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

Autor: Yap CX; Mater Research Institute, University of Queensland, Brisbane, Queensland, Australia.; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Vo DD; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Lifespan Brain Institute at Penn Medicine and The Children's Hospital of Philadelphia, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Heffel MG; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA, USA., Bhattacharya A; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Institute for Quantitative and Computational Biosciences, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Institute for Data Science in Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Wen C; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Yang Y; Mater Research Institute, University of Queensland, Brisbane, Queensland, Australia.; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia., Kemper KE; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia., Zeng J; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia., Zheng Z; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia., Zhu Z; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.; The National Centre for Register-based Research, Aarhus University, Denmark., Hannon E; Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK., Vellame DS; Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK., Franklin A; Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK., Caggiano C; Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA, USA.; Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA., Wamsley B; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.; Center for Autism Research and Treatment, Semel Institute, University of California, Los Angeles, Los Angeles, CA, USA., Geschwind DH; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.; Center for Autism Research and Treatment, Semel Institute, University of California, Los Angeles, Los Angeles, CA, USA., Zaitlen N; Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.; Department of Computational Medicine, University of California Los Angeles, Los Angeles, CA, USA., Gusev A; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.; Division of Genetics, Brigham & Women's Hospital, Boston, MA, USA.; Medical and Population Genetics, Broad Institute, Cambridge, MA, USA., Pasaniuc B; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Department of Computational Medicine, University of California Los Angeles, Los Angeles, CA, USA.; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA., Mill J; Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK., Luo C; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Gandal MJ; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Lifespan Brain Institute at Penn Medicine and The Children's Hospital of Philadelphia, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 May 24; Vol. 10 (21), pp. eadn7655. Date of Electronic Publication: 2024 May 23.
DOI: 10.1126/sciadv.adn7655
Abstrakt: 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.
Databáze: MEDLINE