Browsing by Author "Lynch, Timothy"

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    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 Medicine
    Objective: 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.
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    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 Medicine
    Background: 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.