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1. Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Author

Wu, Lesley Yue, Real, Raquel, Martinez-Carrasco, Alejandro, Chia, Ruth, Lawton, Michael A, Shoai, Maryam, Bresner, Catherine, Blauwendraat, Cornelis, Singleton, Andrew B, Ryten, Mina, Abramzon, Yevgeniya, Ahmed, Sarah, Alba, Camille, Albert, Marilyn S, Bacikova, Dagmar, Barrett, Matthew J, Beach, Thomas G, Bennett, David A, Besser, Lilah M, Bigio, Eileen H, Boeve, Bradley F, Bohannan, Ryan C, Caraway, Chad A, Palma, Jose-Alberto, Dalgard, Clifton L, Dickson, Dennis, Ding, Jinhui, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David, Graff-Radford, Neill R, Hu, Heng-Chen, Hupalo, Daniel, Kaiser, Scott M, Kaufmann, Horacio, Kim, Ronald C, Klein, Gregory, Kukull, Walter, Kuzma, Amanda, Leverenz, James, Lopez, Grisel, Mao, Qinwen, Martinez-McGrath, Elisa, Masliah, Eliezer, Monuki, Ed, Newell, Kathy L, Norcliffe-Kaufmann, Lucy, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Ross, Owen A, Sabir, Marya S, Scherzer, Clemens R, Scholz, Sonja W, Serrano, Geidy, Shakkotai, Vikram, Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Traynor, Bryan J, Troncoso, Juan C, Viollet, Coralie, Walton, Ronald L, Woltjer, Randy, Wszolek, Zbigniew K, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Ferrari, Raffaele, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Reynolds, Regina H, Thomas, Alan J, Tilley, Bension S, Troakes, Claire, Brett, Francesca, Brice, Alexis, and Duyckaerts, Charles

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Genetics, Prevention, Aging, Lewy Body Dementia, Brain Disorders, Dementia, Alzheimer's Disease Related Dementias (ADRD), Parkinson's Disease, Human Genome, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Neurological, International Lewy Body Dementia Genomics Consortium, APOE, Lewy body diseases, dementia, genome-wide association studies, Clinical sciences, Biological psychology
Abstract

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

Published
2024

2. Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci.

Author

Bayram, Ece, Reho, Paolo, Litvan, Irene, Ding, Jinhui, Gibbs, J, Dalgard, Clifton, Traynor, Bryan, Scholz, Sonja, and Chia, Ruth

Abstract

Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequence data from 2591 LBD cases and 4391 controls. We identified a significant risk locus within intron 1 of MAP3K15 (rs141773145, odds ratio = 2.42, 95% confidence interval = 1.65-3.56, p-value = 7.0 × 10-6) in female LBD cases conditioned for APOE ε4 dosage. The locus includes an enhancer region that regulates MAP3K15 expression in ganglionic eminence cells derived from primary cultured neurospheres. Rare variant burden testing showed differential enrichment of missense mutations in TEX13A in female LBD cases, that did not reach significance (p-value = 1.34 × 10-4). These findings support the sex-specific effects of genetic factors and a potential role of Alzheimers-related risk for females with LBD.

Published
2024

3. Characterizing a complex CT-rich haplotype in intron 4 of SNCA using large-scale targeted amplicon long-read sequencing

Author

Alvarez Jerez, Pilar, Daida, Kensuke, Grenn, Francis P., Malik, Laksh, Miano-Burkhardt, Abigail, Makarious, Mary B., Ding, Jinhui, Gibbs, J. Raphael, Moore, Anni, Reed, Xylena, Nalls, Mike A., Shah, Syed, Mahmoud, Medhat, Sedlazeck, Fritz J., Dolzhenko, Egor, Park, Morgan, Iwaki, Hirotaka, Casey, Bradford, Ryten, Mina, Blauwendraat, Cornelis, Singleton, Andrew B., and Billingsley, Kimberley J.

Published
2024
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4. Profiling complex repeat expansions in RFC1 in Parkinson’s disease

Author

Alvarez Jerez, Pilar, Daida, Kensuke, Miano-Burkhardt, Abigail, Iwaki, Hirotaka, Malik, Laksh, Cogan, Guillaume, Makarious, Mary B., Sullivan, Roisin, Vandrovcova, Jana, Ding, Jinhui, Gibbs, J. Raphael, Markham, Androo, Nalls, Mike A., Kesharwani, Rupesh K., Sedlazeck, Fritz J., Casey, Bradford, Hardy, John, Houlden, Henry, Blauwendraat, Cornelis, Singleton, Andrew B., and Billingsley, Kimberley J.

Published
2024
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5. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author

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, Jerez, Pilar Alvarez, 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, Soltis, Anthony R, Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Martinez, Elisa McGrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N, Adeleye, Adelani, Wilkerson, Matthew D, Pollard, Harvey B, Dalgard, Clifton L, Gan-Or, Ziv, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian G, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J, Troakes, Claire, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, and Gibbs, J Raphael

Subjects
Biological Sciences, Genetics, Brain Disorders, Dementia, ALS, Rare Diseases, Neurodegenerative, Neurosciences, Human Genome, Frontotemporal Dementia (FTD), Alzheimer's Disease, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aging, Aetiology, 2.1 Biological and endogenous factors, Neurological, American Genome Center, International LBD Genomics Consortium, International ALS/FTD Consortium, PROSPECT Consortium, Lewy body dementia, amyotrophic lateral sclerosis, case-control study, frontotemporal dementia, genome-wide association study, non–Alzheimer's dementia, resource, structural variant
Abstract

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.

Published
2023

6. The Foundational Data Initiative for Parkinson Disease: Enabling efficient translation from genetic maps to mechanism

Author

Bressan, Elisangela, Reed, Xylena, Bansal, Vikas, Hutchins, Elizabeth, Cobb, Melanie M, Webb, Michelle G, Alsop, Eric, Grenn, Francis P, Illarionova, Anastasia, Savytska, Natalia, Violich, Ivo, Broeer, Stefanie, Fernandes, Noémia, Sivakumar, Ramiyapriya, Beilina, Alexandra, Billingsley, Kimberley J, Berghausen, Joos, Pantazis, Caroline B, Pitz, Vanessa, Patel, Dhairya, Daida, Kensuke, Meechoovet, Bessie, Reiman, Rebecca, Courtright-Lim, Amanda, Logemann, Amber, Antone, Jerry, Barch, Mariya, Kitchen, Robert, Li, Yan, Dalgard, Clifton L, Center, The American Genome, Rizzu, Patrizia, Hernandez, Dena G, Hjelm, Brooke E, Nalls, Mike, Gibbs, J Raphael, Finkbeiner, Steven, Cookson, Mark R, Van Keuren-Jensen, Kendall, Craig, David W, Singleton, Andrew B, Heutink, Peter, and Blauwendraat, Cornelis

Subjects
Biological Sciences, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research - Induced Pluripotent Stem Cell, Neurosciences, Stem Cell Research, Aging, Parkinson's Disease, Neurodegenerative, Brain Disorders, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, American Genome Center, Parkinson disease, dopaminergic neurons, genetic risk, induced pluripotent stem cell, omics single-cell RNA sequencing single-cell ATAC sequencing SNCA LRRK2 GBA1
Abstract

The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.

Published
2023

7. Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data

Author

Baloh, Robert H., Bowser, Robert, Brady, Christopher B., Brice, Alexis, Broach, James, Camu, William, Chia, Ruth, Chio, Adriano, Cooper-Knock, John, Cusi, Daniele, Ding, Jinhui, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Feldman, Eva, Floeter, Mary Kay, Fratta, Pietro, Gerhard, Glenn, Gibbs, J. Raphael, Gibson, Summer B., Glass, Jonathan D., Goutman, Stephen A., Hardy, John, Harms, Matthew B., Heiman-Patterson, Terry D., Jansson, Lilja, Kirby, Janine, Laaksovirta, Hannu, Landers, John E., Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, Guissart, Claire, MacGowan, Daniel JL., Maragakis, Nicholas J., Mora, Gabriele, Mouzat, Kevin, Myllykangas, Liisa, Orrell, Richard W., Ostrow, Lyle W., Pickering-Brown, Stuart, Pioro, Erik P., Pulst, Stefan M., Ravits, John M., Renton, Alan E., Robberecht, Wim, Rogaeva, Ekaterina, Rothstein, Jeffrey D., Salvi, Erika, Scholz, Sonja W., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Stone, David J., Tienari, Pentti J., Traynor, Bryan J., Trojanowski, John Q., Troncoso, Juan C., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, Angelocola, Stefania M., Ausiello, Francesco P., Barberis, Marco, Bartolomei, Ilaria, Battistini, Stefania, Bersano, Enrica, Bisogni, Giulia, Borghero, Giuseppe, Brunetti, Maura, Cabona, Corrado, Calvo, Andrea, Canale, Fabrizio, Canosa, Antonio, Cantisani, Teresa A., Capasso, Margherita, Caponnetto, Claudia, Cardinali, Patrizio, Carrera, Paola, Casale, Federico, Colletti, Tiziana, Conforti, Francesca L., Conte, Amelia, Conti, Elisa, Corbo, Massimo, Cuccu, Stefania, Bella, Eleonora Dalla, D'Errico, Eustachio, DeMarco, Giovanni, Dubbioso, Raffaele, Ferrarese, Carlo, Ferraro, Pilar M., Filippi, Massimo, Fini, Nicola, Floris, Gianluca, Fuda, Giuseppe, Gallone, Salvatore, Gianferrari, Giulia, Giannini, Fabio, Grassano, Maurizio, Greco, Lucia, Iazzolino, Barbara, Introna, Alessandro, La Bella, Vincenzo, Lattante, Serena, Lauria, Giuseppe, Liguori, Rocco, Logroscino, Giancarlo, Logullo, Francesco O., Lunetta, Christian, Mandich, Paola, Mandrioli, Jessica, Manera, Umberto, Manganelli, Fiore, Marangi, Giuseppe, Marinou, Kalliopi, Marrosu, Maria Giovanna, Martinelli, Ilaria, Messina, Sonia, Moglia, Cristina, Monsurrò, Maria Rosaria, Mosca, Lorena, Murru, Maria R., Origone, Paola, Passaniti, Carla, Petrelli, Cristina, Petrucci, Antonio, Pirisi, Angelo, Pozzi, Susanna, Pugliatti, Maura, Quattrini, Angelo, Ricci, Claudia, Riolo, Giulia, Riva, Nilo, Russo, Massimo, Sabatelli, Mario, Salamone, Paolina, Salivetto, Marco, Salvi, Fabrizio, Santarelli, Marialuisa, Sbaiz, Luca, Sideri, Riccardo, Simone, Isabella, Simonini, Cecilia, Spataro, Rossella, Tanel, Raffaella, Tedeschi, Gioacchino, Ticca, Anna, Torriello, Antonella, Tranquilli, Stefania, Tremolizzo, Lucio, Trojsi, Francesca, Vasta, Rosario, Vacchiano, Veria, Vita, Giuseppe, Volanti, Paolo, Zollino, Marcella, Zucchi, Elisabetta, Silani, Vincenzo, Fogh, Isabella, Ticozzi, Nicola, Ratti, Antonia, Tiloca, Cinzia, Peverelli, Silvia, Gellera, Cinzia, Pinter, Giuseppe Lauria, Taroni, Franco, Pensato, Viviana, Castellotti, Barbara, Comi, Giacomo P., Corti, Stefania, Del Bo, Roberto, Cereda, Cristina, Ceroni, Mauro, Gagliardi, Stella, Corrado, Lucia, Mazzini, Letizia, Sorarù, Gianni, Raggi, Flavia, Siciliano, Gabriele, Simoncini, Costanza, Lo Gerfo, Annalisa, Filosto, Massimiliano, Inghilleri, Maurizio, Ferlini, Alessandra, Corcia, Philippe, Couratier, Philippe, Vourc'h, Patrick, Hardiman, Orla, McLaughlin, Russell, Gotkine, Marc, Drory, Vivian, van den Veldink, Jan H., Berg, Leonard H., de Carvalho, Mamede, Mora Pardina, Jesus S., Povedano, Monica, Andersen, Peter, Weber, Markus, Başak, Ayşe Nazlı, Al-Chalabi, Ammar, Shaw, Chris, Morrison, Karen E., Adeleye, Adelani, Alba, Camille, Bacikova, Dagmar, Dalgard, Clifton L., Hupalo, Daniel N., McGrath Martinez, Elisa, Soltis, Anthony R., Sukumar, Gauthaman, Viollet, Coralie, Wilkerson, Matthew D., Saez-Atienzar, Sara, Souza, Cleide dos Santos, Beal, Selina N., Lorenzini, Ileana, Huang, Ruili, Levy, Jennifer, Burciu, Camelia, Jones, Ashley, Dewan, Ramita, van Vugt, Joke J.F.A., van Rheenen, Wouter, Tunca, Ceren, Bayraktar, Elif, Xia, Menghang, Iacoangeli, Alfredo, Shatunov, Aleksey, Verde, Federico, Kenna, Kevin, Al Khleifat, Ahmad, Opie-Martin, Sarah, Piccinelli, Stefano Cotti, Padovani, Alessandro, Galimberti, Daniela, Serpente, Maria, Fenoglio, Chiara, Scarpini, Elio, Curtis, Charles J., Lee, Sang Hyuck, Chung, Raymond, Patel, Hamel, Cooper-Knock, Johnathan, Breen, Gerome, Dobson, Richard J.B., van den Berg, Leonard H., D’Alfonso, Sandra, Chandran, Siddharthan, Pal, Suvankar, Johnson, Kory, Doucet-O’Hare, Tara, Pasternack, Nicholas, Wang, Tongguang, Nath, Avindra, Veldink, Jan H., Chiò, Adriano, Sattler, Rita, Shaw, Christopher E., and Ferraiuolo, Laura

Published
2024
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8. Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups.

Author

Kaivola, Karri, Shah, Zalak, Chia, Ruth, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian G, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J, Troakes, Claire, Albert, Marilyn S, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dalgard, Clifton L, Dawson, Ted M, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David S, Graff-Radford, Neill R, Kaufmann, Horacio, Kukull, Walter A, Leverenz, James B, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L, Palma, Jose Alberto, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Rosenthal, Liana S, Ross, Owen A, Scherzer, Clemens R, Serrano, Geidy E, Shakkottai, Vikram G, Sidransky, Ellen, Tanaka, Toshiko, Topol, Eric, Torkamani, Ali, Troncoso, Juan C, Woltjer, Randy, Wszolek, Zbigniew K, and Scholz, Sonja W

Subjects
Genetics, Lewy Body Dementia, Neurodegenerative, Aging, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Alzheimer's Disease, Acquired Cognitive Impairment, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Alzheimer Disease, Apolipoprotein E4, Genome-Wide Association Study, Humans, Lewy Body Disease, alpha-Synuclein, International LBD Genomics Consortium, APOE, Alzheimer’s disease, co-pathology, dementia with Lewy bodies, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 6.58 × 10-9, OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 × 10-32, OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

Published
2022

11. A Phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis

Author

Yazici, Y, McAlindon, TE, Gibofsky, A, Lane, NE, Lattermann, C, Skrepnik, N, Swearingen, CJ, Simsek, I, Ghandehari, H, DiFrancesco, A, Gibbs, J, Tambiah, JRS, and Hochberg, MC

Subjects
Clinical Trials and Supportive Activities, Aging, Pain Research, Clinical Research, Arthritis, Chronic Pain, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Musculoskeletal, Anti-Inflammatory Agents, Double-Blind Method, Female, Humans, Imidazoles, Indazoles, Injections, Intra-Articular, Male, Middle Aged, Osteoarthritis, Knee, Pain Measurement, Patient Reported Outcome Measures, Pyridines, Radiography, Clinical trial, Wnt pathway, Patient-reported outcomes, CLK2, DYRK1A, Knee pain, Biomedical Engineering, Clinical Sciences, Human Movement and Sports Sciences, Arthritis & Rheumatology
Abstract

ObjectiveLorecivivint (LOR; SM04690), an investigational Wnt pathway modulator, previously demonstrated patient-reported and radiographic outcome improvements vs placebo in clinically relevant subjects with moderate to severe knee osteoarthritis (OA). This study's objective was to identify effective LOR doses.DesignSubjects in this 24-week, Phase 2b, multicenter, randomized, double-blind, placebo (PBO)-controlled trial received an intra-articular injection of 2 mL LOR (0.03, 0.07, 0.15, or 0.23 mg), PBO, or dry-needle sham. The primary efficacy endpoints were changes in Pain NRS [0-10], WOMAC Pain [0-100], WOMAC Function [0-100], and radiographic mJSW outcomes, which were measured using baseline-adjusted analysis of covariance at Week 24. Multiple Comparison Procedure-Modeling (MCP-Mod) was performed for dose modeling.ResultsIn total, 695/700 subjects were treated. Pain NRS showed significant improvements vs PBO after treatment with 0.07 mg and 0.23 mg LOR at Weeks 12 (-0.96, 95% CI [-1.54, -0.37], P = 0.001; -0.78 [-1.39, -0.17], P = 0.012) and 24 (-0.70 [-1.34, -0.06], P = 0.031; -0.82 [-1.51, -0.12], P = 0.022). Additionally, 0.07 mg LOR significantly improved WOMAC Pain and Function subscores vs PBO at Week 12 (P = 0.04, P = 0.021), and 0.23 mg LOR significantly improved both WOMAC subscores at Week 24 (P = 0.031, P = 0.017). No significant differences from PBO were observed for other doses. No radiographic progression was observed in any group at Week 24. MCP-Mod identified 0.07 mg LOR as the lowest effective dose.ConclusionThis 24-week Phase 2b trial demonstrated the efficacy of LOR on PROs in knee OA subjects. The optimal dose for future studies was identified as 0.07 mg LOR.

Published
2021

12. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author

Soltis, Anthony R., Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, McGrath Martinez, Elisa, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., Dalgard, Clifton L., Black, Sandra E., Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A., Hodges, Angela K., Love, Seth, McKeith, Ian G., Morris, Christopher M., Morris, Huw R., Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J., Troakes, Claire, Albert, Marilyn S., Barrett, Matthew J., Beach, Thomas G., Bekris, Lynn M., Bennett, David A., Boeve, Bradley F., Dawson, Ted M., Dickson, Dennis W., Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E., Foroud, Tatiana M., Ghetti, Bernardino, Gibbs, J. Raphael, Goate, Alison, Goldstein, David S., Graff-Radford, Neill R., Kaufmann, Horacio, Kukull, Walter A., Leverenz, James B., Lopez, Grisel, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L., Palma, Jose-Alberto, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E., Resnick, Susan M., Rosenthal, Liana S., Ross, Owen A., Scherzer, Clemens R., Serrano, Geidy E., Shakkottai, Vikram G., Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Topol, Eric, Torkamani, Ali, Troncoso, Juan C., Woltjer, Randy, Wszolek, Zbigniew K., Scholz, Sonja W., Baloh, Robert H., Bowser, Robert, Broach, James, Camu, William, Chiò, Adriano, Cooper-Knock, John, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Feldman, Eva, Fratta, Pietro, Gerhard, Glenn, Gibson, Summer B., Glass, Jonathan D., Harms, Matthew B., Heiman-Patterson, Terry D., Jansson, Lilja, Kirby, Janine, Kwan, Justin, Laaksovirta, Hannu, Landers, John E., Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J.L., Maragakis, Nicholas J., Mouzat, Kevin, Myllykangas, Liisa, Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pioro, Erik, Pulst, Stefan M., Ravits, John M., Robberecht, Wim, Rothstein, Jeffrey D., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Stein, Thor, Stone, David J., Tienari, Pentti J., Traynor, Bryan J., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, 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, Tienari, Pentti, Mazzini, Letizia, D'Alfonso, Sandra, Moglia, Cristina, and De Jager, Philip L.

Published
2023
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14. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Author

Nalls, Mike A, Blauwendraat, Cornelis, Vallerga, Costanza L, Heilbron, Karl, Bandres-Ciga, Sara, Chang, Diana, Tan, Manuela, Kia, Demis A, Noyce, Alastair J, Xue, Angli, Bras, Jose, Young, Emily, von Coelln, Rainer, Simón-Sánchez, Javier, Schulte, Claudia, Sharma, Manu, Krohn, Lynne, Pihlstrøm, Lasse, Siitonen, Ari, Iwaki, Hirotaka, Leonard, Hampton, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Scholz, Sonja W, Botia, Juan A, Martinez, Maria, Corvol, Jean-Christophe, Lesage, Suzanne, Jankovic, Joseph, Shulman, Lisa M, Sutherland, Margaret, Tienari, Pentti, Majamaa, Kari, Toft, Mathias, Andreassen, Ole A, Bangale, Tushar, Brice, Alexis, Yang, Jian, Gan-Or, Ziv, Gasser, Thomas, Heutink, Peter, Shulman, Joshua M, Wood, Nicholas W, Hinds, David A, Hardy, John A, Morris, Huw R, Gratten, Jacob, Visscher, Peter M, Graham, Robert R, Singleton, Andrew B, Team, 23andMe Research, Consortium, System Genomics of Parkinson's Disease, Consortium, International Parkinson's Disease Genomics, Adarmes-Gómez, Astrid D, Aguilar, Miquel, Aitkulova, Akbota, Akhmetzhanov, Vadim, Alcalay, Roy N, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesús Alberto Bergareche, Bernal-Bernal, Inmaculada, Billingsley, Kimberley, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Brockmann, Kathrin, Bubb, Vivien, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Chelban, Viorica, Clarimón, Jordi, Clarke, Carl, Compta, Yaroslau, Cookson, Mark R, Craig, David W, Danjou, Fabrice, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Escott-Price, Valentina, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, and Finkbeiner, Steven

Subjects
Neurosciences, Parkinson's Disease, Brain Disorders, Aging, Biotechnology, Prevention, Genetics, Human Genome, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Databases, Genetic, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Parkinson Disease, Risk Factors, 23andMe Research Team, System Genomics of Parkinson's Disease Consortium, International Parkinson's Disease Genomics Consortium, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundGenome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease.MethodsWe did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation.FindingsBetween Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10-7).InterpretationThese data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data.FundingThe National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).

Published
2019

15. Deep learning cardiac motion analysis for human survival prediction

Author

Bello, Ghalib A., Dawes, Timothy J. W., Duan, Jinming, Biffi, Carlo, de Marvao, Antonio, Howard, Luke S. G. E., Gibbs, J. Simon R., Wilkins, Martin R., Cook, Stuart A., Rueckert, Daniel, and O'Regan, Declan P.

Subjects
Computer Science - Machine Learning, Computer Science - Computer Vision and Pattern Recognition, Statistics - Machine Learning
Abstract

Motion analysis is used in computer vision to understand the behaviour of moving objects in sequences of images. Optimising the interpretation of dynamic biological systems requires accurate and precise motion tracking as well as efficient representations of high-dimensional motion trajectories so that these can be used for prediction tasks. Here we use image sequences of the heart, acquired using cardiac magnetic resonance imaging, to create time-resolved three-dimensional segmentations using a fully convolutional network trained on anatomical shape priors. This dense motion model formed the input to a supervised denoising autoencoder (4Dsurvival), which is a hybrid network consisting of an autoencoder that learns a task-specific latent code representation trained on observed outcome data, yielding a latent representation optimised for survival prediction. To handle right-censored survival outcomes, our network used a Cox partial likelihood loss function. In a study of 302 patients the predictive accuracy (quantified by Harrell's C-index) was significantly higher (p < .0001) for our model C=0.73 (95$\%$ CI: 0.68 - 0.78) than the human benchmark of C=0.59 (95$\%$ CI: 0.53 - 0.65). This work demonstrates how a complex computer vision task using high-dimensional medical image data can efficiently predict human survival.

Published
2018
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16. The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease

Author

Bandres‐Ciga, Sara, Saez‐Atienzar, Sara, Bonet‐Ponce, Luis, Billingsley, Kimberley, Vitale, Dan, Blauwendraat, Cornelis, Gibbs, Jesse Raphael, Pihlstrøm, Lasse, Gan‐Or, Ziv, Noyce, Alastair J, Kaiyrzhanov, Rauan, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Morris, Huw R, Plun‐Favreau, Helene, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Bras, Jose, Quinn, John, Mok, Kin Y, Kinghorn, Kerri J, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, RņBibo, Lea, Manzoni, Claudia, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott‐Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean‐Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, SimɃn‐Sȥnchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Nicolas, Aude, Cookson, Mark R, Craig, David W, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Van Keuren‐Jensen, Kendall, Shulman, Joshua M, Iwaki, Hirotaka, Leonard, Hampton L, Nalls, Mike A, Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Reed, Xylena, Alcalay, Roy N, Rouleau, Guy A, Hilten, Jacobus J, Marinus, Johan, Adarmes‐GɃmez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesɐs Alberto Bergareche, Bernal‐Bernal, Inmaculada, Blazquez, Marta, Bonilla‐Toribio, Marta, Botȷa, Juan A, Boungiorno, Marȷa Teresa, Buiza‐Rueda, Dolores, Cȥmara, Ana, Carrillo, Fȥtima, CarriɃn‐Claro, Mario, Cerdan, Debora, ClarimɃn, Jordi, Compta, Yaroslau, Casa, Beatrȷz, Diez‐Fairen, Monica, Dols‐Icardo, Oriol, and Duarte, Jacinto

Subjects
Parkinson's Disease, Human Genome, Genetics, Neurosciences, Brain Disorders, Prevention, Neurodegenerative, Genetic Testing, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Aetiology, Decent Work and Economic Growth, Endocytosis, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Parkinson Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, International Parkinson's Disease Genomics Consortium, Parkinson's disease, endocytosis, genetic risk, heritability, polygenic risk score, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract

BackgroundPD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane-trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway-specific genetic risk factors is yet to be performed.ObjectivesTo comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD.MethodsLinkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane-trafficking pathway including genome-wide association studies data from 18,869 cases and 22,452 controls. We used pathway-specific single-nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow-up functional studies, summary-data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci.ResultsThe heritability estimate attributed to endocytic membrane-trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane-trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane-trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane-trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane-trafficking pathway genes showing functional consequence associated to PD risk.ConclusionsWe provide compelling genetic evidence that the endocytic membrane-trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to identify potential avenues within this biological process suitable for therapeutic interventions. © 2019 International Parkinson and Movement Disorder Society.

Published
2019

17. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author

Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia M, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stéphanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe GN, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, Ross, Robert V MacKenzie, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem H, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R, Treacy, Carmen M, Noordegraaf, Anton Vonk, Waisfisz, Quinten, and Walsworth, Anna K

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Genetics, Human Genome, Lung, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, HLA-DP alpha-Chains, HLA-DP beta-Chains, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Arterial Hypertension, Risk Assessment, SOXF Transcription Factors, Signal Transduction, Survival Analysis, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium, Public Health and Health Services, Other Medical and Health Sciences, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.InterpretationThis is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Published
2019

18. Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset

Author

Billingsley, Kimberley J, Barbosa, Ines A, Bandrés-Ciga, Sara, Quinn, John P, Bubb, Vivien J, Deshpande, Charu, Botia, Juan A, Reynolds, Regina H, Zhang, David, Simpson, Michael A, Blauwendraat, Cornelis, Gan-Or, Ziv, Gibbs, J Raphael, Nalls, Mike A, Singleton, Andrew, Ryten, Mina, and Koks, Sulev

Subjects
Aging, Brain Disorders, Neurosciences, Parkinson's Disease, Neurodegenerative, Genetics, 2.1 Biological and endogenous factors, Aetiology, Neurological, International Parkinson’s Disease Genomics Consortium, Medical genetics, Risk factors
Abstract

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson's disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial function-associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.

Published
2019

20. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Author

Gräf, Stefan, Haimel, Matthias, Bleda, Marta, Hadinnapola, Charaka, Southgate, Laura, Li, Wei, Hodgson, Joshua, Liu, Bin, Salmon, Richard M, Southwood, Mark, Machado, Rajiv D, Martin, Jennifer M, Treacy, Carmen M, Yates, Katherine, Daugherty, Louise C, Shamardina, Olga, Whitehorn, Deborah, Holden, Simon, Aldred, Micheala, Bogaard, Harm J, Church, Colin, Coghlan, Gerry, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Eyries, Mélanie, Gall, Henning, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Girerd, Barbara, Houweling, Arjan C, Howard, Luke, Humbert, Marc, Kiely, David G, Kovacs, Gabor, MacKenzie Ross, Robert V, Moledina, Shahin, Montani, David, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Peacock, Andrew J, Pepke-Zaba, Joanna, Prokopenko, Inga, Rhodes, Christopher J, Scelsi, Laura, Seeger, Werner, Soubrier, Florent, Stein, Dan F, Suntharalingam, Jay, Swietlik, Emilia M, Toshner, Mark R, van Heel, David A, Vonk Noordegraaf, Anton, Waisfisz, Quinten, Wharton, John, Wort, Stephen J, Ouwehand, Willem H, Soranzo, Nicole, Lawrie, Allan, Upton, Paul D, Wilkins, Martin R, Trembath, Richard C, and Morrell, Nicholas W

Subjects
Humans, Genetic Predisposition to Disease, Transforming Growth Factor beta, Membrane Transport Proteins, Prognosis, Case-Control Studies, Signal Transduction, Gene Expression Regulation, Base Sequence, Mutation, Models, Molecular, Adult, Female, Male, Aquaporin 1, Bone Morphogenetic Protein Receptors, Type II, Adenosine Triphosphatases, Growth Differentiation Factors, SOXF Transcription Factors, HEK293 Cells, Familial Primary Pulmonary Hypertension, Whole Genome Sequencing, Bone Morphogenetic Protein Receptors, Type II, Models, Molecular
Abstract

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Published
2018

23. Crop production in the USA is frequently limited by a lack of pollinators

Author

Reilly, J. R., Artz, D. R., Biddinger, D., Bobiwash, K., Boyle, N. K., Brittain, C., Brokaw, J., Campbell, J. W., Daniels, J., Elle, E., Ellis, J. D., Fleischer, S. J., Gibbs, J., Gillespie, R. L., Gundersen, K. B., Gut, L., Hoffman, G., Joshi, N., Lundin, O., Mason, K., McGrady, C. M., Peterson, S. S., Pitts-Singer, T. L., Rao, S., Rothwell, N., Rowe, L., Ward, K. L., Williams, N. M., Wilson, J. K., Isaacs, R., and Winfree, R.

Published
2020

25. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial

Author

Olschewski, H, Delcroix, M, Andrade-Lima, M, de Amorim Corrêac, R, Figueiredo Campos, F, Ota Arakaki, J, Meyer, G, De Souza, R, Langleben, D, Al-Hiti, H, Jansa, P, Mellemkjær, S, Bauer, F, Montani, D, Simonneau, G, Drömann, D, Ghofrani, H-A, Grünig, E, Halank, M, Held, M, Hoeper, MM, Klose, H, Kneidinger, N, Leuchte, H, Opitz, C, Rosenkranz, S, Wilkens, H, Wirtz, H, Karvounis, H, Pitsiou, G, Orfanos, S, D'Alto, M, Ghio, S, Vizza, CD, Vitulo, P, Nakayama, T, Maki, H, Tatebe, S, de los Rios Ibarra, M, Pulido, T, Van Dijk, A, Vonk-Noordegraaf, A, Roleder, T, Castro, G, Loureiro, MJ, Robalo-Martins, S, Barberá, JA, Lázaro, M, Perez-Penate, GM, Román, A, Cheng, C-C, Hsu, C-H, Hsu, H-H, Atahan, E, Mogulkoc Bishop, N, Okumus, NG, Onen, Z, Chang, H-J, Chang, S-A, Lee, J-S, Kim, H-K, Coghlan, JG, Corris, PA, Church, AC, Condliffe, R, Gibbs, JSR, Peacock, AJ, Wort, S, Allen, R, Allen, S, Awdish, R, Benza, RL, DeSouza, S, Feldman, J, Johri, S, Klinger, JR, Layish, D, McConnell, J, McLaughlin, VV, Migliore, C, Rahaghi, F, Rischard, F, Robbins, I, Satterwhite, L, Shah, T, Sulica, R, White, RJ, Hoeper, Marius M, Al-Hiti, Hikmet, Benza, Raymond L, Chang, Sung-A, Corris, Paul A, Gibbs, J Simon R, Grünig, Ekkehard, Jansa, Pavel, Klinger, James R, Langleben, David, McLaughlin, Vallerie V, Meyer, Gisela M B, Ota-Arakaki, Jaquelina, Peacock, Andrew J, Pulido, Tomás, Rosenkranz, Stephan, Vizza, Carmine Dario, Vonk-Noordegraaf, Anton, White, R James, Chang, Mikyung, Kleinjung, Frank, Meier, Christian, Paraschin, Karen, Ghofrani, Hossein Ardeschir, and Simonneau, Gérald

Published
2021
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26. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases.

Author

Witoelar, Aree, Jansen, Iris E, Wang, Yunpeng, Desikan, Rahul S, Gibbs, J Raphael, Blauwendraat, Cornelis, Thompson, Wesley K, Hernandez, Dena G, Djurovic, Srdjan, Schork, Andrew J, Bettella, Francesco, Ellinghaus, David, Franke, Andre, Lie, Benedicte A, McEvoy, Linda K, Karlsen, Tom H, Lesage, Suzanne, Morris, Huw R, Brice, Alexis, Wood, Nicholas W, Heutink, Peter, Hardy, John, Singleton, Andrew B, Dale, Anders M, Gasser, Thomas, Andreassen, Ole A, Sharma, Manu, and International Parkinson’s Disease Genomics Consortium (IPDGC), North American Brain Expression Consortium (NABEC), and United Kingdom Brain Expression Consortium (UKBEC) Investigators

Subjects
International Parkinson’s Disease Genomics Consortium (IPDGC), North American Brain Expression Consortium (NABEC), and United Kingdom Brain Expression Consortium (UKBEC) Investigators, Humans, Arthritis, Rheumatoid, Colitis, Ulcerative, Crohn Disease, Celiac Disease, Multiple Sclerosis, Parkinson Disease, Psoriasis, Diabetes Mellitus, Type 1, Autoimmune Diseases, Genetic Predisposition to Disease, Risk Factors, Genome-Wide Association Study, Genetic Loci, Genetic Pleiotropy, Prevention, Neurosciences, Brain Disorders, Digestive Diseases, Autoimmune Disease, Aging, Arthritis, Biotechnology, Neurodegenerative, Parkinson's Disease, Genetics, Human Genome, Inflammatory Bowel Disease, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Neurological, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ImportanceRecent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes.ObjectivesTo test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach.Design, setting, and participantsUsing the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017.Main outcomes and measuresThe primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases.ResultsGenome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes.Conclusions and relevanceThe study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

Published
2017

27. Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study

Author

Mok, Kin Y., Murphy, David P., Al-Sarraj, Safa, Troakes, Claire, Gentleman, Steve M., Allinson, Kieren S.J., Jaunmuktane, Zane, Holton, Janice L., Lees, Andrew J., Morris, Christopher M., Compta, Yaroslau, Gelpi, Ellen, van Swieten, John C., Rajput, Alex, Ferguson, Leslie, Cookson, Mark R., Gibbs, J. Raphael, Blauwendraat, Cornelis, Ding, Jinhui, Chia, Ruth, Traynor, Bryan J., Pantelyat, Alexander, Viollet, Coralie, Pletnikova, Olga, Troncoso, Juan C., Rosenthal, Liana S., Boxer, Adam L., Respondek, Gesine, Arzberger, Thomas, Roeber, Sigrun, Giese, Armin, Burn, David J., Pavese, Nicola, Gerhard, Alexander, Kobylecki, Christopher, Leigh, P. Nigel, Church, Alistair, T.M. Hu, Michele, Jabbari, Edwin, Koga, Shunsuke, Valentino, Rebecca R, Reynolds, Regina H, Ferrari, Raffaele, Tan, Manuela M X, Rowe, James B, Dalgard, Clifton L, Scholz, Sonja W, Dickson, Dennis W, Warner, Thomas T, Revesz, Tamas, Höglinger, Günter U, Ross, Owen A, Ryten, Mina, Hardy, John, Shoai, Maryam, and Morris, Huw R

Published
2021
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28. A Systematic Scoping Review of Indigenous People's Experience of Healing and Recovery from Child Sexual Abuse.

Author

Gibbs, J, Milroy, H, Mulder, S, Black, C, Lloyd-Johnsen, C, Brown, S, Gee, G, Gibbs, J, Milroy, H, Mulder, S, Black, C, Lloyd-Johnsen, C, Brown, S, and Gee, G

Abstract

Child sexual abuse is a form of violence that occurs across nations and cultures. Collective efforts are being made to address this issue within many Indigenous communities. In Australia, Aboriginal and Torres Strait Islander communities have expressed the need for cultural models of healing child sexual abuse. A preliminary exploration of the relevant literature shows a lack of synthesis with regard to the current evidence base. This protocol outlines the methods and background for a scoping review that aims to explore and collate the broad scope of literature related to healing from child sexual abuse within an Indigenous context. The proposed review utilises a 'population, concept, and context structure' from the Joanna Briggs Institute to explore the broad scope of the literature within a scoping review framework. The target population is Indigenous survivors of child sexual abuse, including Indigenous populations from six distinct regions: Aboriginal and Torres Strait Islander peoples from Australia; Māori peoples from Aotearoa (New Zealand); First Nations, Inuit and Métis peoples from Canada; Native American peoples from North America; Native peoples from Alaska; and the Sámi peoples of the Sápmi region in Northern Europe. The concept within the review is healing from an Indigenous perspective, which includes a broad range of processes related to both recovery and personal growth. The contexts explored within this review are any context in which healing from child sexual abuse can occur. This may include processes related to disclosure and accessing services, specific interventions or programs for survivors of child sexual abuse, as well as broader non-specific healing programs and personal experiences of healing without intervention. The scoping review will use search strings with broad inclusion and exclusion criteria to capture the potential breadth of perspectives. The search will be conducted across several academic databases and will also include an exte

Published
2024

29. Expression quantitative trait loci in human brain tissues

Author

Gibbs, J. R.

Subjects
612.8
Abstract

To what extent genetic variability influences gene expression in human primary tissues is a critical question in molecular genetics. Work investigating this phenomenon is not only interesting biologically, but also has the potential to provide mechanistic insight into traits, including disease. The past decade has seen tremendous progress in this field, and this thesis includes a description of work that spanned from the relatively early stages of this type of work, to current, more refined efforts. This work sought to ask three questions: first, are eQTL detectable in brain tissues using whole genome methods; second, are eQTL measurably different in different parts of the brain; and third, does the investigation of eQTL in a particular neuronal cell type offer significant advantages over similar studies in tissue with a mixed cellular composition. In the first part of this work, I present a pilot study aimed at assessing the feasibility of eQTL detection in brain tissue. This study showed that the use of genome wide genotyping and expression arrays revealed a number of significant eQTL, and that in general, when genetic variability was associated with expression, the genetic locus and the expressed transcript were physically close. This work was then expanded to assess eQTL in multiple brain regions, with an attempt to assess whether eQTL were measurably different between distinct brain regions. In this work, tissue from cerebral frontal cortex, cerebral temporal cortex, caudal pons, and cerebellum was used. The analysis showed that there are region-specific eQTL, but that many of the strongest eQTL were present in multiple tissues. Lastly, I show using data from laser capture microdissected Purkinje cells that additional cell-type specific eQTL may be found that are not revealed when performing eQTL in heterogeneous tissue containing this cell type. In summary this work initially revealed the feasibility of eQTL work in human brain, showed that eQTL were measurably different, but generally similar across varied brain tissues, and showed that there are likely several advantages in pursuing single cell type work in tandem with whole tissue efforts.

Published
2016

30. Idiopathic pulmonary arterial hypertension phenotypes determined by cluster analysis from the COMPERA registry

Author

Hoeper, Marius M., Pausch, Christine, Grünig, Ekkehard, Klose, Hans, Staehler, Gerd, Huscher, Doerte, Pittrow, David, Olsson, Karen M., Vizza, Carmine Dario, Gall, Henning, Benjamin, Nicola, Distler, Oliver, Opitz, Christian, Gibbs, J. Simon R., Delcroix, Marion, Ghofrani, H. Ardeschir, Rosenkranz, Stephan, Ewert, Ralf, Kaemmerer, Harald, Lange, Tobias J., Kabitz, Hans-Joachim, Skowasch, Dirk, Skride, Andris, Jureviciene, Elena, Paleviciute, Egle, Miliauskas, Skaidrius, Claussen, Martin, Behr, Juergen, Milger, Katrin, Halank, Michael, Wilkens, Heinrike, Wirtz, Hubert, Pfeuffer-Jovic, Elena, Harbaum, Lars, Scholtz, Werner, Dumitrescu, Daniel, Bruch, Leonhard, Coghlan, Gerry, Neurohr, Claus, Tsangaris, Iraklis, Gorenflo, Matthias, Scelsi, Laura, Vonk-Noordegraaf, Anton, Ulrich, Silvia, and Held, Matthias

Published
2020
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31. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

Author

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., and Scholz, Sonja W.

Published
2021
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36. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Author

Adarmes-Gómez, Astrid D, Aguilar, Miquel, Aitkulova, Akbota, Akhmetzhanov, Vadim, Alcalay, Roy N, Alvarez, Ignacio, Alvarez, Victoria, Bandres-Ciga, Sara, Barrero, Francisco Javier, Bergareche Yarza, Jesús Alberto, Bernal-Bernal, Inmaculada, Billingsley, Kimberley, Blauwendraat, Cornelis, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Bras, Jose, Brice, Alexis, Brockmann, Kathrin, Bubb, Vivien, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Chelban, Viorica, Clarimón, Jordi, Clarke, Carl, Compta, Yaroslau, Cookson, Mark R, Corvol, Jean-Christophe, Craig, David W, Danjou, Fabrice, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Escott-Price, Valentina, Ezquerra, Mario, Faghri, Faraz, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Finkbeiner, Steven, Foltynie, Thomas, Gan-Or, Ziv, Garcia, Ciara, García-Ruiz, Pedro, Gasser, Thomas, Gibbs, J Raphael, Gomez Heredia, Maria Jose, Gómez-Garre, Pilar, González, Manuel Menéndez, Gonzalez-Aramburu, Isabel, Guelfi, Sebastian, Guerreiro, Rita, Hardy, John, Hassin-Baer, Sharon, Hernandez, Dena G, Heutink, Peter, Hoenicka, Janet, Holmans, Peter, Houlden, Henry, Infante, Jon, Iwaki, Hirotaka, Jesús, Silvia, Jimenez-Escrig, Adriano, Kaishybayeva, Gulnaz, Kaiyrzhanov, Rauan, Karimova, Altynay, Kia, Demis A, Kinghorn, Kerri J, Koks, Sulev, Krohn, Lynne, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A, Leonard, Hampton L, Lesage, Suzanne, Lewis, Patrick, Lopez-Sendon, Jose Luis, Lovering, Ruth, Lubbe, Steven, Lungu, Codrin, Macias, Daniel, Majamaa, Kari, Manzoni, Claudia, Marín, Juan, Marinus, Johan, Marti, Maria Jose, Martinez, Maria, Martínez Torres, Irene, Martínez-Castrillo, Juan Carlos, Mata, Marina, Mencacci, Niccolo E, Méndez-del-Barrio, Carlota, Middlehurst, Ben, Mínguez, Adolfo, Mir, Pablo, Mok, Kin Y, Morris, Huw R, Muñoz, Esteban, Nalls, Mike A, Narendra, Derek, Noyce, Alastair J, Ojo, Oluwadamilola O, Okubadejo, Njideka U, Pagola, Ana Gorostidi, Pastor, Pau, Perez Errazquin, Francisco, Periñán-Tocino, Teresa, Pihlstrom, Lasse, Plun-Favreau, Helene, Quinn, John, R'Bibo, Lea, Reed, Xylena, Rezola, Elisabet Mondragon, Rizig, Mie, Rizzu, Patrizia, Robak, Laurie, Rodriguez, Antonio Sanchez, Rouleau, Guy A, Ruiz-Martínez, Javier, Ruz, Clara, Ryten, Mina, Sadykova, Dinara, Scholz, Sonja W, Schreglmann, Sebastian, Schulte, Claudia, Sharma, Manu, Shashkin, Chingiz, Shulman, Joshua M, Sierra, María, Siitonen, Ari, Simón-Sánchez, Javier, Singleton, Andrew B, Suarez-Sanmartin, Esther, Taba, Pille, Tabernero, Cesar, Tan, Manuela X, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Toft, Mathias, Tolosa, Eduard, Trabzuni, Daniah, Valldeoriola, Francesc, van Hilten, Jacobus J, Van Keuren-Jensen, Kendall, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Williams, Nigel, Wood, Nicholas W, Zharkinbekova, Nazira, Zharmukhanov, Zharkyn, Zholdybayeva, Elena, Zimprich, Alexander, Ylikotila, Pauli, Shulman, Lisa M., von Coelln, Rainer, Reich, Stephen, Savitt, Joseph, Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Huber, Karen E., Hicks, Barry, Jewett, Ethan M., Jiang, Yunxuan, Kleinman, Aaron, Lin, Keng-Han, Litterman, Nadia K., McCreight, Jennifer C., McIntyre, Matthew H., McManus, Kimberly F., Mountain, Joanna L., Noblin, Elizabeth S., Northover, Carrie A.M., Pitts, Steven J., Poznik, G. David, Sathirapongsasuti, J. Fah, Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce, Vacic, Vladimir, Wang, Xin, Wilson, Catherine H., Anderson, Tim, Bentley, Steven, Dalrymple-Alford, John, Fowdar, Javed, Gratten, Jacob, Halliday, Glenda, Henders, Anjali K., Hickie, Ian, Kassam, Irfahan, Kennedy, Martin, Kwok, John, Lewis, Simon, Mellick, George, Montgomery, Grant, Pearson, John, Pitcher, Toni, Sidorenko, Julia, Silburn, Peter A., Vallerga, Costanza L., Visscher, Peter M., Wallace, Leanne, Wray, Naomi R., Xue, Angli, Yang, Jian, Zhang, Futao, Vallerga, Costanza L, Heilbron, Karl, Chang, Diana, Tan, Manuela, Young, Emily, Pihlstrøm, Lasse, Leonard, Hampton, Botia, Juan A, Jankovic, Joseph, Shulman, Lisa M, Sutherland, Margaret, Tienari, Pentti, Andreassen, Ole A, Bangale, Tushar, Hinds, David A, Hardy, John A, Visscher, Peter M, and Graham, Robert R

Published
2019
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38. Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study

Author

Nalls, Mike A, McLean, Cory Y, Rick, Jacqueline, Eberly, Shirley, Hutten, Samantha J, Gwinn, Katrina, Sutherland, Margaret, Martinez, Maria, Heutink, Peter, Williams, Nigel M, Hardy, John, Gasser, Thomas, Brice, Alexis, Price, T Ryan, Nicolas, Aude, Keller, Margaux F, Molony, Cliona, Gibbs, J Raphael, Chen-Plotkin, Alice, Suh, Eunran, Letson, Christopher, Fiandaca, Massimo S, Mapstone, Mark, Federoff, Howard J, Noyce, Alastair J, Morris, Huw, Van Deerlin, Vivianna M, Weintraub, Daniel, Zabetian, Cyrus, Hernandez, Dena G, Lesage, Suzanne, Mullins, Meghan, Conley, Emily Drabant, Northover, Carrie AM, Frasier, Mark, Marek, Ken, Day-Williams, Aaron G, Stone, David J, Ioannidis, John PA, Singleton, Andrew B, and investigators*, Parkinson's Disease Biomarkers Program and Parkinson's Progression Marker Initiative

Subjects
Aging, Prevention, Neurodegenerative, Brain Disorders, Neurosciences, Parkinson's Disease, Clinical Research, 2.1 Biological and endogenous factors, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Good Health and Well Being, Aged, Cohort Studies, Disease Progression, Female, Humans, Male, Middle Aged, Models, Statistical, Parkinson Disease, Prodromal Symptoms, Parkinson's Disease Biomarkers Program and Parkinson's Progression Marker Initiative investigators, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundAccurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts.MethodsWe developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD).FindingsIn the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900-0·946) with high sensitivity (0·834, 95% CI 0·711-0·883) and specificity (0·903, 95% CI 0·824-0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867-0·921) in the PDBP cohort, 0·998 (0·992-1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896-0·962) in LABS-PD, and 0·939 (0·891-0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003).InterpretationOur model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions.FundingNational Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.

Published
2015

39. A Genome-Wide Association Study of Myasthenia Gravis

Author

Renton, Alan E, Pliner, Hannah A, Provenzano, Carlo, Evoli, Amelia, Ricciardi, Roberta, Nalls, Michael A, Marangi, Giuseppe, Abramzon, Yevgeniya, Arepalli, Sampath, Chong, Sean, Hernandez, Dena G, Johnson, Janel O, Bartoccioni, Emanuela, Scuderi, Flavia, Maestri, Michelangelo, Gibbs, J Raphael, Errichiello, Edoardo, Chiò, Adriano, Restagno, Gabriella, Sabatelli, Mario, Macek, Mark, Scholz, Sonja W, Corse, Andrea, Chaudhry, Vinay, Benatar, Michael, Barohn, Richard J, McVey, April, Pasnoor, Mamatha, Dimachkie, Mazen M, Rowin, Julie, Kissel, John, Freimer, Miriam, Kaminski, Henry J, Sanders, Donald B, Lipscomb, Bernadette, Massey, Janice M, Chopra, Manisha, Howard, James F, Koopman, Wilma J, Nicolle, Michael W, Pascuzzi, Robert M, Pestronk, Alan, Wulf, Charlie, Florence, Julaine, Blackmore, Derrick, Soloway, Aimee, Siddiqi, Zaeem, Muppidi, Srikanth, Wolfe, Gil, Richman, David, Mezei, Michelle M, Jiwa, Theresa, Oger, Joel, Drachman, Daniel B, and Traynor, Bryan J

Subjects
Rare Diseases, Genetics, Neurosciences, Autoimmune Disease, Myasthenia Gravis, Clinical Research, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Adult, Age of Onset, CTLA-4 Antigen, Case-Control Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, HLA-DQ alpha-Chains, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, United States, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ImportanceMyasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood.ObjectiveTo identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study.Design, setting, and participantsDNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication.Main outcomes and measuresWe calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing.ResultsIn the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases.Conclusions and relevanceOur genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

Published
2015

40. Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes

Author

Wood, Andrew R, Tuke, Marcus A, Nalls, Mike, Hernandez, Dena, Gibbs, J Raphael, Lin, Haoxiang, Xu, Christopher S, Li, Qibin, Shen, Juan, Jun, Goo, Almeida, Marcio, Tanaka, Toshiko, Perry, John RB, Gaulton, Kyle, Rivas, Manny, Pearson, Richard, Curran, Joanne E, Johnson, Matthew P, Göring, Harald HH, Duggirala, Ravindranath, Blangero, John, Mccarthy, Mark I, Bandinelli, Stefania, Murray, Anna, Weedon, Michael N, Singleton, Andrew, Melzer, David, Ferrucci, Luigi, and Frayling, Timothy M

Subjects
Clinical Research, Human Genome, Genetics, Detection, screening and diagnosis, Aetiology, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Adult, Aged, Aged, 80 and over, Female, Gene Frequency, Genetic Association Studies, Genetic Markers, Genetic Variation, Genome, Human, Genotyping Techniques, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Young Adult, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Initial results from sequencing studies suggest that there are relatively few low-frequency (

Published
2015

41. NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases

Author

Nalls, Mike A, Bras, Jose, Hernandez, Dena G, Keller, Margaux F, Majounie, Elisa, Renton, Alan E, Saad, Mohamad, Jansen, Iris, Guerreiro, Rita, Lubbe, Steven, Plagnol, Vincent, Gibbs, J Raphael, Schulte, Claudia, Pankratz, Nathan, Sutherland, Margaret, Bertram, Lars, Lill, Christina M, DeStefano, Anita L, Faroud, Tatiana, Eriksson, Nicholas, Tung, Joyce Y, Edsall, Connor, Nichols, Noah, Brooks, Janet, Arepalli, Sampath, Pliner, Hannah, Letson, Chris, Heutink, Peter, Martinez, Maria, Gasser, Thomas, Traynor, Bryan J, Wood, Nick, Hardy, John, Singleton, Andrew B, Consortium, International Parkinson's Disease Genomics, and consortium, Parkinson's Disease meta-analysis

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Genetics, Genetic Testing, Human Genome, Neurodegenerative, Clinical Research, Rare Diseases, Alleles, Costs and Cost Analysis, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotyping Techniques, Neurodegenerative Diseases, Oligonucleotide Array Sequence Analysis, Genotyping, Methods, Neurodegeneration, Parkinson's, Meta-analysis, Imputation, International Parkinson's Disease Genomics Consortium, Parkinson's Disease meta-analysis consortium, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted to make the content of the platform open to any investigator without restriction. In designing this array we prioritized a number of types of genetic variability for inclusion, such as known risk alleles, disease-causing mutations, putative risk alleles, and other functionally important variants. The array was primarily designed to allow rapid screening of samples for disease-causing mutations and large population studies of risk factors. Notably, an explicit aim was to make this array widely available to facilitate data sharing across and within diseases. The resulting array, NeuroX, is a remarkably cost and time effective solution for high-quality genotyping. NeuroX comprises a backbone of standard Illumina exome content of approximately 240,000 variants, and over 24,000 custom content variants focusing on neurologic diseases. Data are generated at approximately $50-$60 per sample using a 12-sample format chip and regular Infinium infrastructure; thus, genotyping is rapid and accessible to many investigators. Here, we describe the design of NeuroX, discuss the utility of NeuroX in the analyses of rare and common risk variants, and present quality control metrics and a brief primer for the analysis of NeuroX derived data.

Published
2015

42. New Young Star Candidates in BRC 27 and BRC 34

Author

Rebull, L. M., Johnson, C. H., Gibbs, J. C., Linahan, M., Sartore, D., Laher, R., Legassie, M., Armstrong, J. D., Allen, L. E., McGehee, P., Padgett, D. L., Aryal, S., Badura, K. S., Canakapalli, T. S., Carlson, S., Clark, M., Ezyk, N., Fagan, J., Killingstad, N., Koop, S., McCanna, T., Nishida, M. M., Nuthmann, T. R., O'Bryan, A., PUllinger, A., Rameswaram, A., Ravelomanantsoa, T., Sprow, H., and Tilley, C. M.

Subjects
Astrophysics - Solar and Stellar Astrophysics
Abstract

We used archival Spitzer Space Telescope mid-infrared data to search for young stellar objects (YSOs) in the immediate vicinity of two bright-rimmed clouds, BRC 27 (part of CMa R1) and BRC 34 (part of the IC 1396 complex). These regions both appear to be actively forming young stars, perhaps triggered by the proximate OB stars. In BRC 27, we find clear infrared excesses around 22 of the 26 YSOs or YSO candidates identified in the literature, and identify 16 new YSO candidates that appear to have IR excesses. In BRC 34, the one literature-identified YSO has an IR excess, and we suggest 13 new YSO candidates in this region, including a new Class I object. Considering the entire ensemble, both BRCs are likely of comparable ages, within the uncertainties of small number statistics and without spectroscopy to confirm or refute the YSO candidates. Similarly, no clear conclusions can yet be drawn about any possible age gradients that may be present across the BRCs., Comment: 54 pages, 19 figures, accepted by AJ

Published
2012
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43. How do we measure unmet need within sexual and reproductive health? A systematic review.

Author

Solomon, D, Cabecinha, M, Gibbs, J, Burns, F, and Sabin, CA

Abstract

Background: Addressing health inequality with sexual and reproductive health requires an understanding of unmet need within a range of populations. This review examined the methods and definitions that have been used to measure unmet need, and the populations most frequently assessed. Methods: Five databases (PubMed, Web of Science, Scopus, The Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Health Management and Policy Database (HMIC)) were searched for studies that described quantitative measurement of unmet need within sexual and/or reproductive health between 2010 and 2021. A narrative synthesis was then undertaken to ascertain themes within the literature. Results: The database search yielded 19,747 papers; 216 papers were included after screening. 190 studies assessed unmet reproductive health need, of which 137 were analyses of trends among people living in low/lower-middle income countries; 181 used cross-sectional data, with only nine analyses being longitudinal. Eighteen studies analysed unmet sexual health need, of which 12 focused on high and upper-middle income populations. 16 papers used cross-sectional analyses. The remaining 10 studies examined unmet need for a combination of sexual and reproductive health services, eight among populations from upper-middle or high income countries. All were cross-sectional analyses. 165 studies used the Demographic and Health Surveys (DHS) definition of unmet need; no other standardised definition was used among the remaining papers. Discussion: There is a significant focus on unmet need for contraception among women in low income countries within the published literature, leaving considerable evidence gaps in relation to unmet need within sexual health generally and among men in particular, and unmet reproductive health need in high income settings. In addition, using an increased range of data collection methods, analyses and definitions of unmet need would enable better understanding of health inequality in this area. [ABSTRACT FROM AUTHOR]

Published
2024
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45. Long‐Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease

Author

Daida, Kensuke, primary, Funayama, Manabu, additional, Billingsley, Kimberley J., additional, Malik, Laksh, additional, Miano‐Burkhardt, Abigail, additional, Leonard, Hampton L., additional, Makarious, Mary B., additional, Iwaki, Hirotaka, additional, Ding, Jinhui, additional, Gibbs, J. Raphael, additional, Ishiguro, Mayu, additional, Yoshino, Hiroyo, additional, Ogaki, Kotaro, additional, Oyama, Genko, additional, Nishioka, Kenya, additional, Nonaka, Risa, additional, Akamatsu, Wado, additional, Blauwendraat, Cornelis, additional, and Hattori, Nobutaka, additional

Published
2023
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46. Long-Term Effects of Sotatercept on Right Ventricular Function

Author

Gomberg-Maitland, Mardi, primary, McLaughlin, Vallerie V., additional, Badesch, David B., additional, Ghofrani, Hossein-Ardeschir, additional, Hoeper, Marius M., additional, Humbert, Marc, additional, Preston, Ioana R., additional, Souza, Rogerio, additional, Waxman, Aaron B., additional, de Oliveira Pena, Janethe, additional, Lu, Jonathan T., additional, Manimaran, Solaiappan, additional, and Gibbs, J. Simon R., additional

Published
2023
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47. Late Breaking Abstract - A long-term follow-up (LTFU) study of sotatercept for pulmonary arterial hypertension (PAH)

Author

Preston, Ioana R, primary, Badesch, David, additional, Ghofrani, Hossein-Ardeschir, additional, Gibbs, J. Simon R., additional, Gomberg-Maitland, Mardi, additional, Hoeper, Marius M., additional, Humbert, Marc, additional, Mclaughlin, Vallerie V., additional, Waxman, Aaron B., additional, Manimaran, Solaiappan, additional, Mikhailova, Elina, additional, De Oliveira Pena, Janethe, additional, and De Souza, Rogerio, additional

Published
2023
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48. Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial

Author

Souza, Rogerio, primary, Badesch, David B., additional, Ghofrani, H. Ardeschir, additional, Gibbs, J. Simon R., additional, Gomberg-Maitland, Mardi, additional, McLaughlin, Vallerie V., additional, Preston, Ioana R., additional, Waxman, Aaron B., additional, Grünig, Ekkehard, additional, Kopeć, Grzegorz, additional, Meyer, Gisela, additional, Olsson, Karen M., additional, Rosenkranz, Stephan, additional, Lin, Jianxin, additional, Johnson-Levonas, Amy O., additional, de Oliveira Pena, Janethe, additional, Humbert, Marc, additional, and Hoeper, Marius M., additional

Published
2023
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