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

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

doi:10.1093/braincomms/fcae190

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

Brain Commun. 2024 May 31;6(4):fcae190. doi: 10.1093/braincomms/fcae190. eCollection 2024.

Authors

Lesley Yue Wu^{1

2

3}, Raquel Real^{1

2

3}, Alejandro Martinez-Carrasco^{1

2

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

6

7}, Catherine Bresner⁸, Cornelis Blauwendraat^{9

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

11

12

13

14}; International Lewy Body Dementia Genomics Consortium; Sonja W Scholz^{15

16}, Bryan J Traynor^{4

16

17}, Nigel M Williams⁸, Michele T M Hu^{18

19}, Yoav Ben-Shlomo⁵, Donald G Grosset²⁰, John Hardy^{3

6

7

17

21

22}, Huw R Morris^{1

2

3}

Collaborators

International Lewy Body Dementia Genomics Consortium:
Yevgeniya Abramzon, Sarah Ahmed, Camille Alba, Marilyn S Albert, Dagmar Bacikova, Matthew J Barrett, Thomas G Beach, David A Bennett, Lilah M Besser, Eileen H Bigio, Bradley F Boeve, Ryan C Bohannan, Chad A Caraway, Jose-Alberto Palma, Ruth Chia, Clifton L Dalgard, Dennis Dickson, Jinhui Ding, Kelley Faber, Tanis Ferman, Luigi Ferrucci, Margaret E Flanagan, Tatiana M Foroud, Bernardino Ghetti, J Raphael Gibbs, Alison Goate, David Goldstein, Neill R Graff-Radford, Heng-Chen Hu, Daniel Hupalo, Scott M Kaiser, Horacio Kaufmann, Ronald C Kim, Gregory Klein, Walter Kukull, Amanda Kuzma, James Leverenz, Grisel Lopez, Qinwen Mao, Elisa Martinez-McGrath, Eliezer Masliah, Ed Monuki, Kathy L Newell, Lucy Norcliffe-Kaufmann, Matthew Perkins, Olga Pletnikova, Alan E Renton, Susan M Resnick, Owen A Ross, Marya S Sabir, Clemens R Scherzer, Sonja W Scholz, Geidy Serrano, Vikram Shakkotai, Ellen Sidransky, Andrew B Singleton, Toshiko Tanaka, Nahid Tayebi, Bryan J Traynor, Juan C Troncoso, Coralie Viollet, Ronald L Walton, Randy Woltjer, Zbigniew K Wszolek, Sandra E Black, Ziv Gan-Or, Julia Keith, Mario Masellis, Ekaterina Rogaeva, Dag Aarsland, Safa Al-Sarraj, Johannes Attems, Raffaele Ferrari, Steve Gentleman, John A Hardy, Angela K Hodges, Seth Love, Ian McKeith, Christopher M Morris, Huw R Morris, Laura Palmer, Stuart Pickering-Brown, Regina H Reynolds, Mina Ryten, Alan J Thomas, Bension S Tilley, Claire Troakes, Francesca Brett, Alexis Brice, Charles Duyckaerts, Suzanne Lesage, Maura Brunetti, Andrea Calvo, Antonio Canosa, Adriano Chiò, Gianluca Floris, Giancarlo Logroscino, Chiara Zecca, Jordi Clarimon, Monica Diez-Fairen, Juan Fortea, Isabel González-Aramburu, Jon Infante, Carmen Lage, Alberto Lleó, Pau Pastor, Laura Porcel-Molina, Eloy Rodríguez-Rodríguez, Pascual Sanchez-Juan, Rejko Krüger, Patrick May, Georgia Xiromerisiou

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 20814, 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 20814, USA.
¹⁰ Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, MD 20892, USA.
¹¹ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
¹² Genetics and Genomic Medicine, NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK.
¹³ UK Dementia Research Institute at The University of Cambridge, Cambridge, UK.
¹⁴ Department of Clinical Neurosciences, School of Clinical Medicine, The University of Cambridge, Cambridge, UK.
¹⁵ Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
¹⁶ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD 21287, USA.
¹⁷ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK.
¹⁸ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford, Oxford OX3 9DU, UK.
¹⁹ Oxford Parkinson's Disease Centre, University of Oxford, Oxford OX1 3QU, UK.
²⁰ School of Neuroscience and Psychology, University of Glasgow, Glasgow G12 8QQ, UK.
²¹ National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London W1T 7DN, UK.
²² 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 the 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 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study 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 allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

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

Grants and funding

P30 AG066518/AG/NIA NIH HHS/United States