open access publication

Article, 2024

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

Science Advances, ISSN 2375-2548, Volume 10, 21, Page eadn7655, 10.1126/sciadv.adn7655

Contributors

Yap, Chloe X 0000-0002-1788-2842 (Corresponding author) [1] [2] Vo, Daniel D 0000-0003-2057-969X [1] [3] Heffel, Matthew G [1] Bhattacharya, Arjun 0000-0003-1196-4385 [1] [4] Wen, Cindy 0000-0001-8747-8231 [1] Yang, Yuanhao 0000-0002-5857-0124 [2] Kemper, Kathryn E 0000-0002-9288-4522 [2] Zeng, Jian 0000-0001-8801-5220 [2] Zheng, Zhili [2] Zhu, Zhi-Hong 0000-0002-6783-3037 [2] [5] Hannon, Eilis J 0000-0001-6840-072X [6] Vellame, Dorothea Seiler 0000-0002-6905-0474 [6] Franklin, Alice [6] Caggiano, Christa 0000-0001-5755-1274 [1] Wamsley, Brie [1] Geschwind, Daniel H [1] Zaitlen, Noah A 0000-0002-3553-3670 [1] Gusev, Alexander S 0000-0002-7980-4620 [7] [8] [9] [10] Pasaniuc, Bogdan 0000-0002-0227-2056 [1] Mill, Jonathan Sutherland 0000-0003-1115-3224 [6] Luo, Chongyuan [1] Gandal, Michael J 0000-0001-5800-5128 (Corresponding author) [1] [3]

Affiliations

  1. [1] University of California, Los Angeles
    2. [NORA names: United States; America, North; OECD];
  2. [2] University of Queensland
    3. [NORA names: Australia; Oceania; OECD];
  3. [3] University of Pennsylvania
    4. [NORA names: United States; America, North; OECD];
  4. [4] The University of Texas MD Anderson Cancer Center
    5. [NORA names: United States; America, North; OECD];
  5. [5] Aarhus University
    6. [NORA names: AU Aarhus University; University; Denmark; Europe, EU; Nordic; OECD];

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

Alzheimer, Alzheimer's disease, DNA, DNA methylation profiles, advances, association, autism, biomarkers, brain, cell loss, cell types, cell-type composition, cells, changes, composition, compositional shifts, consensus, decreased oligodendrocytes, disease, disorders, effect, endothelial cell loss, evidence, excitatory neurons, foundational questions, functional units, genes, genetics, genome-wide association, genotypes, high-resolution, increased microglia, individuals, lack consensus, large-scale molecular studies, layers of evidence, leverage, leverage advances, loss, methylation profiles, methylome, microglia, molecular studies, multiple layers, multiple layers of evidence, neurons, neuropsychiatric disorders, neurovascular unit, older people, oligodendrocytes, pathophysiology, pathophysiology of neuropsychiatric disorders, people, postmortem, postmortem brains, profile, quantitative shifts, questions, results, schizophrenia, sex-related changes, shift, single-cell methylomes, study, type, units

Funders

  • Simons Foundation
  • National Center for Advancing Translational Sciences
  • National Institute of Mental Health
  • National Institute on Drug Abuse
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
  • Illinois Department of Public Health
  • National Institute on Aging

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