Cross-tissue meta-analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease

Author:

Silva Tiago C.ORCID,Young Juan I.,Zhang Lanyu,Gomez Lissette,Schmidt Michael A.,Varma Achintya,Chen X. Steven,Martin Eden R.,Wang LilyORCID

Abstract

ABSTRACTWe performed a meta-analysis of two large independent blood-based Alzheimer’s disease (AD) epigenome-wide association studies, the ADNI and AIBL studies, and identified 5 CpGs, mapped to the SPIDR, CDH6 genes, and intergenic regions, that were significantly associated with AD diagnosis. A cross-tissue analysis that combined these blood DNA methylation datasets with four additional methylation datasets prioritized 97 CpGs and 10 genomic regions that are significantly associated with both AD neuropathology and AD diagnosis. Our integrative analysis revealed expressions levels of 13 genes and 10 pathways were significantly associated with the AD-associated methylation differences in both brain and blood, many are involved in the immune responses in AD, such as the CD79A, LY86, SP100, CD163, CD200, and MS4A1 genes and the neutrophil degranulation, antigen processing and presentation, interferon signaling pathways. An out-of-sample validation using the AddNeuroMed dataset showed the best performing logistic regression model included age, sex, cell types and methylation risk score based on prioritized CpGs from cross-tissue analysis (AUC = 0.696, 95% CI: 0.616 - 0.770, P-value = 2.78 × 10−5). Our study provides a valuable resource for future mechanistic and biomarker studies in AD.

Publisher

Cold Spring Harbor Laboratory

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