Brain cell-type shifts in Alzheimer's disease, autism, and schizophrenia interrogated using methylomics and genetics

Chloe X. Yap, Daniel D. Vo, Matthew G. Heffel, Arjun Bhattacharya, Cindy Wen, Yuanhao Yang, Kathryn E. Kemper, Jian Zeng, Zhili Zheng, Zhihong Zhu, Eilis Hannon, Dorothea Seiler Vellame, Alice Franklin, Christa Caggiano, Brie Wamsley, Daniel H. Geschwind, Noah Zaitlen, Alexander Gusev, Bogdan Pasaniuc, Jonathan MillChongyuan Luo, Michael J. Gandal

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numberadn7655
JournalScience advances
Volume10
Issue number21
DOIs
StatePublished - 24 May 2024
Externally publishedYes

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