Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

Tatiana Orme¹, Dena Hernandez², Owen A Ross³, Celia Kun-Rodrigues⁴, Lee Darwent¹, Claire E Shepherd⁵, Laura Parkkinen⁶, Olaf Ansorge⁶, Lorraine Clark⁷, Lawrence S Honig⁷, Karen Marder⁷, Afina Lemstra⁸, Ekaterina Rogaeva⁹, Peter St George-Hyslop⁹, Elisabet Londos¹⁰, Henrik Zetterberg^{1

11}, Kevin Morgan¹², Claire Troakes¹³, Safa Al-Sarraj¹³, Tammaryn Lashley¹⁴, Janice Holton¹⁴, Yaroslau Compta^{14

15}, Vivianna Van Deerlin¹⁶, John Q Trojanowski¹⁶, Geidy E Serrano¹⁷, Thomas G Beach¹⁷, Suzanne Lesage^{18

19}, Douglas Galasko¹⁹, Eliezer Masliah²⁰, Isabel Santana²¹, Pau Pastor^{22

23}, Pentti J Tienari²⁴, Liisa Myllykangas²⁵, Minna Oinas²⁶, Tamas Revesz¹⁴, Andrew Lees¹⁴, Brad F Boeve²⁷, Ronald C Petersen²⁸, Tanis J Ferman²⁸, Valentina Escott-Price²⁹, Neill Graff-Radford³⁰, Nigel J Cairns³¹, John C Morris³², Stuart Pickering-Brown³², David Mann³², Glenda Halliday⁵, David J Stone³³, Dennis W Dickson³, John Hardy¹, Andrew Singleton², Rita Guerreiro⁴, Jose Bras³⁴

Affiliations

¹ UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
² Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA.
³ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁴ Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.
⁵ Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁶ Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
⁷ Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology and Neurology, Columbia University Medical Center, New York, NY, USA.
⁸ Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
⁹ Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.
¹⁰ Clinical Memory Research Unit, Institution of Clinical Sciences Malmö, Lund University, Lund, Sweden.
¹¹ Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
¹² Human Genetics, School of Life Sciences, University of Nottingham, Nottingham, UK.
¹³ Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹⁴ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
¹⁵ Parkinson's Disease & Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clínic, Institut de Neurociències, University Universitat de Barcelona, IDIBAPS, Barcelona, Catalonia, Spain.
¹⁶ Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, Philadelphia, USA.
¹⁷ Banner Sun Health Research Institute, 10515 W Santa Fe Drive, Sun City, AZ, 85351, USA.
¹⁸ Sorbonne Université, Université Pierre et Marie Curie-Paris 06, Inserm, Centre National de la Reserche Scientifique, and Institute du Cerveau et de la Moelle épinière, Paris, France.
¹⁹ Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France.
²⁰ Division of Neurosciences and Laboratory of Neurogenetics, National Institute on Aging/NIH, Bethesda, MD, USA.
²¹ Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.
²² Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain.
²³ Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
²⁴ Translational Immunology, Research Programs Unit, Department of Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
²⁵ Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
²⁶ Department of Neuropathology and Neurosurgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
²⁷ Neurology Department, Mayo Clinic, Rochester, MN, USA.
²⁸ Department of Psychiatry and Department of Psychology, Mayo Clinic, Jacksonville, FL, USA.
²⁹ UK Dementia Research Institute at Cardiff and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.
³⁰ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
³¹ Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
³² Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
³³ Genetics and Pharmacogenomics, Merck & Co., Inc., West Point, PA, USA.
³⁴ Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA. Jose.Bras@vai.org.

PMID: 31996268
PMCID: PMC6990558
DOI: 10.1186/s40478-020-0879-z

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

Tatiana Orme et al. Acta Neuropathol Commun. 2020.

. 2020 Jan 29;8(1):5.

doi: 10.1186/s40478-020-0879-z.

Authors

Affiliations

¹ UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
² Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA.
³ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁴ Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.
⁵ Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁶ Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
⁷ Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology and Neurology, Columbia University Medical Center, New York, NY, USA.
⁸ Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
⁹ Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.
¹⁰ Clinical Memory Research Unit, Institution of Clinical Sciences Malmö, Lund University, Lund, Sweden.
¹¹ Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
¹² Human Genetics, School of Life Sciences, University of Nottingham, Nottingham, UK.
¹³ Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹⁴ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
¹⁵ Parkinson's Disease & Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clínic, Institut de Neurociències, University Universitat de Barcelona, IDIBAPS, Barcelona, Catalonia, Spain.
¹⁶ Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, Philadelphia, USA.
¹⁷ Banner Sun Health Research Institute, 10515 W Santa Fe Drive, Sun City, AZ, 85351, USA.
¹⁸ Sorbonne Université, Université Pierre et Marie Curie-Paris 06, Inserm, Centre National de la Reserche Scientifique, and Institute du Cerveau et de la Moelle épinière, Paris, France.
¹⁹ Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France.
²⁰ Division of Neurosciences and Laboratory of Neurogenetics, National Institute on Aging/NIH, Bethesda, MD, USA.
²¹ Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.
²² Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain.
²³ Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
²⁴ Translational Immunology, Research Programs Unit, Department of Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
²⁵ Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
²⁶ Department of Neuropathology and Neurosurgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
²⁷ Neurology Department, Mayo Clinic, Rochester, MN, USA.
²⁸ Department of Psychiatry and Department of Psychology, Mayo Clinic, Jacksonville, FL, USA.
²⁹ UK Dementia Research Institute at Cardiff and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.
³⁰ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
³¹ Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
³² Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
³³ Genetics and Pharmacogenomics, Merck & Co., Inc., West Point, PA, USA.
³⁴ Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA. Jose.Bras@vai.org.

PMID: 31996268
PMCID: PMC6990558
DOI: 10.1186/s40478-020-0879-z

Abstract

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

References

1. Adib-Samii P, Brice G, Martin RJ, Markus HS. Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype: study in 200 consecutively recruited individuals. Stroke. 2010;41:630–634. doi: 10.1161/STROKEAHA.109.568402. - DOI - PubMed
1. Amberger J, Bocchini CA, Scott AF, Hamosh A. McKusick’s Online Mendelian Inheritance in Man (OMIM®) Nucleic Acids Res. 2009;37:D793–D796. doi: 10.1093/nar/gkn665. - DOI - PMC - PubMed
1. Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT. Data quality control in genetic case-control association studies. Nat Protoc. 2010;5:1564–1573. doi: 10.1038/nprot.2010.116. - DOI - PMC - PubMed
1. Arai T, Mackenzie IRA, Hasegawa M, Nonoka T, Niizato K, Tsuchiya K, et al. Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol. 2009;117:125–136. doi: 10.1007/s00401-008-0480-1. - DOI - PubMed
1. Arosio B, Abbate C, Galimberti D, Rossi PD, Inglese S, Fenoglio C, et al. GRN Thr272fs clinical heterogeneity: a case with atypical late onset presenting with a dementia with Lewy bodies phenotype. J Alzheimers Dis. 2013;35:669–674. doi: 10.3233/JAD-130053. - DOI - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Consumer Health Information
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

Affiliations

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous