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

Lookup NU author(s): Professor Johannes Attems, Professor Ian McKeith, Dr Christopher Morris

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© The Author(s) 2024.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.

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Author(s): Wu LY, Real R, Martinez-Carrasco A, Chia R, Lawton MA, Shoai M, Bresner C, Blauwendraat C, Singleton AB, Ryten M, Scholz SW, Traynor BJ, Williams NM, Hu MTM, Ben-Shlomo Y, Grosset DG, Hardy J, Morris HR, Abramzon Y, Ahmed S, Alba C, Albert MS, Bacikova D, Barrett MJ, Beach TG, Bennett DA, Besser LM, Bigio EH, Boeve BF, Bohannan RC, Caraway CA, Palma J-A, Dalgard CL, Dickson D, Ding J, Faber K, Ferman T, Ferrucci L, Flanagan ME, Foroud TM, Ghetti B, Gibbs JR, Goate A, Goldstein D, Graff-Radford NR, Hu H-C, Hupalo D, Kaiser SM, Kaufmann H, Kim RC, Klein G, Kukull W, Kuzma A, Leverenz J, Lopez G, Mao Q, Martinez-McGrath E, Masliah E, Monuki E, Newell KL, Norcliffe-Kaufmann L, Perkins M, Pletnikova O, Renton AE, Resnick SM, Ross OA, Sabir MS, Scherzer CR, Serrano G, Shakkotai V, Sidransky E, Tanaka T, Tayebi N, Troncoso JC, Viollet C, Walton RL, Woltjer R, Wszolek ZK, Black SE, Gan-Or Z, Keith J, Masellis M, Rogaeva E, Aarsland D, Al-Sarraj S, Attems J, Ferrari R, Gentleman S, Hardy JA, Hodges AK, Love S, McKeith I, Morris CM, Palmer L, Pickering-Brown S, Reynolds RH, Thomas AJ, Tilley BS, Troakes C, Brett F, Brice A, Duyckaerts C, Lesage S, Brunetti M, Calvo A, Canosa A, Chio A, Floris G, Logroscino G, Zecca C, Clarimon J, Diez-Fairen M, Fortea J, Gonzalez-Aramburu I, Infante J, Lage C, Lleo A, Pastor P, Porcel-Molina L, Rodriguez-Rodriguez E, Sanchez-Juan P, Kruger R, May P, Xiromerisiou G

Publication type: Article

Publication status: Published

Journal: Brain Communications

Year: 2024

Volume: 6

Issue: 4

Online publication date: 31/05/2024

Acceptance date: 30/05/2024

Date deposited: 24/07/2024

ISSN (electronic): 2632-1297

Publisher: Oxford University Press

URL: https://doi.org/10.1093/braincomms/fcae190

DOI: 10.1093/braincomms/fcae190

Data Access Statement: TPD data are available upon access request from https:// www.dpag.ox.ac.uk/opdc/team/proband-tracking-parkinso ns. AMP-PD data are available upon registration at https:// www.amp-pd.org/. OPDC data are available upon request from the Dementias Platform UK (https://portal.dement iasplatform.uk/Apply). HapMap phase 3 data (HapMap3) are available for download at https://www.broadinstitute. org/medical-and-population-genetics/hapmap-3. Cis-QTL eQTLGen data were downloaded from (https://www. eqtlgen.org/cis-eqtls.html). eQTL data from eQTL catalogue can be ftp-accessed (https://www.ebi.ac.uk/eqtl/ Data_access/). Summary statistics from the Parkinson’s disease GWAS (Nalls et al.) 10 used to perform the PRS analysis are available from https://pdgenetics.org/resources. The source code is available on GitHub (https://github. com/huw-morris-lab/LBD-case-case-GWAS; https://doi. org/10.5281/zenodo.8335404)

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