Browsing by Author "Clark, Lorraine"

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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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    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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    Polygenic risk for alcohol use disorder affects cellular responses to ethanol exposure in a human microglial cell model
    (American Association for the Advancement of Science, 2024) Li, Xindi; Liu, Jiayi; Boreland, Andrew J.; Kapadia, Sneha; Zhang, Siwei; Stillitano, Alessandro C.; Abbo, Yara; Clark, Lorraine; Lai, Dongbing; Liu, Yunlong; Barr, Peter B.; Meyers, Jacquelyn L.; Kamarajan, Chella; Kuang, Weipeng; Agrawal, Arpana; Slesinger, Paul A.; Dick, Danielle; Salvatore, Jessica; Tischfield, Jay; Duan, Jubao; Edenberg, Howard J.; Kreimer, Anat; Hart, Ronald P.; Pang, Zhiping P.; Biochemistry and Molecular Biology, School of Medicine
    Polygenic risk scores (PRSs) assess genetic susceptibility to alcohol use disorder (AUD), yet their molecular implications remain underexplored. Neuroimmune interactions, particularly in microglia, are recognized as notable contributors to AUD pathophysiology. We investigated the interplay between AUD PRS and ethanol in human microglia derived from iPSCs from individuals with AUD high-PRS (diagnosed with AUD) or low-PRS (unaffected). Ethanol exposure induced elevated CD68 expression and morphological changes in microglia, with differential responses between high-PRS and low-PRS microglial cells. Transcriptomic analysis revealed expression differences in MHCII complex and phagocytosis-related genes following ethanol exposure; high-PRS microglial cells displayed enhanced phagocytosis and increased CLEC7A expression, unlike low-PRS microglial cells. Synapse numbers in cocultures of induced neurons with microglia after alcohol exposure were lower in high-RPS cocultures, suggesting possible excess synapse pruning. This study provides insights into the intricate relationship between AUD PRS, ethanol, and microglial function, potentially influencing neuronal functions in developing AUD.