. 2019 Mar:75:223.e1-223.e10.

doi: 10.1016/j.neurobiolaging.2018.10.019. Epub 2018 Oct 24.

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

Celia Kun-Rodrigues¹, Tatiana Orme², Susana Carmona², Dena G Hernandez³, Owen A Ross⁴, John D Eicher⁵, Claire Shepherd⁶, Laura Parkkinen⁷, Lee Darwent⁸, Michael G Heckman⁹, Sonja W Scholz¹⁰, Juan C Troncoso¹¹, Olga Pletnikova¹¹, Ted Dawson¹², Liana Rosenthal¹², Olaf Ansorge⁷, Jordi Clarimon¹³, Alberto Lleo¹³, Estrella Morenas-Rodriguez¹³, Lorraine Clark¹⁴, Lawrence S Honig¹⁴, Karen Marder¹⁴, Afina Lemstra¹⁵, Ekaterina Rogaeva¹⁶, Peter St George-Hyslop¹⁷, Elisabet Londos¹⁸, Henrik Zetterberg¹⁹, Imelda Barber²⁰, Anne Braae²⁰, Kristelle Brown²⁰, Kevin Morgan²⁰, Claire Troakes²¹, Safa Al-Sarraj²¹, Tammaryn Lashley²², Janice Holton²², Yaroslau Compta²³, Vivianna Van Deerlin²⁴, Geidy E Serrano²⁵, Thomas G Beach²⁵, Suzanne Lesage²⁶, Douglas Galasko²⁷, Eliezer Masliah²⁸, Isabel Santana²⁹, Pau Pastor³⁰, Monica Diez-Fairen³⁰, Miquel Aguilar³⁰, Pentti J Tienari³¹, Liisa Myllykangas³², Minna Oinas³³, Tamas Revesz²², Andrew Lees²², Brad F Boeve³⁴, Ronald C Petersen³⁴, Tanis J Ferman³⁵, Valentina Escott-Price³⁶, Neill Graff-Radford³⁷, Nigel J Cairns³⁸, John C Morris³⁸, Stuart Pickering-Brown³⁹, David Mann³⁹, Glenda M Halliday⁴⁰, John Hardy¹, John Q Trojanowski²⁴, Dennis W Dickson⁴, Andrew Singleton⁴¹, David J Stone⁴², Rita Guerreiro⁴³, Jose Bras⁴⁴

Affiliations

¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
² Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK.
³ Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA; German Center for Neurodegenerative Diseases (DZNE), Tubingen, Germany.
⁴ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁵ Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, MA, USA.
⁶ Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁷ Nuffield Department of Clinical Neurosciences, Oxford Parkinsons Disease Centre, University of Oxford, Oxford, UK.
⁸ UK Dementia Research Institute (UK DRI) at UCL, London, UK; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
⁹ Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA.
¹⁰ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹¹ Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹³ Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
¹⁴ Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
¹⁵ Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
¹⁶ Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Ontario, Canada.
¹⁷ Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Ontario, Canada; Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
¹⁸ Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Lund, Sweden.
¹⁹ UK Dementia Research Institute at UCL, London UK, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK and Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden.
²⁰ Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
²¹ Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
²² Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
²³ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK and Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Spain.
²⁴ Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.
²⁵ Banner Sun Health Research Institute, Sun City, AZ, USA.
²⁶ Inserm U1127, CNRS UMR7225, Sorbonne Universites, Institut du Cerveau et de la Moelle epiniere, Paris, France.
²⁷ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA.
²⁸ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
²⁹ Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.
³⁰ Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, and Fundacio de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain.
³¹ Molecular Neurology, Research Programs Unit, University of Helsinki, Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
³² Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³³ Department of Neuropathology and Neurosurgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
³⁴ Neurology Department, Mayo Clinic, Rochester, MN, USA.
³⁵ Department of Psychiatry and Department of Psychology, Mayo Clinic, Jacksonville, FL, USA.
³⁶ MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.
³⁷ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
³⁸ Knight Alzheimers Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
³⁹ Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
⁴⁰ Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia; Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia.
⁴¹ Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA.
⁴² Genetics and Pharmacogenomics, Merck and Co, West Point, PA, USA.
⁴³ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK; Department of Medical Sciences and Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro, Portugal.
⁴⁴ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK; Department of Medical Sciences and Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro, Portugal. Electronic address: j.bras@ucl.ac.uk.

PMID: 30448004
PMCID: PMC6541211
DOI: 10.1016/j.neurobiolaging.2018.10.019

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

Celia Kun-Rodrigues et al. Neurobiol Aging. 2019 Mar.

. 2019 Mar:75:223.e1-223.e10.

doi: 10.1016/j.neurobiolaging.2018.10.019. Epub 2018 Oct 24.

Authors

Affiliations

¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
² Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK.
³ Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA; German Center for Neurodegenerative Diseases (DZNE), Tubingen, Germany.
⁴ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁵ Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, MA, USA.
⁶ Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁷ Nuffield Department of Clinical Neurosciences, Oxford Parkinsons Disease Centre, University of Oxford, Oxford, UK.
⁸ UK Dementia Research Institute (UK DRI) at UCL, London, UK; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
⁹ Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA.
¹⁰ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹¹ Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹³ Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
¹⁴ Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
¹⁵ Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
¹⁶ Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Ontario, Canada.
¹⁷ Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Ontario, Canada; Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
¹⁸ Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Lund, Sweden.
¹⁹ UK Dementia Research Institute at UCL, London UK, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK and Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden.
²⁰ Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
²¹ Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
²² Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
²³ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK and Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Spain.
²⁴ Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.
²⁵ Banner Sun Health Research Institute, Sun City, AZ, USA.
²⁶ Inserm U1127, CNRS UMR7225, Sorbonne Universites, Institut du Cerveau et de la Moelle epiniere, Paris, France.
²⁷ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA.
²⁸ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
²⁹ Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.
³⁰ Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, and Fundacio de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain.
³¹ Molecular Neurology, Research Programs Unit, University of Helsinki, Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
³² Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³³ Department of Neuropathology and Neurosurgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
³⁴ Neurology Department, Mayo Clinic, Rochester, MN, USA.
³⁵ Department of Psychiatry and Department of Psychology, Mayo Clinic, Jacksonville, FL, USA.
³⁶ MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.
³⁷ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
³⁸ Knight Alzheimers Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
³⁹ Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
⁴⁰ Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia; Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia.
⁴¹ Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA.
⁴² Genetics and Pharmacogenomics, Merck and Co, West Point, PA, USA.
⁴³ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK; Department of Medical Sciences and Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro, Portugal.
⁴⁴ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK; Department of Medical Sciences and Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro, Portugal. Electronic address: j.bras@ucl.ac.uk.

PMID: 30448004
PMCID: PMC6541211
DOI: 10.1016/j.neurobiolaging.2018.10.019

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.

PubMed Disclaimer

Conflict of interest statement

5.Disclosure

The authors have no actual or potential conflicts of interest.

Figures

**Fig. 1.**
Schematic representation of statistically significant CNVs resulting from the case–control analysis that were not found in controls or publicy available databases. CVNs overlappig *LAPTM4B* in A; and *SPAG9/NME1* in B.Known transcripts are represented at the bottom of each panel. Passing QC SNPs used for the CNV calling are depicted by color according to the genotyping arrary (red: OmniExpress, blue: Omni2.5 M, green: Omni2.5 M for controls). CNVs (duplications) are depicted as bars above the genes. The gray shadow area represents the associated region that is genome-wide significant.

**Fig. 2.**
Duplication identified at the *SNCA* locus. Log R ratio and B alleie frequency plots of the CNV identified in the *SNCA* locus. Each point represents an SNP according to location in chromosome 4 (position on X axis). The genomic duplication is indicated by an increase in log R ratio and B allele frequency clusters outside the expected values of 1 (B/B), 0.5 (A/B), and 0 (A/A). Genes are represented at the bottom as black bars. SNPs inside the CNV region are represented in red. SNPs outside the CNV region are represented in blue, and SNPs in SNCA are represented in green.

**Fig. 3.**
Duplications identified at the *MAPT* locus. Log R ratio and B allele frequency plots of the CNVs identified at the *MAPT* locus in 2 clinically diagnosed DLB cases. Each point represents an SNP according to location in chromosome 17 (position on X axis). The genomic duplication is indicated by an increase in log R ratio and B allele frequency clusters outside the expected values of 1 (B/B), 0.5 (A/B), and 0 (A/A). Genes are represented at the bottom as black bars. SNPs inside the CNV regions are represented in red, SNPs outside the CNV regions are represented in blue, and SNPs in *MAPT* are represented in green.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous