Multicenter Study

. 2018 Jan;17(1):64-74.

doi: 10.1016/S1474-4422(17)30400-3. Epub 2017 Dec 16.

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

Rita Guerreiro¹, Owen A Ross², Celia Kun-Rodrigues³, Dena G Hernandez⁴, Tatiana Orme³, John D Eicher⁵, Claire E Shepherd⁶, Laura Parkkinen⁷, Lee Darwent³, Michael G Heckman⁸, Sonja W Scholz⁹, Juan C Troncoso¹⁰, Olga Pletnikova¹⁰, Olaf Ansorge⁷, Jordi Clarimon¹¹, Alberto Lleo¹¹, Estrella Morenas-Rodriguez¹¹, Lorraine Clark¹², Lawrence S Honig¹², Karen Marder¹², Afina Lemstra¹³, Ekaterina Rogaeva¹⁴, Peter St George-Hyslop¹⁵, Elisabet Londos¹⁶, Henrik Zetterberg¹⁷, Imelda Barber¹⁸, Anne Braae¹⁸, Kristelle Brown¹⁸, Kevin Morgan¹⁸, Claire Troakes¹⁹, Safa Al-Sarraj¹⁹, Tammaryn Lashley²⁰, Janice Holton²⁰, Yaroslau Compta²¹, Vivianna Van Deerlin²², Geidy E Serrano²³, Thomas G Beach²³, Suzanne Lesage²⁴, Douglas Galasko²⁵, Eliezer Masliah²⁶, Isabel Santana²⁷, Pau Pastor²⁸, Monica Diez-Fairen²⁸, Miquel Aguilar²⁸, Pentti J Tienari²⁹, Liisa Myllykangas³⁰, Minna Oinas³¹, Tamas Revesz²⁰, Andrew Lees²⁰, Brad F Boeve³², Ronald C Petersen³², Tanis J Ferman³³, Valentina Escott-Price³⁴, Neill Graff-Radford³⁵, Nigel J Cairns³⁶, John C Morris³⁶, Stuart Pickering-Brown³⁷, David Mann³⁷, Glenda M Halliday³⁸, John Hardy³⁹, John Q Trojanowski²², Dennis W Dickson², Andrew Singleton⁴⁰, David J Stone⁴¹, Jose Bras⁴²

Affiliations

¹ UK Dementia Research Institute, University College London, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Department of Medical Sciences and Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro, Portugal.
² Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
³ Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
⁴ Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA; German Center for Neurodegenerative Diseases, Tubingen, Germany.
⁵ Merck & Co, Boston, MA, USA.
⁶ Neuroscience Research Australia, Sydney, NSW, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
⁷ Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
⁸ Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA.
⁹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹⁰ Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ 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.
¹² Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
¹³ Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
¹⁴ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada; Department of Medicine, University of Toronto, ON, Canada.
¹⁵ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada; Department of Medicine, University of Toronto, ON, Canada; Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
¹⁶ Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Sweden.
¹⁷ UK Dementia Research Institute, University College London, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Molndal, Sweden.
¹⁸ Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
¹⁹ Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²⁰ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
²¹ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Parkinson's Disease & Movement Disorders Unit, Neurology Service, Hospital Clinic, IDIBAPS, CIBERNED, Department of Biomedicine, University of Barcelona, Barcelona, Spain.
²² Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²³ Banner Sun Health Research Institute, Sun City, AZ, USA.
²⁴ Inserm U1127, CNRS UMR7225, Sorbonne Universites, UPMC Univ Paris 06, UMR, Paris, France; S1127, Institut du Cerveau et de la Moelle epiniere, Paris, France.
²⁵ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA.
²⁶ Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA; Division of Neurosciences, National Institutes of Health, Bethesda, MD, USA.
²⁷ Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.
²⁸ Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Barcelona, Spain; Fundacio de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain.
²⁹ Molecular Neurology, Research Programs Unit, University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
³⁰ Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland; HUSLAB, Helsinki, Finland.
³¹ Department of Neurosurgery, University of Helsinki, Helsinki, Finland; Department of Neuropathology and Neurosurgery, Helsinki University Hospital, Helsinki, Finland.
³² Department of Neurology, Mayo Clinic, Rochester, MN, USA.
³³ Department of Psychiatry, Mayo Clinic, Jacksonville, FL, USA.
³⁴ MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.
³⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
³⁶ Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
³⁷ Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
³⁸ Neuroscience Research Australia, Sydney, NSW, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Brain and Mind Centre, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
³⁹ UK Dementia Research Institute, University College London, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
⁴⁰ Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
⁴¹ Merck & Co, West Point, PA, USA.
⁴² UK Dementia Research Institute, University College London, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Department of Medical Sciences and Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro, Portugal. Electronic address: j.bras@ucl.ac.uk.

PMID: 29263008
PMCID: PMC5805394
DOI: 10.1016/S1474-4422(17)30400-3

Multicenter Study

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

Rita Guerreiro et al. Lancet Neurol. 2018 Jan.

. 2018 Jan;17(1):64-74.

doi: 10.1016/S1474-4422(17)30400-3. Epub 2017 Dec 16.

Authors

Affiliations

¹ UK Dementia Research Institute, University College London, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Department of Medical Sciences and Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro, Portugal.
² Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
³ Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
⁴ Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA; German Center for Neurodegenerative Diseases, Tubingen, Germany.
⁵ Merck & Co, Boston, MA, USA.
⁶ Neuroscience Research Australia, Sydney, NSW, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
⁷ Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
⁸ Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA.
⁹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹⁰ Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ 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.
¹² Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
¹³ Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
¹⁴ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada; Department of Medicine, University of Toronto, ON, Canada.
¹⁵ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada; Department of Medicine, University of Toronto, ON, Canada; Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
¹⁶ Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Sweden.
¹⁷ UK Dementia Research Institute, University College London, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Molndal, Sweden.
¹⁸ Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
¹⁹ Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²⁰ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
²¹ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Parkinson's Disease & Movement Disorders Unit, Neurology Service, Hospital Clinic, IDIBAPS, CIBERNED, Department of Biomedicine, University of Barcelona, Barcelona, Spain.
²² Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²³ Banner Sun Health Research Institute, Sun City, AZ, USA.
²⁴ Inserm U1127, CNRS UMR7225, Sorbonne Universites, UPMC Univ Paris 06, UMR, Paris, France; S1127, Institut du Cerveau et de la Moelle epiniere, Paris, France.
²⁵ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA.
²⁶ Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA; Division of Neurosciences, National Institutes of Health, Bethesda, MD, USA.
²⁷ Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.
²⁸ Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Barcelona, Spain; Fundacio de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain.
²⁹ Molecular Neurology, Research Programs Unit, University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
³⁰ Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland; HUSLAB, Helsinki, Finland.
³¹ Department of Neurosurgery, University of Helsinki, Helsinki, Finland; Department of Neuropathology and Neurosurgery, Helsinki University Hospital, Helsinki, Finland.
³² Department of Neurology, Mayo Clinic, Rochester, MN, USA.
³³ Department of Psychiatry, Mayo Clinic, Jacksonville, FL, USA.
³⁴ MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.
³⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
³⁶ Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
³⁷ Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
³⁸ Neuroscience Research Australia, Sydney, NSW, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Brain and Mind Centre, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
³⁹ UK Dementia Research Institute, University College London, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
⁴⁰ Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
⁴¹ Merck & Co, West Point, PA, USA.
⁴² UK Dementia Research Institute, University College London, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Department of Medical Sciences and Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro, Portugal. Electronic address: j.bras@ucl.ac.uk.

PMID: 29263008
PMCID: PMC5805394
DOI: 10.1016/S1474-4422(17)30400-3

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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Conflict of interest statement

Declaration of interests

We declare no competing interests.

Figures

**Figure 1. Manhattan plot showing genome-wide p values of association**
The p values were obtained by logistic-regression analysis using the first six principal components and sex as covariates. The y axis shows −log₁₀ p values of 8 397 716 single nucleotide polymorphisms, and the x axis shows their chromosomal positions. The horizontal red dotted line represents the threshold of p=5 × 10⁻⁸ for Bonferroni significance and the green dotted line represents the threshold of p=5 × 10⁻⁶ for selecting single nucleotide polymorphisms for replication.

**Figure 2. Regional association plot for the *SNCA* locus**
Purple represents variant rs1372517, at chromosome 4, position 90755909, which is the most associated SNP at the locus also present in the 1000Genomes dataset. The variant rs1372517 is in complete linkage disequilibrium with rs7681440. Colours represent linkage disequilibrium derived from 1000Genomes between each variant and the most associated SNP. SNP=single nucleotide polymorphism. R² represents the level of pairwise linkage disequilibrium between the top variant and each other variant plotted, using data from the 1000 Genomes project.

**Figure 3. Associations between genotypes and gene expression in the cerebellum of post-mortem controls**
(A) Association between rs7681440 genotypes and *RP11-67M1.1* expression in 103 disease-free post-mortem cerebellum samples (p=2·00 × 10⁻⁷) from the Genotype-Tissue Expression (GTEx) Project Consortium. Carriers of the GG genotype (alternative allele) show the lowest levels of expression of the gene. Details on methods are on GTEx website. (B) Association between rs7681154 and *SNCA* expression (p=2·87 × 10⁻¹¹) in 468 disease-free cerebellum samples from postmortem individuals from the Harvard Brain Bank Resource Center. Individuals with the alternative allele C had increased *SNCA* expression in the cerebellum, on average, compared with individuals with the reference allele G. Details on the subjects, experiments, and analytical methods of the expression quantitative trait loci study of the Harvard Brain Bank Resource Center samples are described by Zhang and colleagues and on the Harvard Brain Bank website. Boxplots for both panels show medians, IQRs, and individual data points.

**Figure 4. Dementia with Lewy bodies heritability by chromosome**
Heritability (y axis) per chromosome is plotted against chromosome length (x axis). The red line represents heritability regressed on chromosome length and the shaded area represents the 95% CI of the regression model.

See this image and copyright information in PMC

Comment in

The genetic architecture of dementia with Lewy bodies is shaping up.
Fornage M. Fornage M. Lancet Neurol. 2018 Jan;17(1):25-26. doi: 10.1016/S1474-4422(17)30411-8. Epub 2017 Dec 16. Lancet Neurol. 2018. PMID: 29262999 No abstract available.

References

1. Rahkonen T, Eloniemi-Sulkava U, Rissanen S, Vatanen A, Viramo P, Sulkava R. Dementia with Lewy bodies according to the consensus criteria in a general population aged 75 years or older. J Neurol Neurosurg Psychiatry. 2003;74:720–24. - PMC - PubMed
1. Bogaerts V, Engelborghs S, Kumar-Singh S, et al. A novel locus for dementia with Lewy bodies: a clinically and genetically heterogeneous disorder. Brain. 2007;130:2277–91. - PubMed
1. Walker Z, Possin KL, Boeve BF, Aarsland D. Lewy body dementias. Lancet. 2015;386:1683–97. - PMC - PubMed
1. Keogh MJ, Kurzawa-Akanbi M, Griffin H, et al. Exome sequencing in dementia with Lewy bodies. Transl Psychiatry. 2016;6:e728. - PMC - PubMed
1. Geiger JT, Ding J, Crain B, et al. Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies. Neurobiol Dis. 2016;94:55–62. - PMC - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

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