Browsing by Author "Morris, Huw R."

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    Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes
    (medRxiv, 2024-02-28) Wang, Hui; Chang, Timothy S.; Dombroski, Beth A.; Cheng, Po-Liang; Si, Ya-Qin; Tucci, Albert; Patil, Vishakha; Valiente-Banuet, Leopoldo; Farrell, Kurt; Mclean, Catriona; Molina-Porcel, Laura; Alex, Rajput; De Deyn, Peter Paul; Le Bastard, Nathalie; Gearing, Marla; Donker Kaat, Laura; Van Swieten, John C.; Dopper, Elise; Ghetti, Bernardino F.; Newell, Kathy L.; Troakes, Claire; de Yébenes, Justo G.; Rábano-Gutierrez, Alberto; Meller, Tina; Oertel, Wolfgang H.; Respondek, Gesine; Stamelou, Maria; Arzberger, Thomas; Roeber, Sigrun; Müller, Ulrich; Hopfner, Franziska; Pastor, Pau; Brice, Alexis; Durr, Alexandra; Le Ber, Isabelle; Beach, Thomas G.; Serrano, Geidy E.; Hazrati, Lili-Naz; Litvan, Irene; Rademakers, Rosa; Ross, Owen A.; Galasko, Douglas; Boxer, Adam L.; Miller, Bruce L.; Seeley, Willian W.; Van Deerlin, Vivianna M.; Lee, Edward B.; White, Charles L., III; Morris, Huw R.; de Silva, Rohan; Crary, John F.; Goate, Alison M.; Friedman, Jeffrey S.; Leung, Yuk Yee; Coppola, Giovanni; Naj, Adam C.; Wang, Li-San; PSP genetics study group; Dickson, Dennis W.; Höglinger, Günter U.; Tzeng, Jung-Ying; Geschwind, Daniel H.; Schellenberg, Gerard D.; Lee, Wan-Ping; Pathology and Laboratory Medicine, School of Medicine
    Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, β, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, β, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, β, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and β were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1β1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1β1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1β1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1β1γ4. Moreover, H1β1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1β1γ1 to 77% in H1β1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.
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    Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease
    (medRxiv, 2023-04-24) Valentino, Rebecca R.; Scotton, William J.; Roemer, Shanu F.; Lashley, Tammaryn; Heckman, Michael G.; Shoai, Maryam; Martinez-Carrasco, Alejandro; Tamvaka, Nicole; Walton, Ronald L.; Baker, Matthew C.; Macpherson, Hannah L.; Real, Raquel; Soto-Beasley, Alexandra I.; Mok, Kin; Revesz, Tamas; Warner, Thomas T.; Jaunmuktane, Zane; Boeve, Bradley F.; Christopher, Elizabeth A.; DeTure, Michael; Duara, Ranjan; Graff-Radford, Neill R.; Josephs, Keith A.; Knopman, David S.; Koga, Shunsuke; Murray, Melissa E.; Lyons, Kelly E.; Pahwa, Rajesh; Parisi, Joseph E.; Petersen, Ronald C.; Whitwell, Jennifer; Grinberg, Lea T.; Miller, Bruce; Schlereth, Athena; Seeley, William W.; Spina, Salvatore; Grossman, Murray; Irwin, David J.; Lee, Edward B.; Suh, EunRan; Trojanowski, John Q.; Van Deerlin, Vivianna M.; Wolk, David A.; Connors, Theresa R.; Dooley, Patrick M.; Frosch, Matthew P.; Oakley, Derek H.; Aldecoa, Iban; Balasa, Mircea; Gelpi, Ellen; Borrego-Écija, Sergi; de Eugenio Huélamo, Rosa Maria; Gascon-Bayarri, Jordi; Sánchez-Valle, Raquel; Sanz-Cartagena, Pilar; Piñol-Ripoll, Gerard; Molina-Porcel, Laura; Bigio, Eileen H.; Flanagan, Margaret E.; Gefen, Tamar; Rogalski, Emily J.; Weintraub, Sandra; Redding-Ochoa, Javier; Chang, Koping; Troncoso, Juan C.; Prokop, Stefan; Newell, Kathy L.; Ghetti, Bernardino; Jones, Matthew; Richardson, Anna; Robinson, Andrew C.; Roncaroli, Federico; Snowden, Julie; Allinson, Kieren; Green, Oliver; Rowe, James B.; Singh, Poonam; Beach, Thomas G.; Serrano, Geidy E.; Flowers, Xena E.; Goldman, James E.; Heaps, Allison C.; Leskinen, Sandra P.; Teich, Andrew F.; Black, Sandra E.; Keith, Julia L.; Masellis, Mario; Bodi, Istvan; King, Andrew; Sarraj, Safa-Al; Troakes, Claire; Halliday, Glenda M.; Hodges, John R.; Kril, Jillian J.; Kwok, John B.; Piguet, Olivier; Gearing, Marla; Arzberger, Thomas; Roeber, Sigrun; Attems, Johannes; Morris, Christopher M.; Thomas, Alan J.; Evers, Bret M.; White, Charles L.; Mechawar, Naguib; Sieben, Anne A.; Cras, Patrick P.; De Vil, Bart B.; De Deyn, Peter Paul P. P.; Duyckaerts, Charles; Le Ber, Isabelle; Seihean, Danielle; Turbant-Leclere, Sabrina; MacKenzie, Ian R.; McLean, Catriona; Cykowski, Matthew D.; Ervin, John F.; Wang, Shih-Hsiu J.; Graff, Caroline; Nennesmo, Inger; Nagra, Rashed M.; Riehl, James; Kovacs, Gabor G.; Giaccone, Giorgio; Nacmias, Benedetta; Neumann, Manuela; Ang, Lee-Cyn; Finger, Elizabeth C.; Blauwendraat, Cornelis; Nalls, Mike A.; Singleton, Andrew B.; Vitale, Dan; Cunha, Cristina; Carvalho, Agostinho; Wszolek, Zbigniew K.; Morris, Huw R.; Rademakers, Rosa; Hardy, John A.; Dickson, Dennis W.; Rohrer, Jonathan D.; Ross, Owen A.; Pathology and Laboratory Medicine, School of Medicine
    Background: Pick's disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the MAPT gene. The MAPT H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between MAPT H2 and risk of PiD. Methods: We established the Pick's disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521). Findings: Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype MAPT H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65). Interpretation: The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.
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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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    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 structural variant analysis identifies risk loci for non-Alzheimer's dementias
    (Elsevier, 2023-05-04) Kaivola, Karri; Chia, Ruth; Ding, Jinhui; Rasheed, Memoona; Fujita, Masashi; Menon, Vilas; Walton, Ronald L.; Collins, Ryan L.; Billingsley, Kimberley; Brand, Harrison; Talkowski, Michael; Zhao, Xuefang; Dewan, Ramita; Stark, Ali; Ray, Anindita; Solaiman, Sultana; Alvarez Jerez, Pilar; Malik, Laksh; Dawson, Ted M.; Rosenthal, Liana S.; Albert, Marilyn S.; Pletnikova, Olga; Troncoso, Juan C.; Masellis, Mario; Keith, Julia; Black, Sandra E.; Ferrucci, Luigi; Resnick, Susan M.; Tanaka, Toshiko; American Genome Center; International LBD Genomics Consortium; International ALS/FTD Consortium; PROSPECT Consortium; Topol, Eric; Torkamani, Ali; Tienari, Pentti; Foroud, Tatiana M.; Ghetti, Bernardino; Landers, John E.; Ryten, Mina; Morris, Huw R.; Hardy, John A.; Mazzini, Letizia; D'Alfonso, Sandra; Moglia, Cristina; Calvo, Andrea; Serrano, Geidy E.; Beach, Thomas G.; Ferman, Tanis; Graff-Radford, Neill R.; Boeve, Bradley F.; Wszolek, Zbigniew K.; Dickson, Dennis W.; Chiò, Adriano; Bennett, David A.; De Jager, Philip L.; Ross, Owen A.; Dalgard, Clifton L.; Gibbs, J. Raphael; Traynor, Bryan J.; Scholz, Sonja W.; Medical and Molecular Genetics, School of Medicine
    We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.