Browsing by Author "Makarious, Mary B."

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    Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)
    (Springer Nature, 2023-09-12) Towns, Clodagh; Richer, Madeleine; Jasaityte, Simona; Stafford, Eleanor J.; Joubert, Julie; Antar, Tarek; Martinez-Carrasco, Alejandro; Makarious, Mary B.; Casey, Bradford; Vitale, Dan; Levine, Kristin; Leonard, Hampton; Pantazis, Caroline B.; Screven, Laurel A.; Hernandez, Dena G.; Wegel, Claire E.; Solle, Justin; Nalls, Mike A.; Blauwendraat, Cornelis; Singleton, Andrew B.; Tan, Manuela M. X.; Iwaki, Hirotaka; Morris, Huw R.; Global Parkinson’s Genetics Program (GP2); Medical and Molecular Genetics, School of Medicine
    The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia.
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    Differences in the Presentation and Progression of Parkinson's Disease by Sex
    (Wiley, 2021) Iwaki, Hirotaka; Blauwendraat, Cornelis; Leonard, Hampton L.; Makarious, Mary B.; Kim, Jonggeol J.; Liu, Ganqiang; Maple-Grødem, Jodie; Corvol, Jean-Christophe; Pihlstrøm, Lasse; van Nimwegen, Marlies; Smolensky, Luba; Amondikar, Ninad; Hutten, Samantha J.; Frasier, Mark; Nguyen, Khanh-Dung H.; Rick, Jacqueline; Eberly, Shirley; Faghri, Faraz; Auinger, Peggy; Scott, Kirsten M.; Wijeyekoon, Ruwani; Van Deerlin, Vivianna M.; Hernandez, Dena G.; Gibbs, Raphael J.; Day-Williams, Aaron G.; Brice, Alexis; Alves, Guido; Noyce, Alastair J.; Tysnes, Ole-Bjørn; Evans, Jonathan R.; Breen, David P.; Estrada, Karol; Wegel, Claire E.; Danjou, Fabrice; Simon, David K.; Andreassen, Ole A.; Ravina, Bernard; Toft, Mathias; Heutink, Peter; Bloem, Bastiaan R.; Weintraub, Daniel; Barker, Roger A.; Williams-Gray, Caroline H.; van de Warrenburg, Bart P.; Van Hilten, Jacobus J.; Scherzer, Clemens R.; Singleton, Andrew B.; Nalls, Mike A.; Medical and Molecular Genetics, School of Medicine
    Background: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. Objectives: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. Methods: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. Results: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. Conclusions: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management.
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    Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture
    (Springer Nature, 2021-03) Chia, Ruth; Sabir, Marya S.; Bandres-Ciga, Sara; Saez-Atienzar, Sara; Reynolds, Regina H.; Gustavsson, Emil; Walton, Ronald L.; Ahmed, Sarah; Viollet, Coralie; Ding, Jinhui; Makarious, Mary B.; Diez-Fairen, Monica; Portley, Makayla K.; Shah, Zalak; Abramzon, Yevgeniya; Hernandez, Dena G.; Blauwendraat, Cornelis; Stone, David J.; Eicher, John; Parkkinen, Laura; Ansorge, Olaf; Clark, Lorraine; Honig, Lawrence S.; Marder, Karen; Lemstra, Afina; St. George-Hyslop, Peter; Londos, Elisabet; Morgan, Kevin; Lashley, Tammaryn; Warner, Thomas T.; Jaunmuktane, Zane; Galasko, Douglas; Santana, Isabel; Tienari, Pentti J.; Myllykangas, Liisa; Oinas, Minna; Cairns, Nigel J.; Morris, John C.; Halliday, Glenda M.; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Grassano, Maurizio; Calvo, Andrea; Mora, Gabriele; Canosa, Antonio; Floris, Gianluca; Bohannan, Ryan C.; Brett, Francesca; Gan-Or, Ziv; Geiger, Joshua T.; Moore, Anni; May, Patrick; Krüger, Rejko; Goldstein, David S.; Lopez, Grisel; Tayebi, Nahid; Sidransky, Ellen; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio; Shakkottai, Vikram G.; Perkins, Matthew; Newell, Kathy L.; Gasser, Thomas; Schulte, Claudia; Landi, Francesco; Salvi, Erika; Cusi, Daniele; Masliah, Eliezer; Kim, Ronald C.; Caraway, Chad A.; Monuki, Edwin S.; Brunetti, Maura; Dawson, Ted M.; Rosenthal, Liana S.; Albert, Marilyn S.; Pletnikova, Olga; Troncoso, Juan C.; Flanagan, Margaret E.; Mao, Qinwen; Bigio, Eileen H.; Rodríguez-Rodríguez, Eloy; Infante, Jon; Lage, Carmen; González-Aramburu, Isabel; Sanchez-Juan, Pascual; Ghetti, Bernardino; Keith, Julia; Black, Sandra E.; Masellis, Mario; Rogaeva, Ekaterina; Duyckaerts, Charles; Brice, Alexis; Lesage, Suzanne; Xiromerisiou, Georgia; Barrett, Matthew J.; Tilley, Bension S.; Gentleman, Steve; Logroscino, Giancarlo; Serrano, Geidy E.; Beach, Thomas G.; McKeith, Ian G.; Thomas, Alan J.; Attems, Johannes; Morris, Christopher M.; Palmer, Laura; Love, Seth; Troakes, Claire; Al-Sarraj, Safa; Hodges, Angela K.; Aarsland, Dag; Klein, Gregory; Kaiser, Scott M.; Woltjer, Randy; Pastor, Pau; Bekris, Lynn M.; Leverenz, James B.; Besser, Lilah M.; Kuzma, Amanda; Renton, Alan E.; Goate, Alison; Bennett, David A.; Scherzer, Clemens R.; Morris, Huw R.; Ferrari, Raffaele; Albani, Diego; Pickering-Brown, Stuart; Faber, Kelley; Kukull, Walter A.; Morenas-Rodriguez, Estrella; Lleó, Alberto; Fortea, Juan; Alcolea, Daniel; Clarimon, Jordi; Nalls, Mike A.; Ferrucci, Luigi; Resnick, Susan M.; Tanaka, Toshiko; Foroud, Tatiana M.; Graff-Radford, Neill R.; Wszolek, Zbigniew K.; Ferman, Tanis; Boeve, Bradley F.; Hardy, John A.; Topol, Eric J.; Torkamani, Ali; Singleton, Andrew B.; Ryten, Mina; Dickson, Dennis W.; Chiò, Adriano; Ross, Owen A.; Gibbs, J. Raphael; Dalgard, Clifton L.; Traynor, Bryan J.; Scholz, Sonja W.; Pathology and Laboratory Medicine, School of Medicine
    The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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    Genome-wide case-only analysis of gene-gene interactions with known Parkinson's disease risk variants reveals link between LRRK2 and SYT10
    (Springer Nature, 2023-06-29) 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.; The International Parkinson Disease Genomics Consortium; Grünewald, Anne; Kaiser, Frank; Klein, Christine; Krawczak, Michael; Dempfle, Astrid; Medical and Molecular Genetics, School of Medicine
    The effects of one genetic factor upon Parkinson’s disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the ‘missing heritability’ of PD and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson’s Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the LRRK2 gene. It yielded the lowest interaction p-value overall with SNP rs1007709 in the promoter region of the SYT10 gene (interaction OR = 1.80, 95% CI: 1.65–1.95, p = 2.7 × 10−43). SNPs around SYT10 were also associated with the age-at-onset of PD in an independent cohort of carriers of LRRK2 mutation p.G2019S. Moreover, SYT10 gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving the LRRK2 and SYT10 gene regions, is biologically plausible owing to the known link between PD and LRRK2, its involvement in neural plasticity, and the contribution of SYT10 to the exocytosis of secretory vesicles in neurons.