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 | |
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
Other files and links
Fingerprint
Dive into the research topics of 'A comprehensive screening of copy number variability in dementia with Lewy bodies'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
In: Neurobiology of aging, Vol. 75, 03.2019, p. 223.e1-223.e10.
Research output: Contribution to journal › Article › peer-review
}
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 -