Brain cell-type shifts in Alzheimer’s disease, autism, and schizophrenia interrogated using methylomics and genetics-Reference-Cited by-同舟云学术

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

Published:2024-05-24 Issue:21 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Yap Chloe X.¹²³⁴^ORCID,Vo Daniel D.³⁴⁵⁶⁷^ORCID,Heffel Matthew G.⁵⁸,Bhattacharya Arjun⁹¹⁰¹¹¹²^ORCID,Wen Cindy³⁴⁵^ORCID,Yang Yuanhao¹²^ORCID,Kemper Kathryn E.²^ORCID,Zeng Jian²^ORCID,Zheng Zhili²^ORCID,Zhu Zhihong²¹³^ORCID,Hannon Eilis¹⁴^ORCID,Vellame Dorothea Seiler¹⁴^ORCID,Franklin Alice¹⁴^ORCID,Caggiano Christa⁸¹⁵,Wamsley Brie³⁴¹⁵¹⁶^ORCID,Geschwind Daniel H.³⁴⁵¹⁵¹⁶^ORCID,Zaitlen Noah¹⁵¹⁷^ORCID,Gusev Alexander¹⁸¹⁹²⁰^ORCID,Pasaniuc Bogdan⁵⁸⁹¹⁷²¹,Mill Jonathan¹⁴^ORCID,Luo Chongyuan⁵,Gandal Michael J.³⁴⁵⁶⁷^ORCID

Affiliation:

1. Mater Research Institute, University of Queensland, Brisbane, Queensland, Australia.

2. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

3. Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

4. Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

5. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

6. Lifespan Brain Institute at Penn Medicine and The Children’s Hospital of Philadelphia, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.

7. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

8. Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA, USA.

9. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

10. Institute for Quantitative and Computational Biosciences, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

11. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

12. Institute for Data Science in Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

13. The National Centre for Register-based Research, Aarhus University, Denmark.

14. Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.

15. Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.

16. Center for Autism Research and Treatment, Semel Institute, University of California, Los Angeles, Los Angeles, CA, USA.

17. Department of Computational Medicine, University of California Los Angeles, Los Angeles, CA, USA.

18. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

19. Division of Genetics, Brigham & Women’s Hospital, Boston, MA, USA.

20. Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.

21. Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adn7655

Reference112 articles.

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2. Microglia in Alzheimer’s disease

3. Altered human oligodendrocyte heterogeneity in multiple sclerosis

4. Using genetic data to strengthen causal inference in observational research

5. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci

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