Neurodegenerative diseases are a group of disorders characterised by neuronal cell death causing a variety of physical and mental problems. While these disorders can be characterised by their phenotypic presentation within the nervous system, their aetiologies differ to varying degrees. Some disorders, such as Lewy body dementia and Parkinson's disease, show overlap in the major proteins found in aggregates, and some diseases, like Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease, are influenced by the same non-neuronal cell types (microglia), suggesting partly shared aetiologies. The identification of shared genetic risk factors common to many neurodegenerative diseases may highlight fundamental biological processes involved in neurodegeneration and provide promising targets for treatment and drug repurposing. The majority of genetic evidence for overlap between neurodegenerative diseases has been pairwise, with little genetic evidence for genes or biological processes found across more than two neurodegenerative diseases. In this study, we aimed to identify overlap between the four investigated neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease) at the variant, gene, genomic locus, gene-set, cell, or tissue level, with specific interest in overlap between three or more diseases. Using local genetic correlation, we found that the TMEM175 locus was a shared locus between amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease, and the HLA region was shared between Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. We also highlighted genes, genomic loci, gene-sets, cell types, and tissue types which may be important to two or more disorders by analysing the association of variants with a common factor estimated from the four disorders. Our study successfully highlighted genetic loci and tissues associated with two or more neurodegenerative diseases.

The authors have declared no competing interest.

DP was funded by The Netherlands Organization for Scientific Research (NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057). DW was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). IEJ was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). JES was supported by funding from the Amsterdam Neuroscience Alliance Project. CR was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SurfSARA.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The data used in this study were obtained from 4 previous studies, three of studies have publically available data. Access to data from Nalls et al. (2019), Chia et al. (2021), and van Rheenen et al. (2021) is possible through their original publications. Nalls et al. (2019) https://doi.org/10.1016/s1474-4422(19)30320-5 Chia et al. (2019) https://doi.org/10.1038/s41588-021-00785-3 van Rheenen et al. (2021) https://doi.org/10.1038/s41588-021-00973-1 The remaining data included in this study was obtained by request from Wightman et al. (2021) https://doi.org/10.1038/s41588-021-00921-z. For this data, informed consent was obtained from all participants and complied with all relevant ethical regulations. The dataset approval for this data is included below: deCODE: The study was approved by the National Bioethics Committee and the Icelandic Data Protection Authority. STSA: approved by the Regional Ethics Board in Stockholm and the Institutional Review Board at the University of Southern California. TwinGene: approved by the Regional Ethics Board in Stockholm.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

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The summary statistics from the common factor model analysis and AD summary statistics will be made available at https://ctg.cncr.nl/software/summary_statistics after publication. The summary statistics for the ALS, LBD, and PD can be obtained from their original publications: Nalls et al. (2019) https://doi.org/10.1016/s1474-4422(19)30320-5 Chia et al. (2019) https://doi.org/10.1038/s41588-021-00785-3 van Rheenen et al. (2021) https://doi.org/10.1038/s41588-021-00973-1.