TY - JOUR
T1 - Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
AU - Orme, Tatiana
AU - Hernandez, Dena
AU - Ross, Owen A.
AU - Kun-Rodrigues, Celia
AU - Darwent, Lee
AU - Shepherd, Claire E.
AU - Parkkinen, Laura
AU - Ansorge, Olaf
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 - Morgan, Kevin
AU - Troakes, Claire
AU - Al-Sarraj, Safa
AU - Lashley, Tammaryn
AU - Holton, Janice
AU - Compta, Yaroslau
AU - Van Deerlin, Vivianna
AU - Trojanowski, John Q.
AU - Serrano, Geidy E.
AU - Beach, Thomas G.
AU - Lesage, Suzanne
AU - Galasko, Douglas
AU - Masliah, Eliezer
AU - Santana, Isabel
AU - Pastor, Pau
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
AU - Stone, David J.
AU - Dickson, Dennis W.
AU - Hardy, John
AU - Singleton, Andrew
AU - Guerreiro, Rita
AU - Bras, Jose
N1 - Funding Information:
This work was supported in part by the National Institutes of Neurological Disease and Stroke and by the Alzheimer’s Society. TO was supported by a scholarship from the Lewy Body Society. We would like to thank Dr. Daniela Hansen from the Reta Lila Weston Institute at the Institute of Neurology, UCL. 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. We 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 Centre. We would like to thank the South West Dementia Brain Bank (SWDBB) for providing brain tissue for this study. The SWDBB is part of the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK and Alzheimer’s Society and is supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) and the Medical Research Council. Regarding the brain samples and/or bio samples that were obtained from The Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam (open access: www.brainbank.nl): all Material has 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 Canadian Consortium on Neurodegeneration in Aging (Rogaeva and St. George-Hyslop). 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 (L. Clark), P50AG008702 (P.I. Scott Small), P50NS038370 (P.I. R. Burke), and UL1TR000040 (P.I. H. Ginsberg). O.A.R. is supported by the Michael J. Fox Foundation, 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 Brain and Body Donation Program (TGB) has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. 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 Centre 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). The authors would like to thank the Genome Aggregation Database and the groups that provided exome and genome variant data for comparison. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/. 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, the Sigrid Juselius Foundation, the Folkhälsan Research Foundation and the Finnish Academy. HZ is a Wallenberg Academy Fellow and is further supported by the UK Dementia Research Institute at UCL, the European Research Council and the Swedish Research Council.
Publisher Copyright:
© 2020 The Author(s).
PY - 2020/1/29
Y1 - 2020/1/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078689290&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078689290&partnerID=8YFLogxK
U2 - 10.1186/s40478-020-0879-z
DO - 10.1186/s40478-020-0879-z
M3 - Article
C2 - 31996268
AN - SCOPUS:85078689290
SN - 2051-5960
VL - 8
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
IS - 1
M1 - 5
ER -