A comprehensive screening of copy number variability in dementia with Lewy bodies
Por:
Kun-Rodrigues, C, Orme, T, Carmona, S, Hernandez, DG, Ross, OA, Eicher, JD, Shepherd, C, Parkkinen, L, Darwent, L, Heckman, MG, Scholz, SW, Troncoso, JC, Pletnikova, O, Dawson, T, Rosenthal, L, Ansorge, O, Clarimonm, J, Lleo, A, Morenas-Rodriguez, E, Clark, L, Honig, LS, Marder, K, Lemstra, A, Rogaeva, E, St George-Hyslop, P, Londos, E, Zetterberg, H, Barber, I, Braae, A, Brown, K, Morgan, K, Troakes, C, Al-Sarraj, S, Lashley, T, Holton, J, Compta, Y, Van Deerlin, V, Serrano, GE, Beach, TG, Lesage, S, Galasko, D, Masliah, E, Santana, I, Pastor, P, Diez-Fairen, M, Aguilar, M, Tienari, PJ, Myllykangas, L, Oinas, M, Revesz, T, Lees, A, Boeve, BF, Petersen, RC, Ferman, TJ, Escott-Price, V, Graff-Radford, N, Cairns, NJ, Morris, JC, Pickering-Brown, S, Mann, D, Halliday, GM, Hardy, J, Trojanowski, JQ, Dickson, DW, Singleton, A, Stone, DJ, Guerreiro, R, Bras, J
Publicada:
1 mar 2019
Resumen:
The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk. (C) 2019 Elsevier Inc. All rights reserved.
Filiaciones:
Kun-Rodrigues, C:
UCL, Dept Neurodegenerat Dis, Inst Neurol, London, England
Orme, T:
UCL, Dept Neurodegenerat Dis, Inst Neurol, London, England
UCL, UK DRI, London, England
Carmona, S:
UCL, Dept Neurodegenerat Dis, Inst Neurol, London, England
UCL, UK DRI, London, England
Hernandez, DG:
NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA
German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany
Ross, OA:
Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA
Eicher, JD:
Merck Res Labs, Genet & Pharmacogen, Boston, MA USA
Shepherd, C:
Neurosci Res Australia, Sydney, NSW, Australia
Univ New South Wales, Sch Med Sci, Fac Med, Sydney, NSW, Australia
Parkkinen, L:
Univ Oxford, Nuffield Dept Clin Neurosci, Oxford Parkinsons Dis Ctr, Oxford, England
Darwent, L:
UCL, Dept Neurodegenerat Dis, Inst Neurol, London, England
UCL, UK DRI, London, England
Heckman, MG:
Mayo Clin, Div Biomed Stat & Informat, Jacksonville, FL 32224 USA
Scholz, SW:
NINDS, Neurodegenerat Dis Res Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA
Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA
Troncoso, JC:
Johns Hopkins Univ, Sch Med, Dept Pathol Neuropathol, Baltimore, MD USA
Pletnikova, O:
Johns Hopkins Univ, Sch Med, Dept Pathol Neuropathol, Baltimore, MD USA
Dawson, T:
Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA
Rosenthal, L:
Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA
Ansorge, O:
Univ Oxford, Nuffield Dept Clin Neurosci, Oxford Parkinsons Dis Ctr, Oxford, England
Clarimonm, J:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, IIB St Pau,Hosp Santa Creu & St Pau, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Lleo, A:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, IIB St Pau,Hosp Santa Creu & St Pau, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Morenas-Rodriguez, E:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, IIB St Pau,Hosp Santa Creu & St Pau, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Clark, L:
Columbia Univ, Taub Inst Alzheimer Dis & Aging Brain, New York, NY USA
Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA
Honig, LS:
Columbia Univ, Taub Inst Alzheimer Dis & Aging Brain, New York, NY USA
Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA
Marder, K:
Columbia Univ, Taub Inst Alzheimer Dis & Aging Brain, New York, NY USA
Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA
Lemstra, A:
Vrije Univ Amsterdam Med Ctr, Dept Neurol, Neurosci Campus Amsterdam, Amsterdam, Netherlands
Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Neurosci Campus Amsterdam, Amsterdam, Netherlands
Rogaeva, E:
Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
Univ Toronto, Dept Med, Toronto, ON, Canada
St George-Hyslop, P:
Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
Univ Toronto, Dept Med, Toronto, ON, Canada
Univ Cambridge, Dept Clin Neurosci, Cambridge Inst Med Res, Cambridge, England
Londos, E:
Lund Univ, Clin Memory Res Unit, Inst Clin Sci Malmo, Lund, Sweden
Zetterberg, H:
UCL, UK DRI, London, England
UCL, Dept Mol Neurosci, Inst Neurol, London, England
Univ Gothenburg, Clin Neurochem Lab, Inst Neurosci & Physiol, Sahlgrenska Acad, Molndal, Sweden
Barber, I:
Univ Nottingham, Human Genet, Sch Life Sci, Queens Med Ctr, Nottingham, England
Braae, A:
Univ Nottingham, Human Genet, Sch Life Sci, Queens Med Ctr, Nottingham, England
Brown, K:
Univ Nottingham, Human Genet, Sch Life Sci, Queens Med Ctr, Nottingham, England
Morgan, K:
Univ Nottingham, Human Genet, Sch Life Sci, Queens Med Ctr, Nottingham, England
Troakes, C:
Kings Coll London, Dept Basic & Clin Neurosci, London, England
Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England
Al-Sarraj, S:
Kings Coll London, Dept Basic & Clin Neurosci, London, England
Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England
Lashley, T:
UCL, Inst Neurol, Queen Sq Brain Bank, Dept Mol Neurosci, London, England
Holton, J:
UCL, Inst Neurol, Queen Sq Brain Bank, Dept Mol Neurosci, London, England
Compta, Y:
UCL, Inst Neurol, Queen Sq Brain Bank, Dept Mol Neurosci, London, England
Univ Barcelona, IDIBAPS, Movement Disorders Unit, Neurol Serv,ICN,Hosp Clin, Barcelona, Spain
Van Deerlin, V:
Univ Penn, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Philadelphia, PA USA
Serrano, GE:
Banner Sun Hlth Res Inst, Sun City, AZ USA
Beach, TG:
Banner Sun Hlth Res Inst, Sun City, AZ USA
Lesage, S:
Sorbonne Univ, INSERM, U1127, CNRS,UMR7225,Inst Cerveau & Moelle Epiniere, Paris, France
Galasko, D:
Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
Vet Affairs San Diego Healthcare Syst, La Jolla, CA USA
Masliah, E:
Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA
Santana, I:
Univ Coimbra Hosp, Neurol Serv, Coimbra, Portugal
Pastor, P:
Univ Barcelona, Memory Unit, Dept Neurol, Univ Hosp Mutua Terrassa, Barcelona, Spain
Fundacio Docencia & Recerca Mutua Terrassa, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurdegenerat, Barcelona, Spain
Diez-Fairen, M:
Univ Barcelona, Memory Unit, Dept Neurol, Univ Hosp Mutua Terrassa, Barcelona, Spain
Fundacio Docencia & Recerca Mutua Terrassa, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurdegenerat, Barcelona, Spain
Aguilar, M:
Univ Barcelona, Memory Unit, Dept Neurol, Univ Hosp Mutua Terrassa, Barcelona, Spain
Fundacio Docencia & Recerca Mutua Terrassa, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurdegenerat, Barcelona, Spain
Tienari, PJ:
Univ Helsinki, Mol Neurol, Res Programs Unit, Dept Neurol,Helsinki Univ Hosp, Helsinki, Finland
Myllykangas, L:
Univ Helsinki, Dept Pathol, Helsinki, Finland
Helsinki Univ Hosp, Helsinki, Finland
Oinas, M:
Helsinki Univ Hosp, Dept Neuropathol & Neurosurg, Helsinki, Finland
Univ Helsinki, Helsinki, Finland
Revesz, T:
UCL, Inst Neurol, Queen Sq Brain Bank, Dept Mol Neurosci, London, England
Lees, A:
UCL, Inst Neurol, Queen Sq Brain Bank, Dept Mol Neurosci, London, England
Boeve, BF:
Mayo Clin, Dept Neurol, Rochester, MN USA
Petersen, RC:
Mayo Clin, Dept Neurol, Rochester, MN USA
Ferman, TJ:
Mayo Clin, Dept Psychiat, Jacksonville, FL 32224 USA
Mayo Clin, Dept Psychol, Jacksonville, FL 32224 USA
Escott-Price, V:
Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Sch Med, Cardiff, S Glam, Wales
Graff-Radford, N:
Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA
Cairns, NJ:
Washington Univ, Sch Med, Dept Neurol, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA
Morris, JC:
Washington Univ, Sch Med, Dept Neurol, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA
Pickering-Brown, S:
Univ Manchester, Inst Brain Behav & Mental Hlth, Fac Med & Human Sci, Manchester, Lancs, England
Mann, D:
Univ Manchester, Inst Brain Behav & Mental Hlth, Fac Med & Human Sci, Manchester, Lancs, England
Halliday, GM:
Neurosci Res Australia, Sydney, NSW, Australia
Univ New South Wales, Sch Med Sci, Fac Med, Sydney, NSW, Australia
Univ Sydney, Brain & Mind Ctr, Sydney Med Sch, Sydney, NSW, Australia
Hardy, J:
UCL, Dept Neurodegenerat Dis, Inst Neurol, London, England
Trojanowski, JQ:
Univ Penn, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Philadelphia, PA USA
Dickson, DW:
Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA
Singleton, A:
NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA
Stone, DJ:
Merck & Co Inc, Genet & Pharmacogen, West Point, PA USA
Guerreiro, R:
UCL, Dept Neurodegenerat Dis, Inst Neurol, London, England
UCL, UK DRI, London, England
Univ Aveiro, Dept Med Sci, iBiMED, Aveiro, Portugal
Univ Aveiro, Inst Biomed, IBiMED, Aveiro, Portugal
Bras, J:
UCL, Dept Neurodegenerat Dis, Inst Neurol, London, England
UCL, UK DRI, London, England
Univ Aveiro, Dept Med Sci, iBiMED, Aveiro, Portugal
Univ Aveiro, Inst Biomed, IBiMED, Aveiro, Portugal
Green Published, Green Accepted
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