Regional genetic correlations highlight relationships between neurodegenerative diseases and the immune system

Abstract

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD) and amyotrophic lateral sclerosis (ALS), are devastating complex diseases that result in a physical and psychological burden to patients and their families. There have been significant efforts to understand the genetic basis of neurodegenerative diseases resulting in the identification of disease risk-associated variants involved in several molecular mechanisms, including those that influence immune-related pathways. Regional genetic correlations, in contrast to genome-wide correlations, between pairs of immune and neurodegenerative traits have not been comprehensively explored, but such a regional assessment could shed light on additional immune-mediated risk-associated loci. Here, we systematically assessed the potential role of the immune system in five neurodegenerative diseases, by estimating regional genetic correlations between neurodegenerative diseases and immune-cell-derived single-cell expression quantitative trait loci (sc-eQTLs), using the recently developed method of Local Analysis of [co]Variant Association (LAVA). We used the most recently published genome-wide association studies (GWASes) for five neurodegenerative diseases and publicly available sc-eQTLs derived from 982 individuals from the OneK1K Consortium, capturing aspects of the innate and adaptive immune systems. Additionally, we tested GWASes from well-established immune-mediated diseases, Crohn's disease (CD) and ulcerative colitis (UC), the immune-mediated neurodegenerative disease, multiple sclerosis (MS) and a well-powered GWAS with strong signal in the HLA region, schizophrenia (SCZ), as positive controls. Finally, we also performed regional genetic correlations between diseases and protein levels. We observed significant (FDR < 0.01) regional genetic correlations between sc-eQTLs and neurodegenerative diseases across 151 unique genes, spanning both the innate and adaptive immune systems, across most diseases tested (except for frontotemporal dementia (FTD) and LBD). Colocalization analyses on followed-up regional correlations highlighted immune-related candidate causal risk genes associated with neurodegenerative diseases. We also observed significant regional correlations with protein levels across 156 unique proteins, across all diseases tested, except for FTD. The outcomes of this study will improve our understanding of the immune component of neurodegeneration, which can be potentially used to repurpose existing immunotherapies used in clinical care for other immune-mediated diseases, to slow the progression of neurodegenerative diseases.

Competing Interest Statement

SWS serves on the Scientific Advisory Council of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. She receives research support from Cerevel Therapeutics.

Funding Statement

This research was enabled in part by support provided by Calcul Quebec (https://www.calculquebec.ca/) and the Digital Research Alliance of Canada (alliancecan.ca). SAGT was funded by a Junior 1 award from the Fonds de recherche du Quebec - Sante (FRQS; https://frq.gouv.qc.ca) and by Operational Funds from the Institut de valorisation des donnees (IVADO; https://ivado.ca). SAGT and FLD acknowledge support from a Canadian Institutes of Health Research (CIHR) Project Grant (PJT 183817). SWS was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (program #: ZIANS003154). MR was supported through the award of a UKRI Medical Research Council Clinician Scientist Fellowship (MRC Grant Code: MR/N008324/1).

Author Declarations

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

Yes

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

Source data were openly available before the initiation of this study. The sources of the different datasets used in the study can be located as follows. pQTLs: http://nilanjanchatterjeelab.org/pwas/ eQTLs: https://onek1k.org/ Alzheimer's GWAS: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90012001-GCST90013000/GCST90012877/ ALS GWAS: https://www.projectmine.com/research/download-data/ Chron's disease GWAS: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST004001-GCST005000/GCST004132/ FTD GWAS: https://ifgcsite.wordpress.com/data-access/ Lewy Body dementia GWAS: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90001001-GCST90002000/GCST90001390/ Multiple Sclerosis GWAS: https://imsgc.net/?page_id=31 Parkinson's disease GWAS: https://www.pdgenetics.org/resources Schizophrenia GWAS: https://pgc.unc.edu/for-researchers/download-results/ Ulcerative colitis: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST004001-GCST005000/GCST004133/

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

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).

Yes

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.

Yes

Data Availability

The source of each GWAS summary statistics file is provided in Supplementary Table 1. OneK1K sc-eQTL summary statistics that include effect sizes and standard errors were provided through personal communication with the corresponding author. pQTL summary statistics are available from http://nilanjanchatterjeelab.org/pwas/. All code generated for performing the analyses in the present study is available in the following GitHub repository: https://github.com/GaglianoTaliun-Lab/neuroimmune_genetics_project.

https://github.com/GaglianoTaliun-Lab/neuroimmune_genetics_project

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