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

Lesley Wu; Raquel Real; Alejandro Martinez; Ruth Chia; Michael A Lawton; Maryam Shoai; Catherine Bresner; Leon Hubbard; Cornelis Blauwendraat; Andrew B Singleton; Mina Ryten; Sonja W Scholz; Bryan J Traynor; Nigel Williams; Michele T M Hu; Yoav Ben-Shlomo; Donald G Grosset; John Hardy; Huw R Morris; International LBD Genomic Consortium

doi:10.1101/2023.10.17.23297157

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

medRxiv [Preprint]. 2023 Oct 27:2023.10.17.23297157. doi: 10.1101/2023.10.17.23297157.

Authors

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.

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.

Publication types

Preprint

Abstract

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