Investigation of the genetic aetiology of Lewy body diseases with and without dementia
Author:
Wu Lesley Yue123ORCID, Real Raquel123ORCID, Martinez-Carrasco Alejandro123, Chia Ruth4ORCID, Lawton Michael A5ORCID, Shoai Maryam367, Bresner Catherine8ORCID, Blauwendraat Cornelis910ORCID, Singleton Andrew B10, Ryten Mina311121314ORCID, , Abramzon Yevgeniya, Ahmed Sarah, Alba Camille, Albert Marilyn S, Bacikova Dagmar, Barrett Matthew J, Beach Thomas G, Bennett David A, Besser Lilah M, Bigio Eileen H, Boeve Bradley F, Bohannan Ryan C, Caraway Chad A, Palma Jose-Alberto, Chia Ruth, Dalgard Clifton L, Dickson Dennis, Ding Jinhui, Faber Kelley, Ferman Tanis, Ferrucci Luigi, Flanagan Margaret E, Foroud Tatiana M, Ghetti Bernardino, Gibbs J Raphael, Goate Alison, Goldstein David, Graff-Radford Neill R, Hu Heng-Chen, Hupalo Daniel, Kaiser Scott M, Kaufmann Horacio, Kim Ronald C, Klein Gregory, Kukull Walter, Kuzma Amanda, Leverenz James, Lopez Grisel, Mao Qinwen, Martinez-McGrath Elisa, Masliah Eliezer, Monuki Ed, Newell Kathy L, Norcliffe-Kaufmann Lucy, Perkins Matthew, Pletnikova Olga, Renton Alan E, Resnick Susan M, Ross Owen A, Sabir Marya S, Scherzer Clemens R, Scholz Sonja W, Serrano Geidy, Shakkotai Vikram, Sidransky Ellen, Singleton Andrew B, Tanaka Toshiko, Tayebi Nahid, Traynor Bryan J, Troncoso Juan C, Viollet Coralie, Walton Ronald L, Woltjer Randy, Wszolek Zbigniew K, Black Sandra E, Gan-Or Ziv, Keith Julia, Masellis Mario, Rogaeva Ekaterina, Aarsland Dag, Al-Sarraj Safa, Attems Johannes, Ferrari Raffaele, Gentleman Steve, Hardy John A, Hodges Angela K, Love Seth, McKeith Ian, Morris Christopher M, Morris Huw R, Palmer Laura, Pickering-Brown Stuart, Reynolds Regina H, Ryten Mina, Thomas Alan J, Tilley Bension S, Troakes Claire, Brett Francesca, Brice Alexis, Duyckaerts Charles, Lesage Suzanne, Brunetti Maura, Calvo Andrea, Canosa Antonio, Chiò Adriano, Floris Gianluca, Logroscino Giancarlo, Zecca Chiara, Clarimon Jordi, Diez-Fairen Monica, Fortea Juan, González-Aramburu Isabel, Infante Jon, Lage Carmen, Lleó Alberto, Pastor Pau, Porcel-Molina Laura, Rodríguez-Rodríguez Eloy, Sanchez-Juan Pascual, Krüger Rejko, May Patrick, Xiromerisiou Georgia, Scholz Sonja W1516ORCID, Traynor Bryan J41617, Williams Nigel M8ORCID, Hu Michele T M1819ORCID, Ben-Shlomo Yoav5, Grosset Donald G20ORCID, Hardy John367172122, Morris Huw R123ORCID
Affiliation:
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
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.
Funder
Aligning Science Across Parkinson's Michael J. Fox Foundation Parkinson's Research Medical Research Council MRC National Institute for Health Research University College London Hospitals Biomedical Research Centre University College London Movement Disorders Centre Edmond J. Safra Philanthropic Foundation
Publisher
Oxford University Press (OUP)
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