A comprehensive screening of copy number variability in dementia with Lewy bodies

Celia Kun-Rodrigues; Tatiana Orme; Susana Carmona; Dena G. Hernandez; Owen A. Ross; John D. Eicher; Claire Shepherd; Laura Parkkinen; Lee Darwent; Michael G. Heckman; Sonja W. Scholz; Juan C. Troncoso; Olga Pletnikova; Ted Dawson; Liana Rosenthal; Olaf Ansorge; Jordi Clarimon; Alberto Lleo; Estrella Morenas-Rodriguez; Lorraine Clark; Lawrence S. Honig; Karen Marder; Afina Lemstra; Ekaterina Rogaeva; Peter St. George-Hyslop; Elisabet Londos; Henrik Zetterberg; Imelda Barber; Anne Braae; Kristelle Brown; Kevin Morgan; Claire Troakes; Safa Al-Sarraj; Tammaryn Lashley; Janice Holton; Yaroslau Compta; Vivianna Van Deerlin; Geidy E. Serrano; Thomas G. Beach; Suzanne Lesage; Douglas Galasko; Eliezer Masliah; Isabel Santana; Pau Pastor; Monica Diez-Fairen; Miquel Aguilar; Pentti J. Tienari; Liisa Myllykangas; Minna Oinas; Tamas Revesz; Andrew Lees; Brad F. Boeve; Ronald C. Petersen; Tanis J. Ferman; Valentina Escott-Price; Neill Graff-Radford; Nigel J. Cairns; John C. Morris; Stuart Pickering-Brown; David Mann; Glenda M. Halliday; John Hardy; John Q. Trojanowski; Dennis W. Dickson; Andrew Singleton; David J. Stone; Rita Guerreiro; Jose Bras

doi:10.1016/j.neurobiolaging.2018.10.019

A comprehensive screening of copy number variability in dementia with Lewy bodies

Celia Kun-Rodrigues, Tatiana Orme, Susana Carmona, Dena G. Hernandez, Owen A. Ross, John D. Eicher, Claire Shepherd, Laura Parkkinen, Lee Darwent, Michael G. Heckman, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Lorraine ClarkLawrence S. Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St. George-Hyslop, Elisabet Londos, Henrik Zetterberg, Imelda Barber, Anne Braae, Kristelle Brown, Kevin Morgan, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Vivianna Van Deerlin, Geidy E. Serrano, Thomas G. Beach, Suzanne Lesage, Douglas Galasko, Eliezer Masliah, Isabel Santana, Pau Pastor, Monica Diez-Fairen, Miquel Aguilar, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F. Boeve, Ronald C. Petersen, Tanis J. Ferman, Valentina Escott-Price, Neill Graff-Radford, Nigel J. Cairns, John C. Morris, Stuart Pickering-Brown, David Mann, Glenda M. Halliday, John Hardy, John Q. Trojanowski, Dennis W. Dickson, Andrew Singleton, David J. Stone, Rita Guerreiro, Jose Bras

School of Medicine

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	223.e1-223.e10
Journal	Neurobiology of aging
Volume	75
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.10.019
State	Published - Mar 2019

Keywords

Copy number variants
Dementia with Lewy bodies
Genome-wide
MAPT
SNCA

ASJC Scopus subject areas

Neuroscience(all)
Aging
Clinical Neurology
Developmental Biology
Geriatrics and Gerontology

Access to Document

10.1016/j.neurobiolaging.2018.10.019

Cite this

Kun-Rodrigues, C., Orme, T., Carmona, S., Hernandez, D. G., Ross, O. A., Eicher, J. D., Shepherd, C., Parkkinen, L., Darwent, L., Heckman, M. G., Scholz, S. W., Troncoso, J. C., Pletnikova, O., Dawson, T., Rosenthal, L., Ansorge, O., Clarimon, J., Lleo, A., Morenas-Rodriguez, E., ... Bras, J. (2019). A comprehensive screening of copy number variability in dementia with Lewy bodies. Neurobiology of aging, 75, 223.e1-223.e10. https://doi.org/10.1016/j.neurobiolaging.2018.10.019

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, Clarimon, 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 2019, 'A comprehensive screening of copy number variability in dementia with Lewy bodies', Neurobiology of aging, vol. 75, pp. 223.e1-223.e10. https://doi.org/10.1016/j.neurobiolaging.2018.10.019

@article{64cfd7dbf3564362a9a3f3c491495ab2,

title = "A comprehensive screening of copy number variability in dementia with Lewy bodies",

abstract = "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.",

keywords = "Copy number variants, Dementia with Lewy bodies, Genome-wide, MAPT, SNCA",

author = "Celia Kun-Rodrigues and Tatiana Orme and Susana Carmona and Hernandez, {Dena G.} and Ross, {Owen A.} and Eicher, {John D.} and Claire Shepherd and Laura Parkkinen and Lee Darwent and Heckman, {Michael G.} and Scholz, {Sonja W.} and Troncoso, {Juan C.} and Olga Pletnikova and Ted Dawson and Liana Rosenthal and Olaf Ansorge and Jordi Clarimon and Alberto Lleo and Estrella Morenas-Rodriguez and Lorraine Clark and Honig, {Lawrence S.} and Karen Marder and Afina Lemstra and Ekaterina Rogaeva and {St. George-Hyslop}, Peter and Elisabet Londos and Henrik Zetterberg and Imelda Barber and Anne Braae and Kristelle Brown and Kevin Morgan and Claire Troakes and Safa Al-Sarraj and Tammaryn Lashley and Janice Holton and Yaroslau Compta and {Van Deerlin}, Vivianna and Serrano, {Geidy E.} and Beach, {Thomas G.} and Suzanne Lesage and Douglas Galasko and Eliezer Masliah and Isabel Santana and Pau Pastor and Monica Diez-Fairen and Miquel Aguilar and Tienari, {Pentti J.} and Liisa Myllykangas and Minna Oinas and Tamas Revesz and Andrew Lees and Boeve, {Brad F.} and Petersen, {Ronald C.} and Ferman, {Tanis J.} and Valentina Escott-Price and Neill Graff-Radford and Cairns, {Nigel J.} and Morris, {John C.} and Stuart Pickering-Brown and David Mann and Halliday, {Glenda M.} and John Hardy and Trojanowski, {John Q.} and Dickson, {Dennis W.} and Andrew Singleton and Stone, {David J.} and Rita Guerreiro and Jose Bras",

note = "Funding Information: RG and JB work is funded by fellowships from the Alzheimer's Society. TO work is funded by a scholarship from The Lewy Body Society. For the neuropathologically confirmed samples from Australia, tissues were received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales, and GMH is funded by an NHMRC senior principal research fellowship. The authors thank the South West Dementia Brain Bank (SWDBB) for providing brain tissue for this study. The SWDBB is supported by BRACE (Bristol Research into Alzheimer's and Care of the Elderly), Brains for Dementia Research, and the Medical Research Council. The authors acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the NIHR Oxford Biomedical Research Center. The brain samples and/or bio samples were obtained from The Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam (open access: www.brainbank.nl). All materials have been collected from donors for or from whom a written informed consent for a brain autopsy, and the use of the material and clinical information for research purposes had been obtained by the NBB. This study was also partially funded by the Wellcome Trust, and the Canadian Consortium on Neurodegeneration and Aging of the Canadian Institutes of Health Research (PSGH). Work from YC was supported by the CERCA Program/Generalitat de Catalunya, Barcelona, Catalonia, Spain. The Nottingham Genetics Group is supported by ARUK and The Big Lottery Fund. The effort from Columbia University was supported by the Taub Institute, the Panasci Fund, the Parkinson's Disease Foundation, and NIH grants NS060113 (LC), P50AG008702 (P.I. Scott Small), P50NS038370 (P.I.R. Burke), and UL1TR000040 (P.I.H. Ginsberg). OAR is supported by the Michael J. Fox Foundation for Parkinson's Research, NINDS R01# NS078086. The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187) and is supported by The Little Family Foundation and by the Mangurian Foundation Program for Lewy Body Dementia research and the Alzheimer Disease Research Center (P50 AG016547). The work from the Mayo Clinic Rochester is supported by the National Institute on Aging (P50 AG016574 and U01 AG006786). This work has received support from The Queen Square Brain Bank at the UCL Institute of Neurology, where TL is funded by an ARUK senior fellowship. Some of the tissue samples studied were provided by the MRC London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer's Society and ARUK). This research was supported in part by both the NIHR UCLH Biomedical Research Center and the Queen Square Dementia Biomedical Research Unit. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project AG000951-12. The University of Pennsylvania case collection is funded by the Penn Alzheimer's Disease Core Center (AG10124) and the Penn Morris K. Udall Parkinson's Disease Research Center (NS053488). Tissue samples from UCSD are supported by NIH grant AG05131. The authors thank the brain bank GIE NeuroCEB, the French program “Investissements d'avenir” (ANR-10-IAIHU-06). PJT and LM are supported by the Helsinki University Central Hospital and Sigrid Juselius Foundation and the Finnish Academy. This work was in part supported by the Canadian Consortium on Neurodegeneration in Aging (ER). The authors acknowledge the contribution of data from Genetic Architecture of Smoking and Smoking Cessation accessed through dbGAP. Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 X01 HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of data sets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). This work was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute of Neurological Disorders and Stroke; project ZIA NS003154). Tissue samples for genotyping were provided by the Johns Hopkins Morris K. Udall Center of Excellence for Parkinson's Disease Research (NIH P50 NS38377) and the Johns Hopkins Alzheimer Disease Research Center (NIH P50 AG05146). This study was supported by grants from the National Institutes of Health, the Canadian Institute for Health Research, and the Krembil Foundation. Additional support was provided by the Babcock Memorial Trust and by the Barbara and Neal Henschel Charitable Foundation. Funding Information: RG and JB work is funded by fellowships from the Alzheimer's Society. TO work is funded by a scholarship from The Lewy Body Society. For the neuropathologically confirmed samples from Australia, tissues were received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales, and GMH is funded by an NHMRC senior principal research fellowship. The authors thank the South West Dementia Brain Bank (SWDBB) for providing brain tissue for this study. The SWDBB is supported by BRACE (Bristol Research into Alzheimer's and Care of the Elderly), Brains for Dementia Research, and the Medical Research Council. The authors acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the NIHR Oxford Biomedical Research Center. The brain samples and/or bio samples were obtained from The Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam (open access: www.brainbank.nl ). All materials have been collected from donors for or from whom a written informed consent for a brain autopsy, and the use of the material and clinical information for research purposes had been obtained by the NBB. This study was also partially funded by the Wellcome Trust, and the Canadian Consortium on Neurodegeneration and Aging of the Canadian Institutes of Health Research (PSGH). Work from YC was supported by the CERCA Program/Generalitat de Catalunya, Barcelona, Catalonia, Spain. The Nottingham Genetics Group is supported by ARUK and The Big Lottery Fund. The effort from Columbia University was supported by the Taub Institute, the Panasci Fund, the Parkinson's Disease Foundation, and NIH grants NS060113 (LC), P50AG008702 (P.I. Scott Small), P50NS038370 (P.I.R. Burke), and UL1TR000040 (P.I.H. Ginsberg). OAR is supported by the Michael J. Fox Foundation for Parkinson's Research , NINDS R01# NS078086 . The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187) and is supported by The Little Family Foundation and by the Mangurian Foundation Program for Lewy Body Dementia research and the Alzheimer Disease Research Center ( P50 AG016547 ). The work from the Mayo Clinic Rochester is supported by the National Institute on Aging ( P50 AG016574 and U01 AG006786 ). This work has received support from The Queen Square Brain Bank at the UCL Institute of Neurology, where TL is funded by an ARUK senior fellowship. Some of the tissue samples studied were provided by the MRC London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer's Society and ARUK). This research was supported in part by both the NIHR UCLH Biomedical Research Center and the Queen Square Dementia Biomedical Research Unit. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project AG000951-12. The University of Pennsylvania case collection is funded by the Penn Alzheimer's Disease Core Center (AG10124) and the Penn Morris K. Udall Parkinson's Disease Research Center (NS053488). Tissue samples from UCSD are supported by NIH grant AG05131. The authors thank the brain bank GIE NeuroCEB, the French program “Investissements d'avenir” (ANR-10-IAIHU-06). PJT and LM are supported by the Helsinki University Central Hospital and Sigrid Juselius Foundation and the Finnish Academy. This work was in part supported by the Canadian Consortium on Neurodegeneration in Aging (ER). The authors acknowledge the contribution of data from Genetic Architecture of Smoking and Smoking Cessation accessed through dbGAP. Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 X01 HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of data sets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). This work was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute of Neurological Disorders and Stroke; project ZIA NS003154). Tissue samples for genotyping were provided by the Johns Hopkins Morris K. Udall Center of Excellence for Parkinson's Disease Research (NIH P50 NS38377) and the Johns Hopkins Alzheimer Disease Research Center (NIH P50 AG05146). This study was supported by grants from the National Institutes of Health, the Canadian Institute for Health Research, and the Krembil Foundation. Additional support was provided by the Babcock Memorial Trust and by the Barbara and Neal Henschel Charitable Foundation. Funding Information: RG and JB work is funded by fellowships from the Alzheimer's Society. TO work is funded by a scholarship from The Lewy Body Society. For the neuropathologically confirmed samples from Australia, tissues were received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales, and GMH is funded by an NHMRC senior principal research fellowship. The authors thank the South West Dementia Brain Bank (SWDBB) for providing brain tissue for this study. The SWDBB is supported by BRACE (Bristol Research into Alzheimer's and Care of the Elderly), Brains for Dementia Research, and the Medical Research Council. The authors acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the NIHR Oxford Biomedical Research Center. The brain samples and/or bio samples were obtained from The Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam (open access: www.brainbank.nl). All materials have been collected from donors for or from whom a written informed consent for a brain autopsy, and the use of the material and clinical information for research purposes had been obtained by the NBB. This study was also partially funded by the Wellcome Trust, and the Canadian Consortium on Neurodegeneration and Aging of the Canadian Institutes of Health Research (PSGH). Work from YC was supported by the CERCA Program/Generalitat de Catalunya, Barcelona, Catalonia, Spain. The Nottingham Genetics Group is supported by ARUK and The Big Lottery Fund. The effort from Columbia University was supported by the Taub Institute, the Panasci Fund, the Parkinson's Disease Foundation, and NIH grants NS060113 (LC), P50AG008702 (P.I. Scott Small), P50NS038370 (P.I.R. Burke), and UL1TR000040 (P.I.H. Ginsberg). OAR is supported by the Michael J. Fox Foundation for Parkinson's Research, NINDS R01# NS078086. The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187) and is supported by The Little Family Foundation and by the Mangurian Foundation Program for Lewy Body Dementia research and the Alzheimer Disease Research Center (P50 AG016547). The work from the Mayo Clinic Rochester is supported by the National Institute on Aging (P50 AG016574 and U01 AG006786). This work has received support from The Queen Square Brain Bank at the UCL Institute of Neurology, where TL is funded by an ARUK senior fellowship. Some of the tissue samples studied were provided by the MRC London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer's Society and ARUK). This research was supported in part by both the NIHR UCLH Biomedical Research Center and the Queen Square Dementia Biomedical Research Unit. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project AG000951-12. The University of Pennsylvania case collection is funded by the Penn Alzheimer's Disease Core Center (AG10124) and the Penn Morris K. Udall Parkinson's Disease Research Center (NS053488). Tissue samples from UCSD are supported by NIH grant AG05131. The authors thank the brain bank GIE NeuroCEB, the French program ?Investissements d'avenir? (ANR-10-IAIHU-06). PJT and LM are supported by the Helsinki University Central Hospital and Sigrid Juselius Foundation and the Finnish Academy. This work was in part supported by the Canadian Consortium on Neurodegeneration in Aging (ER). The authors acknowledge the contribution of data from Genetic Architecture of Smoking and Smoking Cessation accessed through dbGAP. Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 X01 HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of data sets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). This work was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute of Neurological Disorders and Stroke; project ZIA NS003154). Tissue samples for genotyping were provided by the Johns Hopkins Morris K. Udall Center of Excellence for Parkinson's Disease Research (NIH P50 NS38377) and the Johns Hopkins Alzheimer Disease Research Center (NIH P50 AG05146). This study was supported by grants from the National Institutes of Health, the Canadian Institute for Health Research, and the Krembil Foundation. Additional support was provided by the Babcock Memorial Trust and by the Barbara and Neal Henschel Charitable Foundation. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = mar,

doi = "10.1016/j.neurobiolaging.2018.10.019",

language = "English (US)",

volume = "75",

pages = "223.e1--223.e10",

journal = "Neurobiology of aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - A comprehensive screening of copy number variability in dementia with Lewy bodies

AU - Kun-Rodrigues, Celia

AU - Orme, Tatiana

AU - Carmona, Susana

AU - Hernandez, Dena G.

AU - Ross, Owen A.

AU - Eicher, John D.

AU - Shepherd, Claire

AU - Parkkinen, Laura

AU - Darwent, Lee

AU - Heckman, Michael G.

AU - Scholz, Sonja W.

AU - Troncoso, Juan C.

AU - Pletnikova, Olga

AU - Dawson, Ted

AU - Rosenthal, Liana

AU - Ansorge, Olaf

AU - Clarimon, Jordi

AU - Lleo, Alberto

AU - Morenas-Rodriguez, Estrella

AU - Clark, Lorraine

AU - Honig, Lawrence S.

AU - Marder, Karen

AU - Lemstra, Afina

AU - Rogaeva, Ekaterina

AU - St. George-Hyslop, Peter

AU - Londos, Elisabet

AU - Zetterberg, Henrik

AU - Barber, Imelda

AU - Braae, Anne

AU - Brown, Kristelle

AU - Morgan, Kevin

AU - Troakes, Claire

AU - Al-Sarraj, Safa

AU - Lashley, Tammaryn

AU - Holton, Janice

AU - Compta, Yaroslau

AU - Van Deerlin, Vivianna

AU - Serrano, Geidy E.

AU - Beach, Thomas G.

AU - Lesage, Suzanne

AU - Galasko, Douglas

AU - Masliah, Eliezer

AU - Santana, Isabel

AU - Pastor, Pau

AU - Diez-Fairen, Monica

AU - Aguilar, Miquel

AU - Tienari, Pentti J.

AU - Myllykangas, Liisa

AU - Oinas, Minna

AU - Revesz, Tamas

AU - Lees, Andrew

AU - Boeve, Brad F.

AU - Petersen, Ronald C.

AU - Ferman, Tanis J.

AU - Escott-Price, Valentina

AU - Graff-Radford, Neill

AU - Cairns, Nigel J.

AU - Morris, John C.

AU - Pickering-Brown, Stuart

AU - Mann, David

AU - Halliday, Glenda M.

AU - Hardy, John

AU - Trojanowski, John Q.

AU - Dickson, Dennis W.

AU - Singleton, Andrew

AU - Stone, David J.

AU - Guerreiro, Rita

AU - Bras, Jose

N1 - Funding Information: RG and JB work is funded by fellowships from the Alzheimer's Society. TO work is funded by a scholarship from The Lewy Body Society. For the neuropathologically confirmed samples from Australia, tissues were received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales, and GMH is funded by an NHMRC senior principal research fellowship. The authors thank the South West Dementia Brain Bank (SWDBB) for providing brain tissue for this study. The SWDBB is supported by BRACE (Bristol Research into Alzheimer's and Care of the Elderly), Brains for Dementia Research, and the Medical Research Council. The authors acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the NIHR Oxford Biomedical Research Center. The brain samples and/or bio samples were obtained from The Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam (open access: www.brainbank.nl). All materials have been collected from donors for or from whom a written informed consent for a brain autopsy, and the use of the material and clinical information for research purposes had been obtained by the NBB. This study was also partially funded by the Wellcome Trust, and the Canadian Consortium on Neurodegeneration and Aging of the Canadian Institutes of Health Research (PSGH). Work from YC was supported by the CERCA Program/Generalitat de Catalunya, Barcelona, Catalonia, Spain. The Nottingham Genetics Group is supported by ARUK and The Big Lottery Fund. The effort from Columbia University was supported by the Taub Institute, the Panasci Fund, the Parkinson's Disease Foundation, and NIH grants NS060113 (LC), P50AG008702 (P.I. Scott Small), P50NS038370 (P.I.R. Burke), and UL1TR000040 (P.I.H. Ginsberg). OAR is supported by the Michael J. Fox Foundation for Parkinson's Research, NINDS R01# NS078086. The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187) and is supported by The Little Family Foundation and by the Mangurian Foundation Program for Lewy Body Dementia research and the Alzheimer Disease Research Center (P50 AG016547). The work from the Mayo Clinic Rochester is supported by the National Institute on Aging (P50 AG016574 and U01 AG006786). This work has received support from The Queen Square Brain Bank at the UCL Institute of Neurology, where TL is funded by an ARUK senior fellowship. Some of the tissue samples studied were provided by the MRC London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer's Society and ARUK). This research was supported in part by both the NIHR UCLH Biomedical Research Center and the Queen Square Dementia Biomedical Research Unit. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project AG000951-12. The University of Pennsylvania case collection is funded by the Penn Alzheimer's Disease Core Center (AG10124) and the Penn Morris K. Udall Parkinson's Disease Research Center (NS053488). Tissue samples from UCSD are supported by NIH grant AG05131. The authors thank the brain bank GIE NeuroCEB, the French program “Investissements d'avenir” (ANR-10-IAIHU-06). PJT and LM are supported by the Helsinki University Central Hospital and Sigrid Juselius Foundation and the Finnish Academy. This work was in part supported by the Canadian Consortium on Neurodegeneration in Aging (ER). The authors acknowledge the contribution of data from Genetic Architecture of Smoking and Smoking Cessation accessed through dbGAP. Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 X01 HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of data sets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). This work was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute of Neurological Disorders and Stroke; project ZIA NS003154). Tissue samples for genotyping were provided by the Johns Hopkins Morris K. Udall Center of Excellence for Parkinson's Disease Research (NIH P50 NS38377) and the Johns Hopkins Alzheimer Disease Research Center (NIH P50 AG05146). This study was supported by grants from the National Institutes of Health, the Canadian Institute for Health Research, and the Krembil Foundation. Additional support was provided by the Babcock Memorial Trust and by the Barbara and Neal Henschel Charitable Foundation. Funding Information: RG and JB work is funded by fellowships from the Alzheimer's Society. TO work is funded by a scholarship from The Lewy Body Society. For the neuropathologically confirmed samples from Australia, tissues were received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales, and GMH is funded by an NHMRC senior principal research fellowship. The authors thank the South West Dementia Brain Bank (SWDBB) for providing brain tissue for this study. The SWDBB is supported by BRACE (Bristol Research into Alzheimer's and Care of the Elderly), Brains for Dementia Research, and the Medical Research Council. The authors acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the NIHR Oxford Biomedical Research Center. The brain samples and/or bio samples were obtained from The Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam (open access: www.brainbank.nl ). All materials have been collected from donors for or from whom a written informed consent for a brain autopsy, and the use of the material and clinical information for research purposes had been obtained by the NBB. This study was also partially funded by the Wellcome Trust, and the Canadian Consortium on Neurodegeneration and Aging of the Canadian Institutes of Health Research (PSGH). Work from YC was supported by the CERCA Program/Generalitat de Catalunya, Barcelona, Catalonia, Spain. The Nottingham Genetics Group is supported by ARUK and The Big Lottery Fund. The effort from Columbia University was supported by the Taub Institute, the Panasci Fund, the Parkinson's Disease Foundation, and NIH grants NS060113 (LC), P50AG008702 (P.I. Scott Small), P50NS038370 (P.I.R. Burke), and UL1TR000040 (P.I.H. Ginsberg). OAR is supported by the Michael J. Fox Foundation for Parkinson's Research , NINDS R01# NS078086 . The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187) and is supported by The Little Family Foundation and by the Mangurian Foundation Program for Lewy Body Dementia research and the Alzheimer Disease Research Center ( P50 AG016547 ). The work from the Mayo Clinic Rochester is supported by the National Institute on Aging ( P50 AG016574 and U01 AG006786 ). This work has received support from The Queen Square Brain Bank at the UCL Institute of Neurology, where TL is funded by an ARUK senior fellowship. Some of the tissue samples studied were provided by the MRC London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer's Society and ARUK). This research was supported in part by both the NIHR UCLH Biomedical Research Center and the Queen Square Dementia Biomedical Research Unit. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project AG000951-12. The University of Pennsylvania case collection is funded by the Penn Alzheimer's Disease Core Center (AG10124) and the Penn Morris K. Udall Parkinson's Disease Research Center (NS053488). Tissue samples from UCSD are supported by NIH grant AG05131. The authors thank the brain bank GIE NeuroCEB, the French program “Investissements d'avenir” (ANR-10-IAIHU-06). PJT and LM are supported by the Helsinki University Central Hospital and Sigrid Juselius Foundation and the Finnish Academy. This work was in part supported by the Canadian Consortium on Neurodegeneration in Aging (ER). The authors acknowledge the contribution of data from Genetic Architecture of Smoking and Smoking Cessation accessed through dbGAP. Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 X01 HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of data sets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). This work was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute of Neurological Disorders and Stroke; project ZIA NS003154). Tissue samples for genotyping were provided by the Johns Hopkins Morris K. Udall Center of Excellence for Parkinson's Disease Research (NIH P50 NS38377) and the Johns Hopkins Alzheimer Disease Research Center (NIH P50 AG05146). This study was supported by grants from the National Institutes of Health, the Canadian Institute for Health Research, and the Krembil Foundation. Additional support was provided by the Babcock Memorial Trust and by the Barbara and Neal Henschel Charitable Foundation. Funding Information: RG and JB work is funded by fellowships from the Alzheimer's Society. TO work is funded by a scholarship from The Lewy Body Society. For the neuropathologically confirmed samples from Australia, tissues were received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales, and GMH is funded by an NHMRC senior principal research fellowship. The authors thank the South West Dementia Brain Bank (SWDBB) for providing brain tissue for this study. The SWDBB is supported by BRACE (Bristol Research into Alzheimer's and Care of the Elderly), Brains for Dementia Research, and the Medical Research Council. The authors acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the NIHR Oxford Biomedical Research Center. The brain samples and/or bio samples were obtained from The Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam (open access: www.brainbank.nl). All materials have been collected from donors for or from whom a written informed consent for a brain autopsy, and the use of the material and clinical information for research purposes had been obtained by the NBB. This study was also partially funded by the Wellcome Trust, and the Canadian Consortium on Neurodegeneration and Aging of the Canadian Institutes of Health Research (PSGH). Work from YC was supported by the CERCA Program/Generalitat de Catalunya, Barcelona, Catalonia, Spain. The Nottingham Genetics Group is supported by ARUK and The Big Lottery Fund. The effort from Columbia University was supported by the Taub Institute, the Panasci Fund, the Parkinson's Disease Foundation, and NIH grants NS060113 (LC), P50AG008702 (P.I. Scott Small), P50NS038370 (P.I.R. Burke), and UL1TR000040 (P.I.H. Ginsberg). OAR is supported by the Michael J. Fox Foundation for Parkinson's Research, NINDS R01# NS078086. The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187) and is supported by The Little Family Foundation and by the Mangurian Foundation Program for Lewy Body Dementia research and the Alzheimer Disease Research Center (P50 AG016547). The work from the Mayo Clinic Rochester is supported by the National Institute on Aging (P50 AG016574 and U01 AG006786). This work has received support from The Queen Square Brain Bank at the UCL Institute of Neurology, where TL is funded by an ARUK senior fellowship. Some of the tissue samples studied were provided by the MRC London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer's Society and ARUK). This research was supported in part by both the NIHR UCLH Biomedical Research Center and the Queen Square Dementia Biomedical Research Unit. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project AG000951-12. The University of Pennsylvania case collection is funded by the Penn Alzheimer's Disease Core Center (AG10124) and the Penn Morris K. Udall Parkinson's Disease Research Center (NS053488). Tissue samples from UCSD are supported by NIH grant AG05131. The authors thank the brain bank GIE NeuroCEB, the French program ?Investissements d'avenir? (ANR-10-IAIHU-06). PJT and LM are supported by the Helsinki University Central Hospital and Sigrid Juselius Foundation and the Finnish Academy. This work was in part supported by the Canadian Consortium on Neurodegeneration in Aging (ER). The authors acknowledge the contribution of data from Genetic Architecture of Smoking and Smoking Cessation accessed through dbGAP. Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 X01 HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of data sets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). This work was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute of Neurological Disorders and Stroke; project ZIA NS003154). Tissue samples for genotyping were provided by the Johns Hopkins Morris K. Udall Center of Excellence for Parkinson's Disease Research (NIH P50 NS38377) and the Johns Hopkins Alzheimer Disease Research Center (NIH P50 AG05146). This study was supported by grants from the National Institutes of Health, the Canadian Institute for Health Research, and the Krembil Foundation. Additional support was provided by the Babcock Memorial Trust and by the Barbara and Neal Henschel Charitable Foundation. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/3

Y1 - 2019/3

N2 - 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.

AB - 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.

KW - Copy number variants

KW - Dementia with Lewy bodies

KW - Genome-wide

KW - MAPT

KW - SNCA

UR - http://www.scopus.com/inward/record.url?scp=85056701141&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056701141&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2018.10.019

DO - 10.1016/j.neurobiolaging.2018.10.019

M3 - Article

C2 - 30448004

AN - SCOPUS:85056701141

SN - 0197-4580

VL - 75

SP - 223.e1-223.e10

JO - Neurobiology of aging

JF - Neurobiology of aging

ER -

A comprehensive screening of copy number variability in dementia with Lewy bodies

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