TY - JOUR
T1 - Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases
AU - FinnGen
AU - Lindbohm, Joni V.
AU - Mars, Nina
AU - Sipilä, Pyry N.
AU - Singh-Manoux, Archana
AU - Runz, Heiko
AU - Livingston, Gill
AU - Seshadri, Sudha
AU - Xavier, Ramnik
AU - Hingorani, Aroon D.
AU - Ripatti, Samuli
AU - Kivimäki, Mika
N1 - Funding Information:
The Whitehall II study was supported by the Wellcome Trust (no. 221854/Z/20/Z), the UK Medical Research Council (no. R024227), the National Institute on Aging (National Institutes of Health, nos. R01AG056477 and RF1AG062553), the British Heart Foundation (no. RG/16/11/32334) and SomaLogic, Inc. In the Whitehall II study, some proteins were measured as an academic–industry partnership project beween UCL and SomaLogic, Inc., which provided expertise in plasma proteins and funded 2,240 SOMAscan assays. In this study, SomaLogic had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. J.V.L. was supported by the Academy of Finland (no. 339568) and the Päivikki and Sakari Sohlberg foundation. N.M. was supported by the Academy of Finland (no. 331671). P.N.S. was supported by the Emil Aaltonen Foundation. G.L. is supported by University College London Hospitals’ National Institute for Health Research (NIHR) Biomedical Research Centre, North Thames NIHR Applied Research Collaboration, as an NIHR Senior Investigator, and by the Wellcome Trust (no. 221854/Z/20/Z) and the UK Medical Research Council (no. MR/S011676,). A.D.H. was supported by the UCL British Heart Foundation Accelerator (no. AA/18/6/34223), the UCL NIHR Biomedical Research Centre and the UKRI/NIHR-funded Multimorbidity Mechanism and Therapeutics Research Collaborative (no. MR/V033867/1). A.D.H. is a NIHR Senior Investigator. S.R. was supported by the Academy of Finland (nos. 285380 and 312062), the Sigrid Jusélius Foundation and University of Helsinki HiLIFE Fellow grant nos. 2017–2020. M.K. was supported by the Wellcome Trust (no. 221854/Z/20/Z), the UK Medical Research Council (nos. MR/S011676 and MR/R024227), the US National Institute on Aging (nos. R01AG062553 and R01AG056477), NordForsk (no. 75021), the Academy of Finland (nos. 311492 and 350426), the Helsinki Institute of Life Science (no. H970) and the Finnish Work Environment Fund (no. 190424). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/10
Y1 - 2022/10
N2 - Immune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood–brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-β, tau and α-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n = 339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer’s disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49–0.88, P = 0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases.
AB - Immune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood–brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-β, tau and α-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n = 339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer’s disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49–0.88, P = 0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases.
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U2 - 10.1038/s43587-022-00293-x
DO - 10.1038/s43587-022-00293-x
M3 - Article
AN - SCOPUS:85140283665
SN - 2662-8465
VL - 2
SP - 956
EP - 972
JO - Nature Aging
JF - Nature Aging
IS - 10
ER -