HCs, there was no longitudinal change in any clinical measures over 2 years or in DAT binding. There were no longitudinal differences in CSF and serum biomarkers between NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but did not change longitudinally. Neither baseline biofluid biomarkers nor the presence of DAT deficit correlated with 2-year change in clinical outcomes. We observed no significant 2-year longitudinal change in clinical or biomarker measures in LRRK2 G2019S NMCs in this large, well-characterized cohort even in the participants with baseline DAT deficit. These findings highlight the essential need for further enrichment biomarker discovery in addition to DAT deficit and longer follow-up to enable the selection of NMCs at the highest risk for conversion to enable future prevention clinical trials.Item Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program(Future Medicine, 2017-05) Gwinn, Katrina; David, Karen K.; Swanson-Fischer, Christine; Albin, Roger; St Hillaire-Clarke, Coryse; Sieber, Beth-Anne; Lungu, Codrin; Bowman, F. DuBois; Alcalay, Roy N.; Babcock, Debra; Dawson, Ted M.; Dewey, Richard B., Jr.; Foroud, Tatiana; German, Dwight; Huang, Xuemei; Petyuk, Vlad; Potashkin, Judith A.; Saunders-Pullman, Rachel; Sutherland, Margaret; Walt, David R.; West, Andrew B.; Zhang, Jing; Chen-Plotkin, Alice; Scherzer, Clemens R.; Vaillancourt, David E.; Rosenthal, Liana S.; Medical and Molecular Genetics, School of MedicineBiomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset.Item Parkinson's disease variant detection and disclosure: PD GENEration, a North American study(Oxford University Press, 2024) Cook, Lola; Verbrugge, Jennifer; Schwantes-An, Tae-Hwi; Schulze, Jeanine; Foroud, Tatiana; Hall, Anne; Marder, Karen S.; Mata, Ignacio F.; Mencacci, Niccolò E.; Nance, Martha A.; Schwarzschild, Michael A.; Simuni, Tanya; Bressman, Susan; Wills, Anne-Marie; Fernandez, Hubert H.; Litvan, Irene; Lyons, Kelly E.; Shill, Holly A.; Singer, Carlos; Tropea, Thomas F.; Vanegas Arroyave, Nora; Carbonell, Janfreisy; Cruz Vicioso, Rossy; Katus, Linn; Quinn, Joseph F.; Hodges, Priscila D.; Meng, Yan; Strom, Samuel P.; Blauwendraat, Cornelis; Lohmann, Katja; Casaceli, Cynthia; Rao, Shilpa C.; Ghosh Galvelis, Kamalini; Naito, Anna; Beck, James C.; Alcalay, Roy N.; Medical and Molecular Genetics, School of MedicineVariants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinson's disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more 'high risk factors' for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinson's disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinson's disease.