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Cited by 270Parkinson's Disease Mechanisms and TreatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

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Guerreiro, Rita, Ross, Owen A, Kun-Rodrigues, Celia, Hernandez, Dena G, Orme, Tatiana, Eicher, John D, Shepherd, Claire E, Parkkinen, Laura +57 more·2018·The Lancet Neurology
DOI 10.1016/s1474-4422(17)30400-3PMC PMC5805394
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Abstract

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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  • The other mechanisms of APOE4 dysfunction probably explain the association with neurodegenerative diseases in general, such as Parkinson's disease, Lewy body dementia, TDP-43 proteinopathy, and vascular dementia.

    “The other mechanisms of APOE4 dysfunction probably explain the association with neurodegenerative diseases in general, such as Parkinson’s disease (odds ratio ~1.6–4.19) and Lewy body dementia (odds ratio ~2.4–6.1) (Bras et al, 2014; Guerreiro et al, 2018; Huang et al, 2006; Irwin et al, 2012; Tropea et al, 2018; Tsuang et al, 2013); TDP-43 proteinopathy (odds ratio ~2) (Josephs et al, 2014; Wenn”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Guerreiro et al, 2018

    The Results report an APOE association with dementia with Lewy bodies (OR 2.40), supporting the lower end of the cited range. The Discussion says APOE ε4 has been implicated in cognitive impairment within Parkinson’s disease, but not in Parkinson’s disease risk itself. The paper does not establish that other mechanisms of APOE4 dysfunction explain these associations. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Guerreiro, R., Ross, O. A., Kun-Rodrigues, C., Hernandez, D. G., Orme, T., Eicher, J. D., Shepherd, C. E., Parkkinen, L., Darwent, L., Heckman, M. G., Scholz, S. W., Troncoso, J. C., Pletnikova, O., Ansorge, O., Clarimon, J., Lleo, A., Morenas-Rodriguez, E., Clark, L., Honig, L. S., Marder, K., Lemstra, A., Rogaeva, E., St George-Hyslop, P., Londos, E., Zetterberg, H., Barber, I., Braae, A., Brown, K., Morgan, K., Troakes, C., Al-Sarraj, S., Lashley, T., Holton, J., Compta, Y., Van Deerlin, V., Serrano, G. E., Beach, T. G., Lesage, S., Galasko, D., Masliah, E., Santana, I., Pastor, P., Diez-Fairen, M., Aguilar, M., Tienari, P. J., Myllykangas, L., Oinas, M., Revesz, T., Lees, A., Boeve, B. F., Petersen, R. C., Ferman, T. J., Escott-Price, V., Graff-Radford, N., Cairns, N. J., Morris, J. C., Pickering-Brown, S., Mann, D., Halliday, G. M., Hardy, J., Trojanowski, J. Q., Dickson, D. W., Singleton, A., Stone, D. J., & Bras, J.
Affiliations
  • UK Dementia Research Institute (GB)
  • Mayo Clinic in Florida (US)
  • National Institutes of Health (US)
  • UCL Queen Square Institute of Neurology (GB)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • UNSW Sydney (AU)
  • University of Oxford (GB)
  • Mayo Clinic (US)
  • Johns Hopkins University (US)
  • Columbia University (US)
  • Amsterdam Neuroscience (NL)
  • University of Toronto (CA)
  • Lund University (SE)
  • University of Nottingham (GB)
  • King's College London (GB)
  • National Hospital for Neurology and Neurosurgery (GB)
  • Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
  • Banner Sun Health Research Institute (US)
  • Centre National de la Recherche Scientifique (FR)
  • University of California San Diego (US)
  • Unidade Local de Saúde de Coimbra (PT)
  • Instituto de Salud Carlos III (ES)
  • University of Helsinki (FI)
  • Washington University in St. Louis (US)
  • University of Manchester (GB)
  • The University of Sydney (AU)
  • University of Pennsylvania (US)
ORCID
Venue
The Lancet Neurology
Publisher
Elsevier BV
Published
2018-01
Volume
17
Issue
1
Pages
64-74
ISSN
1474-4422 (ISSN-L)
DOI
10.1016/s1474-4422(17)30400-3
PMC
PMC5805394
OpenAlex
W2774903942
Cited by
270
References
2
Citations by year
2026: 22 · 2025: 42 · 2024: 32 · 2023: 19 · 2022: 29 · 2021: 30 · 2020: 36 · 2019: 40 · 2018: 18 · 2017: 2
FWCI
17.86
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Neurology (acceptedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • Research Explorer (The University of Manchester) (publishedVersion, cc-by-nc-nd)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Oxford University Research Archive (ORA) (University of Oxford) (acceptedVersion)
  • HAL (submittedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • Nottingham ePrints (University of Nottingham) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion, cc-by-nc-nd)
  • Research Portal (King's College London) (submittedVersion, cc-by-nc-nd)
  • Lund University Publications (Lund University) (submittedVersion)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by-nc-nd)
  • DZNE Pub (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Medical Research Council
  • Generalitat de Catalunya
  • National Institute of Mental Health
  • Canadian Institutes of Health Research (PStG-H)
  • National Institute of Neurological Disorders and Stroke (R01# NS078086)
  • Helene Morgan Babcock and Alfred Babcock Memorial Scholarship Trust
  • Johns Hopkins University (HHSN268200782096C, P01 CA089392)
  • Autistica
  • Mayo Clinic
  • National Institute on Aging (U01 AG006786, P50 AG016574)
  • National Institute on Drug Abuse
  • Parkinson's Disease Foundation
  • Krembil Foundation
  • Neuroscience Research Australia
  • U.S. Department of Health and Human Services (AG000951-12)
  • National Health and Medical Research Council
  • Alzheimer's Society
  • National Heart, Lung, and Blood Institute
  • National Human Genome Research Institute
  • National Cancer Institute
  • National Institutes of Health (NS060113, P50AG008702, P50NS038370, UL1TR000040, R01 AR042742)
  • Wellcome Trust
  • University of New South Wales
  • California Sea Grant, University of California, San Diego (AG05131)
  • Michael J. Fox Foundation for Parkinson's Research
  • Helsingin ja Uudenmaan Sairaanhoitopiiri
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
dementia with Lewy bodies, genetic risk factors, apolipoprotein E, SNCA, glucocerebrosidase, MAPT, genetic architecture, Parkinson's disease, Alzheimer's disease, Lewy bodies, European ancestry, neuropathology, neurodegeneration, genotype imputation, replication study, rs429358
MeSH terms
Humans, Cohort Studies, Lewy Body Disease, Genome-Wide Association Study

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