Genome sequence analyses identify novel risk loci for multiple system atrophy
Por:
Chia, R, Ray, A, Shah, Z, Ding, J, Ruffo, P, Fujita, M, Menon, V, Saez-Atienzar, S, Reho, P, Kaivola, K, Walton, RL, Reynolds, RH, Karra, R, Sait, S, Akcimen, F, Diez-Fairen, M, Alvarez, I, Fanciulli, A, Stefanova, N, Seppi, K, Duerr, S, Leys, F, Krismer, F, Sidoroff, V, Zimprich, A, Pirker, W, Rascol, O, Foubert-Samier, A, Meissner, WG, Tison, F, Pavy-Le Traon, A, Pellecchia, MT, Barone, P, Russillo, MC, Marín-Lahoz, J, Kulisevsky, J, Torres, S, Mir, P, Periñán, MT, Proukakis, C, Chelban, V, Wu, L, Goh, YY, Parkkinen, L, Hu, MT, Kobylecki, C, Saxon, JA, Rollinson, S, Garland, E, Biaggioni, I, Litvan, I, Rubio, I, Alcalay, RN, Kwei, KT, Lubbe, SJ, Mao, QW, Flanagan, ME, Castellani, RJ, Khurana, V, Ndayisaba, A, Calvo, A, Mora, G, Canosa, A, Floris, G, Bohannan, RC, Moore, A, Norcliffe-Kaufmann, L, Palma, JA, Kaufmann, H, Kim, C, Iba, M, Masliah, E, Dawson, TM, Rosenthal, LS, Pantelyat, A, Albert, MS, Pletnikova, O, Troncoso, JC, Infante, J, Lage, C, Sánchez-Juan, P, Serrano, GE, Beach, TG, Pastor, P, Morris, HR, Albani, D, Clarimon, J, Wenning, GK, Hardy, JA, Ryten, M, Topol, E, Torkamani, A, Chio, A, Bennett, DA, De Jager, PL, Low, PA, Singer, W, Cheshire, WP, Wszolek, ZK, Dickson, DW, Traynor, BJ, Gibbs, JR, Dalgard, CL, Ross, OA, Houlden, H, Scholz, SW
Publicada:
3 jul 2024
Resumen:
Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study high-lights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.
Filiaciones:
Chia, R:
NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD USA
Ray, A:
NINDS, Neurodegenerat Dis Res Unit, Bethesda, MD 20892 USA
Shah, Z:
NINDS, Neurodegenerat Dis Res Unit, Bethesda, MD 20892 USA
Ding, J:
NIA, Computat Biol Grp, Lab Neurogenet, Bethesda, MD USA
Ruffo, P:
NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD USA
Univ Calabria, Dept Pharm Hlth & Nutr Sci, Med Genet Lab, Arcavacata Di Rende, Italy
Fujita, M:
Columbia Univ, Ctr Translat & Computat Neuroimmunol, Dept Neurol, Irving Med Ctr, New York, NY USA
Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA
Menon, V:
Columbia Univ, Ctr Translat & Computat Neuroimmunol, Dept Neurol, Irving Med Ctr, New York, NY USA
Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA
Saez-Atienzar, S:
NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD USA
Reho, P:
NINDS, Neurodegenerat Dis Res Unit, Bethesda, MD 20892 USA
Kaivola, K:
NINDS, Neurodegenerat Dis Res Unit, Bethesda, MD 20892 USA
Walton, RL:
Mayo Clin, Dept Neurosci, Jacksonville, FL USA
Reynolds, RH:
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England
UCL, Great Ormond St Inst Child Hlth, Genet & Genom Med, London, England
UCL, Dept Neurodegenerat Dis, UCL Queen Sq Inst Neurol, London, England
Karra, R:
NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD USA
Sait, S:
NINDS, Neurodegenerat Dis Res Unit, Bethesda, MD 20892 USA
Akcimen, F:
NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD USA
Diez-Fairen, M:
Univ Hosp Mutua Terrassa, Dept Neurol, Memory & Movement Disorders Units, Barcelona, Spain
Alvarez, I:
Univ Hosp Mutua Terrassa, Dept Neurol, Memory & Movement Disorders Units, Barcelona, Spain
Fanciulli, A:
Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria
Stefanova, N:
Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria
Seppi, K:
Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria
Duerr, S:
Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria
Leys, F:
Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria
Krismer, F:
Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria
Sidoroff, V:
Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria
Zimprich, A:
Med Univ Vienna, Dept Neurol, Vienna, Austria
Pirker, W:
Klin Ottakring Wilhelminenspital, Dept Neurol, Vienna, Austria
Rascol, O:
Univ Toulouse, MSA French Reference Ctr, Toulouse, France
Univ Toulouse, Dept Clin Pharmacol & Neurosci, CIC 1436, Toulouse, France
Foubert-Samier, A:
CHU Bordeaux, Serv Neurol Malad Neurodegenerat, French Reference Ctr MSA, NS Pk FCRIN Network, Bordeaux, France
Meissner, WG:
CHU Bordeaux, Serv Neurol Malad Neurodegenerat, French Reference Ctr MSA, NS Pk FCRIN Network, Bordeaux, France
Univ Bordeaux, IMN, CNRS, UMR 5293, Bordeaux, France
Univ Otago, Dept Med, Christchurch, New Zealand
New Zealand Brain Res Inst, Christchurch, New Zealand
Tison, F:
CHU Bordeaux, Serv Neurol Malad Neurodegenerat, French Reference Ctr MSA, NS Pk FCRIN Network, Bordeaux, France
Univ Bordeaux, IMN, CNRS, UMR 5293, Bordeaux, France
Pavy-Le Traon, A:
Univ Hosp Toulouse, Ctr Invest Clin Toulouse CIC1436, Dept Neurosci,French Reference Ctr MSA, UMR 1048,Inst Cardiovasc & Metab Dis I2MC,INSERM, Toulouse, France
Pellecchia, MT:
Univ Salerno, Dept Med Surg & Dent, Neurosci Sect, Scuola Med Salernitana, Salerno, Italy
Barone, P:
Univ Salerno, Dept Med Surg & Dent, Neurosci Sect, Scuola Med Salernitana, Salerno, Italy
Russillo, MC:
Univ Salerno, Dept Med Surg & Dent, Neurosci Sect, Scuola Med Salernitana, Salerno, Italy
Marín-Lahoz, J:
Hosp Santa Creu & Sant Pau, Movement Disorders Unit, Neurol Dept, Barcelona, Spain
Univ Autonoma Barcelona, Ctr Invest Red Enfermedades Neurodegenerat CIBERN, Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Hosp Univ Miguel Servet, Serv Neurol, Zaragoza, Spain
Kulisevsky, J:
Hosp Santa Creu & Sant Pau, Movement Disorders Unit, Neurol Dept, Barcelona, Spain
Univ Autonoma Barcelona, Ctr Invest Red Enfermedades Neurodegenerat CIBERN, Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Torres, S:
Univ Autonoma Barcelona, Ctr Invest Red Enfermedades Neurodegenerat CIBERN, Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Mir, P:
Univ Seville, Inst Biomed Sevilla, Unidad Trastornos Movimiento Serv Neurol & Neurof, Hosp Univ Virgen del Rocio, Seville, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Seville, Dept Med, Fac Med, Seville, Spain
Periñán, MT:
Univ Seville, Inst Biomed Sevilla, Unidad Trastornos Movimiento Serv Neurol & Neurof, Hosp Univ Virgen del Rocio, Seville, Spain
Queen Mary Univ, Ctr Prevent Neurol, Wolfson Inst Populat Hlth, London, England
Proukakis, C:
UCL, Dept Clin & Movement Neurosci, Queen Sq Inst Neurol, London, England
Chelban, V:
UCL, Dept Neuromuscular Dis, Queen Sq Inst Neurol, London, England
Natl Hosp Neurol & Neurosurg, London, England
Wu, L:
UCL, Dept Neuromuscular Dis, Queen Sq Inst Neurol, London, England
Goh, YY:
UCL, Dept Neuromuscular Dis, Queen Sq Inst Neurol, London, England
Parkkinen, L:
Univ Oxford, Oxford Parkinsons Dis Ctr, Nuffield Dept Clin Neurosci, Oxford, England
Hu, MT:
Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford, England
Kobylecki, C:
Univ Manchester, Northern Care Alliance NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Dept Neurol, Manchester, Lancs, England
Saxon, JA:
Manchester Ctr Clin Neurosci, Cerebral Funct Unit, Salfort, England
Univ Manchester, Fac Biol, Div Neurosci & Expt Psychol, Manchester, Lancs, England
Rollinson, S:
Univ Manchester, Fac Biol, Div Neurosci & Expt Psychol, Manchester, Lancs, England
Garland, E:
Vanderbilt Univ, Auton Dysfunct Ctr, Med Ctr, Nashville, TN USA
Biaggioni, I:
Vanderbilt Univ, Auton Dysfunct Ctr, Med Ctr, Nashville, TN USA
Litvan, I:
Univ Calif San Diego, Dept Neurosci, San Diego, CA USA
Rubio, I:
Univ Calif San Diego, Dept Neurosci, San Diego, CA USA
Alcalay, RN:
Columbia Univ, Irving Med Ctr, Dept Neurol, New York, NY USA
Tel Aviv Sourasky Med Ctr, Neurol Inst, Tel Aviv, Israel
Kwei, KT:
Columbia Univ, Irving Med Ctr, Dept Neurol, New York, NY USA
Lubbe, SJ:
Northwestern Univ, Feinberg Sch Med, Ken & Ruth Davee Dept Neurol, Chicago, IL USA
Northwestern Univ, Simpson Querrey Ctr Neurogenet, Feinberg Sch Med, Chicago, IL USA
Mao, QW:
Northwestern Univ, Mesulam Ctr Cognit Neurol & Alzheimers Dis, Feinberg Sch Med, Chicago, IL USA
Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT USA
Flanagan, ME:
Northwestern Univ, Mesulam Ctr Cognit Neurol & Alzheimers Dis, Feinberg Sch Med, Chicago, IL USA
UT Hlth San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA
UT Hlth San Antonio, Dept Pathol, San Antonio, TX USA
Castellani, RJ:
Northwestern Univ, Mesulam Ctr Cognit Neurol & Alzheimers Dis, Feinberg Sch Med, Chicago, IL USA
Khurana, V:
Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Dept Neurol, Boston, MA USA
Harvard Med Sch, Boston, MA USA
Broad Inst MIT & Harvard, Cambridge, MA USA
Harvard Stem Cell Inst, Cambridge, MA USA
Ndayisaba, A:
Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria
Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Dept Neurol, Boston, MA USA
Harvard Med Sch, Boston, MA USA
Calvo, A:
Univ Turin, Rita Levi Montalcini Dept Neurosci, Turin, Italy
Mora, G:
IRCCS, Ist Clin Sci Maugeri, Milan, Italy
Canosa, A:
Univ Turin, Rita Levi Montalcini Dept Neurosci, Turin, Italy
Floris, G:
Univ Hosp Cagliari, Dept Neurol, Cagliari, Italy
Bohannan, RC:
Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA USA
Moore, A:
NIA, Computat Biol Grp, Lab Neurogenet, Bethesda, MD USA
Norcliffe-Kaufmann, L:
NYU, Dept Neurol, Sch Med, New York, NY USA
Palma, JA:
NYU, Dept Neurol, Sch Med, New York, NY USA
Kaufmann, H:
NYU, Dept Neurol, Sch Med, New York, NY USA
Kim, C:
NIA, Mol Neuropathol Sect, Lab Neurogenet, Bethesda, MD USA
Iba, M:
NIA, Mol Neuropathol Sect, Lab Neurogenet, Bethesda, MD USA
Masliah, E:
NIA, Mol Neuropathol Sect, Lab Neurogenet, Bethesda, MD USA
Dawson, TM:
Johns Hopkins Univ, Med Ctr, Dept Neurol, Baltimore, MD 21218 USA
Johns Hopkins Univ, Med Ctr, Inst Cell Engn, Neuroregenerat & Stem Cell Programs, Baltimore, MD USA
Johns Hopkins Univ, Med Ctr, Dept Pharmacol & Mol Sci, Baltimore, MD USA
Johns Hopkins Univ, Med Ctr, Solomon H Snyder Dept Neurosci, Baltimore, MD USA
Rosenthal, LS:
Johns Hopkins Univ, Med Ctr, Dept Neurol, Baltimore, MD 21218 USA
Pantelyat, A:
Johns Hopkins Univ, Med Ctr, Dept Neurol, Baltimore, MD 21218 USA
Albert, MS:
Johns Hopkins Univ, Med Ctr, Dept Neurol, Baltimore, MD 21218 USA
Pletnikova, O:
Johns Hopkins Univ, Med Ctr, Dept Pathol Neuropathol, Baltimore, MD USA
Univ Buffalo, Jacobs Sch Med & Biomed Sci, Dept Pathol & Anat Sci, Buffalo, NY USA
Troncoso, JC:
Johns Hopkins Univ, Med Ctr, Dept Pathol Neuropathol, Baltimore, MD USA
Infante, J:
Univ Hosp Marques de Valdecilla IDIVAL UC CIBERNE, Neurol Serv, Santander, Spain
Lage, C:
Univ Hosp Marques de Valdecilla IDIVAL UC CIBERNE, Neurol Serv, Santander, Spain
Sánchez-Juan, P:
Univ Hosp Marques de Valdecilla IDIVAL UC CIBERNE, Neurol Serv, Santander, Spain
Alzheimers Ctr Reina Sofia CIEN Fdn ISCIII, Madrid, Spain
Serrano, GE:
Banner Sun Hlth Res Inst, Civin Lab Neuropathol, Sun City, AZ USA
Beach, TG:
Banner Sun Hlth Res Inst, Civin Lab Neuropathol, Sun City, AZ USA
Pastor, P:
Germans Trias i Pujol Res Inst IGTP, Neurosci, Genom & Transcript Synucleinopathies, Barcelona, Spain
Univ Hosp Germans Trias i Pujol, Dept Neurol, Unit Neurodegenerat Dis, Barcelona, Spain
Morris, HR:
UCL, Dept Clin & Movement Neurosci, UCL Queen Sq Inst Neurol, London, England
Albani, D:
Ist Ric Farmacol Mario Negri IRCCS, Dept Neurosci, Milan, Italy
Clarimon, J:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Wenning, GK:
Med Univ Innsbruck, Dept Neurol, Auton Unit, Div Neurobiol, Innsbruck, Austria
Hardy, JA:
UCL, Dept Neurodegenerat Dis, UCL Queen Sq Inst Neurol, London, England
UCL, UK Dementia Res Inst UCL, UCL Inst Neurol, London, England
UCL, Reta Lila Weston Inst, UCL Queen Sq Inst Neurol, London, England
UCL, UCL Movement Disorders Ctr, London, England
Hong Kong Univ Sci & Technol, Inst Adv Study, Hong Kong, Peoples R China
Ryten, M:
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England
UCL, Great Ormond St Inst Child Hlth, Genet & Genom Med, London, England
Topol, E:
Scripps Res Translat Inst, Scripps Res, La Jolla, CA USA
Torkamani, A:
Scripps Res Translat Inst, Scripps Res, La Jolla, CA USA
Chio, A:
Univ Turin, Rita Levi Montalcini Dept Neurosci, Turin, Italy
CNR, Inst Cognit Sci & Technol, Rome, Italy
Azienda Osped Univ Citta Salute & Sci, Turin, Italy
Bennett, DA:
Rush Univ, Rush Alzheimers Dis Ctr, Med Ctr, Chicago, IL USA
De Jager, PL:
Columbia Univ, Ctr Translat & Computat Neuroimmunol, Dept Neurol, Irving Med Ctr, New York, NY USA
Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA
Low, PA:
Mayo Clin, Dept Neurol, Rochester, MN USA
Singer, W:
Mayo Clin, Dept Neurol, Rochester, MN USA
Cheshire, WP:
Mayo Clin, Dept Neurol, Jacksonville, FL USA
Wszolek, ZK:
Mayo Clin, Dept Neurol, Jacksonville, FL USA
Dickson, DW:
Mayo Clin, Dept Neurosci, Jacksonville, FL USA
Traynor, BJ:
NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD USA
Johns Hopkins Univ, Med Ctr, Dept Neurol, Baltimore, MD 21218 USA
Natl Ctr Adv Translat Sci, Therapeut Dev Branch, Rna Therapeut Lab, Rockville, MD USA
Gibbs, JR:
NIA, Computat Biol Grp, Lab Neurogenet, Bethesda, MD USA
Dalgard, CL:
Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD USA
Ross, OA:
Mayo Clin, Dept Neurosci, Jacksonville, FL USA
Mayo Clin, Dept Clin Genom, Jacksonville, FL USA
Houlden, H:
UCL, Dept Neuromuscular Dis, Queen Sq Inst Neurol, London, England
Natl Hosp Neurol & Neurosurg, London, England
Scholz, SW:
NINDS, Neurodegenerat Dis Res Unit, Bethesda, MD 20892 USA
Johns Hopkins Univ, Med Ctr, Dept Neurol, Baltimore, MD 21218 USA
Green Published, hybrid
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