TY - JOUR
T1 - Investigating the genetic architecture of dementia with Lewy bodies
T2 - a two-stage genome-wide association study
AU - Guerreiro, Rita
AU - Ross, Owen A.
AU - Kun-Rodrigues, Celia
AU - Hernandez, Dena G.
AU - Orme, Tatiana
AU - Eicher, John D.
AU - Shepherd, Claire E.
AU - Parkkinen, Laura
AU - Darwent, Lee
AU - Heckman, Michael G.
AU - Scholz, Sonja W.
AU - Troncoso, Juan C.
AU - Pletnikova, Olga
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 - Bras, Jose
N1 - Funding Information:
The authors would like to thank Ian McKeith for his continued support and encouragement. This study was supported in part by the National Institutes of Neurological Disease and Stroke. JB and RG's work is funded by research fellowships from the Alzheimer's Society. TO is supported 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 a National Health and Medical Research Council senior principal research fellowship. We would like to 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. We acknowledge the Oxford Brain Bank, supported by the Medical Research Council, Brains for Dementia Research (Alzheimer's Society and Alzheimer's Research UK), Autistica UK, and the National Institute for Health Research Oxford Biomedical Research Centre. The brain samples and bio samples were obtained from The Netherlands Brain Bank , Netherlands Institute for Neuroscience, Amsterdam. All tissue samples were collected from donors with written informed consent for a brain autopsy, and the use of the material and clinical information for research purposes was obtained by the Netherlands Brain Bank. This study was also partly funded by the Wellcome Trust, the Medical Research Council, and the Canadian Institutes of Health Research (PStG-H). Research from YC was supported by the CERCA Programme, Generalitat de Catalunya, Barcelona, Catalonia, Spain. The Nottingham Genetics Group is supported by Alzheimer's Research UK and The Big Lottery Fund. The contributions from Columbia University were supported by the Taub Institute, the Panasci Fund, the Parkinson's Disease Foundation, and National Institutes of Health grants NS060113 (LC), P50AG008702, P50NS038370, and UL1TR000040. 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, the Mangurian Foundation Program for Lewy Body Dementia research, and the Alzheimer Disease Research Center (P50 AG016547). The research from the Mayo Clinic Rochester is supported by the National Institute on Aging (P50 AG016574 and U01 AG006786). This research has received support from The Queen Square Brain Bank at the University College London Institute of Neurology (where TL is funded by an Alzheimer's Research UK senior fellowship). Some of the tissue samples studied were provided by the Medical Research Council London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer's Society and Alzheimer's Research UK). This research was supported in part by both the National Institute for Health Research University College London Hospital Biomedical Research Centre and the Queen Square Dementia Biomedical Research Unit. This research 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 University of California San Diego are supported by National Institutes of Health grant AG05131. The authors thank the brain bank GIE NeuroCEB and the French program Investissements d'avenir (ANR-10-IAIHU-06). PJT and LM are supported by the Helsinki University Central Hospital, the Folkhälsan Research Foundation, and the Finnish Academy. This research was partly supported by the Canadian Consortium on Neurodegeneration in Aging (ER). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the National Cancer Institute; the National Human Genome Research Institute; the National Heart, Lung, and Blood Institute; the National Institute on Drug Abuse; the National Institute of Mental Health; and the National Institute of Neurological Disorders and Stroke. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on April 1, 2017. The authors acknowledge the contribution of data from Genetic Architecture of Smoking and Smoking Cessation accessed through the database of Genotypes and Phenotypes. Funding support for genotyping, which was done 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 and general study coordination was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of datasets 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). The data used for the analyses described in this Article were obtained from the database of Genotypes and Phenotypes . Genotype and phenotype data for the Genetic Analysis of Psoriasis and Psoriatic Arthritis study were provided by James T Elder (University of Michigan), with collaborators Dafna Gladman (University of Toronto) and Proton Rahman (Memorial University of Newfoundland) providing samples. This research 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's 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. James T Elder is supported by the Ann Arbor Veterans Affairs Hospital (NIH R01 AR042742). The authors would like to thank the Genome Aggregation Database and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found online.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/1
Y1 - 2018/1
N2 - Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14–2·70; p=1·05 × 10−48), SNCA (rs7681440; OR 0·73, 0·66–0·81; p=6·39 × 10−10), an GBA (rs35749011; OR 2·55, 1·88–3·46; p=1·78 × 10−9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27–1·79; p=2·32 × 10−6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease. Funding The Alzheimer's Society and the Lewy Body Society.
AB - Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14–2·70; p=1·05 × 10−48), SNCA (rs7681440; OR 0·73, 0·66–0·81; p=6·39 × 10−10), an GBA (rs35749011; OR 2·55, 1·88–3·46; p=1·78 × 10−9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27–1·79; p=2·32 × 10−6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease. Funding The Alzheimer's Society and the Lewy Body Society.
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U2 - 10.1016/S1474-4422(17)30400-3
DO - 10.1016/S1474-4422(17)30400-3
M3 - Article
C2 - 29263008
AN - SCOPUS:85039561634
SN - 1474-4422
VL - 17
SP - 64
EP - 74
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 1
ER -