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 - 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
C2 - 37118290
AN - SCOPUS:85140283665
SN - 2662-8465
VL - 2
SP - 956
EP - 972
JO - Nature Aging
JF - Nature Aging
IS - 10
ER -