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[Preprint]. 2023 Oct 27:2023.10.17.23297157.

doi: 10.1101/2023.10.17.23297157.

Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Lesley Wu^{1

2

3}, Raquel Real^{1

2

3}, Alejandro Martinez^{1

2

3}, Ruth Chia⁴, Michael A Lawton⁵, Maryam Shoai^{3

6

7}, Catherine Bresner⁸, Leon Hubbard⁸, Cornelis Blauwendraat^{9

10}, Andrew B Singleton¹⁰, Mina Ryten^{3

11

12}, Sonja W Scholz^{13

14}, Bryan J Traynor^{4

14

15}, Nigel Williams⁸, Michele T M Hu^{16

17}, Yoav Ben-Shlomo⁵, Donald G Grosset¹⁸, John Hardy^{3

6

7

15

19

20}, Huw R Morris^{1

2

3}; International LBD Genomic Consortium

Affiliations

¹ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
² UCL Movement Disorders Centre, University College London, London WC1N 3BG, UK.
³ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
⁴ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
⁵ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PS, UK.
⁶ Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
⁷ UK Dementia Research Institute, University College London, London WC1E 6BT, UK.
⁸ Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff CF24 4HQ, UK.
⁹ Integrative Neurogenomics Unit, National Institute on Aging, Bethesda, MD, USA.
¹⁰ Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, MD, USA.
¹¹ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
¹² NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK.
¹³ Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
¹⁴ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁵ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK.
¹⁶ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford, Oxford OX3 9DU, UK.
¹⁷ Oxford Parkinson's Disease Centre, University of Oxford, Oxford OX1 3QU, UK.
¹⁸ School of Neuroscience and Psychology, University of Glasgow, Glasgow G51 4TF, UK.
¹⁹ National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London W1T 7DN, UK.
²⁰ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.

PMID: 37987016
PMCID: PMC10659505
DOI: 10.1101/2023.10.17.23297157

Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Lesley Wu et al. medRxiv. 2023.

[Preprint]. 2023 Oct 27:2023.10.17.23297157.

doi: 10.1101/2023.10.17.23297157.

Authors

Affiliations

¹ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
² UCL Movement Disorders Centre, University College London, London WC1N 3BG, UK.
³ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
⁴ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
⁵ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PS, UK.
⁶ Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
⁷ UK Dementia Research Institute, University College London, London WC1E 6BT, UK.
⁸ Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff CF24 4HQ, UK.
⁹ Integrative Neurogenomics Unit, National Institute on Aging, Bethesda, MD, USA.
¹⁰ Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, MD, USA.
¹¹ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
¹² NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK.
¹³ Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
¹⁴ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁵ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK.
¹⁶ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford, Oxford OX3 9DU, UK.
¹⁷ Oxford Parkinson's Disease Centre, University of Oxford, Oxford OX1 3QU, UK.
¹⁸ School of Neuroscience and Psychology, University of Glasgow, Glasgow G51 4TF, UK.
¹⁹ National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London W1T 7DN, UK.
²⁰ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.

PMID: 37987016
PMCID: PMC10659505
DOI: 10.1101/2023.10.17.23297157

Update in

Investigation of the genetic aetiology of Lewy body diseases with and without dementia.
Wu LY, Real R, Martinez-Carrasco A, Chia R, Lawton MA, Shoai M, Bresner C, Blauwendraat C, Singleton AB, Ryten M; International Lewy Body Dementia Genomics Consortium; Scholz SW, Traynor BJ, Williams NM, Hu MTM, Ben-Shlomo Y, Grosset DG, Hardy J, Morris HR. Wu LY, et al. Brain Commun. 2024 May 31;6(4):fcae190. doi: 10.1093/braincomms/fcae190. eCollection 2024. Brain Commun. 2024. PMID: 38978726 Free PMC article.

Abstract

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be key to understanding disease pathways and ultimately therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7,804 patients of European ancestry from Tracking Parkinson's (PRoBaND), The Oxford Discovery Cohort, and AMP-PD. We conducted a discrete phenotype genome-wide association studies comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk alleles rs429358 tagging APOEe4 and rs7668531 near the MMRN1 and SNCA-AS1 genes, increase the odds of developing dementia and that an intronic variant rs17442721 tagging LRRK2 G2019S, on chromosome 12 is protective against dementia. These results should be validated in autopsy confirmed cases in future studies.

Keywords: Lewy body diseases; dementia; genome-wide association studies.

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Conflict of interest statement

Competing interests Dr Morris is employed by UCL. In the last 12 months he reports paid consultancy from Roche, Aprinoia, AI Therapeutics and Amylyx ; lecture fees/honoraria - BMJ, Kyowa Kirin, Movement Disorders Society. Research Grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, Medical Research Council, Michael J Fox Foundation. Dr Morris is a co-applicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140)

Figures

**Figure 1.. Manhattan plot of LBD - D vs LBD - ND**
A Manhattan plot representing the results of the GWAS comparing LBD with dementia (LBD-D) to LBD without dementia (LBD-ND), highlight genome-wide significant SNPs on chromosome 4, 12 and 19. Negative logarithm p-value is represented on the Y axis while chromosome position is represented on the X axis. The dotted line indicates genome-wide significant threshold (5×10–8)

**Figure 2.. Regional association plot for eQTL and GWAS signals**
Regional association plot for eQTL and 1) GWAS signal in the region close to LRRK2 (PPH4 = 0.72) and 2) in the region close to FAM181B (PPH4 = 0.70). Negative logarithm p-value is represented on the Y axis while chromosome position is represented on the X axis.

**Figure 3.. Polygenic risk score from PD, AD and DLB GWAS**
Violin plot comparing z-transformed 1) Parkinson’s disease, 2) Alzheimer’s disease and 3) Dementia with Lewy body polygenic risk score distributions in PD and PDD. The centreline of the box plot represents the median and the box limits are the interquartile range. Dots correspond to outliers.

See this image and copyright information in PMC

References

1. Goedert M, Spillantini MG, Del Tredici K, Braak H. 100 years of Lewy pathology. Nat Rev Neurol. 2013. Jan;9(1):13–24. - PubMed
1. Muslimovic D, Post B, Speelman JD, Schmand B. Cognitive profile of patients with newly diagnosed Parkinson disease [Internet]. Vol. 65, Neurology. 2005. p. 1239–45. Available from: 10.1212/01.wnl.0000180516.69442.95 - DOI - PubMed
1. Hely MA, Reid WGJ, Adena MA, Halliday GM, Morris JGL. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord. 2008. Apr 30;23(6):837–44. - PubMed
1. Lo RY, Tanner CM, Albers KB, Leimpeter AD, Fross RD, Bernstein AL, et al. Clinical features in early Parkinson disease and survival. Arch Neurol. 2009. Nov;66(11):1353–8. - PubMed
1. McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017. Jul 4;89(1):88–100. - PMC - PubMed

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This is a preprint.

Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Affiliations

Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

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References

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