A machine learning approach to brain epigenetic analysis reveals kinases associated with Alzheimer’s disease

• Published in: Nature communications Vol. 12; no. 1; pp. 4472 - 12
• Main Authors: Huang, Yanting, Sun, Xiaobo, Jiang, Huige, Yu, Shaojun, Robins, Chloe, Armstrong, Matthew J., Li, Ronghua, Mei, Zhen, Shi, Xiaochuan, Gerasimov, Ekaterina Sergeevna, De Jager, Philip L., Bennett, David A., Wingo, Aliza P., Jin, Peng, Wingo, Thomas S., Qin, Zhaohui S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-07-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114/2397; 631/208/176/1988; 692/617/375/132/1283; Alzheimer Disease - enzymology; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Arrays; Brain; Brain - metabolism; Brain - pathology; Cohort Studies; Computational neuroscience; CpG Islands; DNA Methylation; Environmental factors; Epigenesis, Genetic; Epigenetics; Epigenomics - methods; Genes; Genome-Wide Association Study - methods; Genomes; Humanities and Social Sciences; Humans; Kinases; Learning algorithms; Loci; Machine learning; multidisciplinary; Neurodegenerative diseases; Pathogenesis; Protein Kinases - genetics; Protein Kinases - metabolism; Science; Science (multidisciplinary); Supervised Machine Learning
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24710-8

Alzheimer’s disease (AD) is influenced by both genetic and environmental factors; thus, brain epigenomic alterations may provide insights into AD pathogenesis. Multiple array-based Epigenome-Wide Association Studies (EWASs) have identified robust brain methylation changes in AD; however, array-based assays only test about 2% of all CpG sites in the genome. Here, we develop EWASplus, a computational method that uses a supervised machine learning strategy to extend EWAS coverage to the entire genome. Application to six AD-related traits predicts hundreds of new significant brain CpGs associated with AD, some of which are further validated experimentally. EWASplus also performs well on data collected from independent cohorts and different brain regions. Genes found near top EWASplus loci are enriched for kinases and for genes with evidence for physical interactions with known AD genes. In this work, we show that EWASplus implicates additional epigenetic loci for AD that are not found using array-based AD EWASs.
Array-based epigenome-wide association studies only test about 2% of the CpG sites in the genome. Here, the authors describe EWASplus, a supervised machine learning strategy that extends EWAS coverage to the entire genome, and use it to identify novel brain CpGs associated with Alzheimer’s disease.