Heritability and genetic variance of dementia with Lewy bodies

Rita Guerreiro¹, Valentina Escott-Price², Dena G Hernandez³, Celia Kun-Rodrigues⁴, Owen A Ross⁵, Tatiana Orme¹, Joao Luis Neto¹, Susana Carmona¹, Nadia Dehghani¹, John D Eicher⁶, Claire Shepherd⁷, Laura Parkkinen⁸, Lee Darwent⁹, Michael G Heckman¹⁰, Sonja W Scholz¹¹, Juan C Troncoso¹², Olga Pletnikova¹², Ted Dawson¹³, Liana Rosenthal¹³, Olaf Ansorge⁸, Jordi Clarimon¹⁴, Alberto Lleo¹⁴, Estrella Morenas-Rodriguez¹⁵, Lorraine Clark¹⁶, Lawrence S Honig¹⁶, Karen Marder¹⁶, Afina Lemstra¹⁷, Ekaterina Rogaeva¹⁸, Peter St George-Hyslop¹⁹, Elisabet Londos²⁰, Henrik Zetterberg²¹, Imelda Barber²², Anne Braae²², Kristelle Brown²², Kevin Morgan²², Claire Troakes²³, Safa Al-Sarraj²³, Tammaryn Lashley²⁴, Janice Holton²⁴, Yaroslau Compta²⁵, Vivianna Van Deerlin²⁶, Geidy E Serrano²⁷, Thomas G Beach²⁷, Suzanne Lesage²⁸, Douglas Galasko²⁹, Eliezer Masliah³⁰, Isabel Santana³¹, Pau Pastor³², Monica Diez-Fairen³², Miquel Aguilar³², Pentti J Tienari³³, Liisa Myllykangas³⁴, Minna Oinas³⁵, Tamas Revesz²⁴, Andrew Lees²⁴, Brad F Boeve³⁶, Ronald C Petersen³⁶, Tanis J Ferman³⁷, Neill Graff-Radford³⁸, Nigel J Cairns³⁹, John C Morris³⁹, Stuart Pickering-Brown⁴⁰, David Mann⁴⁰, Glenda M Halliday⁴¹, John Hardy⁴, John Q Trojanowski²⁶, Dennis W Dickson⁵, Andrew Singleton⁴²; International Parkinson's Disease Genomics Consortium; David J Stone⁴³, Jose Bras⁴⁴

Affiliations

¹ Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK.
² UK Dementia Research Institute (UK DRI) at Cardiff, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.
³ Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA; German Center for Neurodegenerative Diseases (DZNE)-Tubingen, Germany.
⁴ Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
⁵ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁶ Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, MA, USA.
⁷ Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁸ Nuffield Department of Clinical Neurosciences, Oxford Parkinsons Disease Centre, University of Oxford, Oxford, UK.
⁹ UK Dementia Research Institute (UK DRI) at UCL, London, UK.
¹⁰ Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA.
¹¹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹² Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁴ Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.
¹⁵ 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.
¹⁶ Taub Institute for Alzheimer Disease and the Aging Brain, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
¹⁷ Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
¹⁸ Tanz Centre for Research in Neurodegenerative Diseases and department of Medicine, University of Toronto, Ontario, Canada.
¹⁹ Tanz Centre for Research in Neurodegenerative Diseases and department of Medicine, University of Toronto, Ontario, Canada; Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
²⁰ Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Sweden.
²¹ UK Dementia Research Institute at UCL, London UK, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden.
²² Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
²³ Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
²⁴ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
²⁵ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK, Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Catalonia, Spain.
²⁶ 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.
²⁷ Banner Sun Health Research Institute, 10515 W Santa Fe Drive, Sun City, AZ 85351, USA.
²⁸ Inserm U1127, CNRS UMR7225, Sorbonne Universites, UPMC Univ Paris 06, UMR and S1127, Institut du Cerveau et de la Moelle epiniere, Paris, France.
²⁹ Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States, Veterans Affairs San Diego Healthcare System, La Jolla, CA, United States.
³⁰ Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States, Department of Pathology, University of California, San Diego, La Jolla, CA, United States.
³¹ Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine and Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
³² Memory Unit, Department of Neurology,University Hospital Mutua de Terrassa, University of Barcelona, Fundacion de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain.
³³ Molecular Neurology, Research Programs Unit, University of Helsinki, Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
³⁴ Department of Pathology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.
³⁵ Department of Neuropathology and Neurosurgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
³⁶ Neurology Department, Mayo Clinic, Rochester, MN, USA.
³⁷ Department of Psychiatry and Department of Psychology, Mayo Clinic, Jacksonville, FL, USA.
³⁸ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
³⁹ Knight Alzheimers Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
⁴⁰ Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
⁴¹ Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia; Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia.
⁴² Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA.
⁴³ Genetics and Pharmacogenomics, Merck Research Laboratories, West Point, PA, USA.
⁴⁴ Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK. Electronic address: j.bras@ucl.ac.uk.

PMID: 30953760
PMCID: PMC6588425
DOI: 10.1016/j.nbd.2019.04.004

Heritability and genetic variance of dementia with Lewy bodies

Rita Guerreiro et al. Neurobiol Dis. 2019 Jul.

. 2019 Jul:127:492-501.

doi: 10.1016/j.nbd.2019.04.004. Epub 2019 Apr 3.

Authors

Affiliations

¹ Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK.
² UK Dementia Research Institute (UK DRI) at Cardiff, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.
³ Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA; German Center for Neurodegenerative Diseases (DZNE)-Tubingen, Germany.
⁴ Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
⁵ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁶ Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, MA, USA.
⁷ Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁸ Nuffield Department of Clinical Neurosciences, Oxford Parkinsons Disease Centre, University of Oxford, Oxford, UK.
⁹ UK Dementia Research Institute (UK DRI) at UCL, London, UK.
¹⁰ Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA.
¹¹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹² Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁴ Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.
¹⁵ 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.
¹⁶ Taub Institute for Alzheimer Disease and the Aging Brain, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
¹⁷ Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
¹⁸ Tanz Centre for Research in Neurodegenerative Diseases and department of Medicine, University of Toronto, Ontario, Canada.
¹⁹ Tanz Centre for Research in Neurodegenerative Diseases and department of Medicine, University of Toronto, Ontario, Canada; Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
²⁰ Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Sweden.
²¹ UK Dementia Research Institute at UCL, London UK, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden.
²² Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
²³ Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
²⁴ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
²⁵ Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK, Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Catalonia, Spain.
²⁶ 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.
²⁷ Banner Sun Health Research Institute, 10515 W Santa Fe Drive, Sun City, AZ 85351, USA.
²⁸ Inserm U1127, CNRS UMR7225, Sorbonne Universites, UPMC Univ Paris 06, UMR and S1127, Institut du Cerveau et de la Moelle epiniere, Paris, France.
²⁹ Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States, Veterans Affairs San Diego Healthcare System, La Jolla, CA, United States.
³⁰ Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States, Department of Pathology, University of California, San Diego, La Jolla, CA, United States.
³¹ Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine and Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
³² Memory Unit, Department of Neurology,University Hospital Mutua de Terrassa, University of Barcelona, Fundacion de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain.
³³ Molecular Neurology, Research Programs Unit, University of Helsinki, Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
³⁴ Department of Pathology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.
³⁵ Department of Neuropathology and Neurosurgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
³⁶ Neurology Department, Mayo Clinic, Rochester, MN, USA.
³⁷ Department of Psychiatry and Department of Psychology, Mayo Clinic, Jacksonville, FL, USA.
³⁸ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
³⁹ Knight Alzheimers Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
⁴⁰ Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
⁴¹ Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia; Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia.
⁴² Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA.
⁴³ Genetics and Pharmacogenomics, Merck Research Laboratories, West Point, PA, USA.
⁴⁴ Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK. Electronic address: j.bras@ucl.ac.uk.

PMID: 30953760
PMCID: PMC6588425
DOI: 10.1016/j.nbd.2019.04.004

Abstract

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

Keywords: Dementia; Genetic correlation; Genetic variance; Lewy bodies.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Statement

Dr Shepherd and Halliday from Australia report no conflict of interests for this work.

Figures

**Figure 1:**
Estimate of the DLB variance explained by HRC-imputed variants by MAF and LD. Segmental LD score increases from the 1st to 4th quartiles. Negative scores are not shown for simplicity but are present in Supplementary Table 1. The estimates of variance explained are from the GREML-LDMS analyses of fitting all the 24 genetic components simultaneously.

**Figure 2:**
Proportion of variance of DLB case-control status explained by PRSs from AD (A), AD excluding the *APOE* locus (B), PD (C) and PD excluding the GBA locus (D). The bars represent PRSs calculated for 9 subsets of markers at different p-value thresholds in the original GWAS publications. Best scores for each PRS are presented in (D). R²: Nagelkerke’s pseudo-R²; Threshold: P-value threshold in original GWAS.

**Figure 3:**
Correlation scores with p-value <0.01 in DLB. Shown are also the scores for those same traits in PD and AD.

See this image and copyright information in PMC

References

1. Aramillo Irizar P, Schäuble S, Esser D, Groth M, Frahm C, Priebe S, Baumgart M, Hartmann N, Marthandan S, Menzel U, Müller J, Schmidt S, Ast V, Caliebe A, König R, Krawczak M, Ristow M, Schuster S, Cellerino A, Diekmann S, Englert C, Hemmerich P, Sühnel J, Guthke R, Witte OW, Platzer M, Ruppin E, Kaleta C, 2018. Transcriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly. Nat. Commun 9, 327. - PMC - PubMed
1. Barnes DE, Yaffe K, 2011. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 10, 819–828. - PMC - PubMed
1. Benyamin B, Pourcain B, Davis OS, Davies G, Hansell NK, Brion M-JA, Kirkpatrick RM, Cents RAM, Franic S, Miller MB, Haworth CMA, Meaburn E, Price TS, Evans DM, Timpson N, Kemp J, Ring S, McArdle W, Medland SE, Yang J, Harris SE, Liewald DC, Scheet P, Xiao X, Hudziak JJ, de Geus EJC, Wellcome Trust Case Control Consortium 2 (WTCCC2), Jaddoe VWV, Starr JM, Verhulst FC, Pennell C, Tiemeier H, Iacono WG, Palmer LJ, Montgomery GW, Martin NG, Boomsma DI, Posthuma D, McGue M, Wright MJ, Davey Smith G, Deary IJ, Plomin R, Visscher PM, 2014. Childhood intelligence is heritable, highly polygenic and associated with FNBP1L. Mol. Psychiatry 19, 253–258. - PMC - PubMed
1. Boyle EA, Li YI, Pritchard JK, 2017. An Expanded View of Complex Traits: From Polygenic to Omnigenic. Cell 169, 1177–1186. - PMC - PubMed
1. Bras J, Guerreiro R, Darwent L, Parkkinen L, Ansorge O, Escott-Price V, Hernandez DG, Nalls MA, Clark LN, Honig LS, Marder K, Van Der Flier WM, Lemstra A, Scheltens P, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Ortega Cubero S, Pastor P, Ferman TJ, Graff-Radford NR, Ross OA, Barber I, Braae A, Brown K, Morgan K, Maetzler W, Berg D, Troakes C, Al-Sarraj S, Lashley T, Compta Y, Revesz T, Lees A, Cairns N, Halliday GM, Mann D, Pickering-Brown S, Dickson DW, Singleton A, Hardy J, 2014. Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum. Mol. Genet 23, 6139–6146. - PMC - PubMed

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Heritability and genetic variance of dementia with Lewy bodies

Affiliations

Heritability and genetic variance of dementia with Lewy bodies

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical