Publication Date
5-24-2024
Journal
Science Advances
Abstract
Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer's disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer's disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial cell loss contributes to Alzheimer's disease, with comparable effect size to APOE genotype among older people. Genome-wide association identified five genetic loci related to cell-type composition, involving plausible genes for the neurovascular unit (P2RX5 and TRPV3) and excitatory neurons (DPY30 and MEMO1). These results implicate specific cell-type shifts in the pathophysiology of neuropsychiatric disorders.
Keywords
Humans, Alzheimer Disease, Schizophrenia, DNA Methylation, Brain, Autistic Disorder, Male, Female, Genome-Wide Association Study, Aged, Endothelial Cells, Epigenomics, Middle Aged, Aged, 80 and over
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Mental and Social Health Commons, Neurology Commons, Neurosciences Commons, Psychiatry and Psychology Commons
Comments
Supplementary Materials
PMID: 38781333