Multi-region omics analysis of microglia in postmortem human brains with neuropsychiatric disorders and elucidation of sex-specific pathophysiology via cross-species comparison with mouse models

The objective of the proposed research is to elucidate the molecular mechanisms underlying psychiatric and neurological disorders by investigating disease-, sex-, and brain region-specific alterations in human microglia. Specifically, we aim to identify inflammatory and transcriptional signatures associated with major depressive disorder, schizophrenia, bipolar disorder, Alzheimer's disease, and progressive supranuclear palsy, and evaluate their conservation through cross-species comparisons with stress-exposed mouse microglial RNA-seq datasets generated in our laboratory.
This study is a retrospective secondary analysis of de-identified datasets obtained from NIAGADS (NG00105), including human postmortem microglial RNA-seq, genotype, and clinical metadata. The study includes healthy controls and individuals with Alzheimer's disease, major depressive disorder, schizophrenia, bipolar disorder, and progressive supranuclear palsy. Analyses will include four brain regions: the middle frontal gyrus (MFG), superior temporal gyrus (STG), thalamus (THA), and subventricular zone (SVZ).
The analysis plan includes differential gene expression, linear mixed-effects modeling, sex- and brain region-specific analyses, and genotype-associated analyses. Genetic variants will be evaluated in association with transcriptomic phenotypes, including gene expression (eQTLs), alternative splicing (sQTLs), disease diagnosis, sex, brain region, and age-related molecular changes. Statistical models will adjust for age, sex, postmortem interval, cerebrospinal fluid pH, ancestry components, and sequencing quality metrics. Pathway and gene set enrichment analyses, together with cross-species comparisons using human–mouse orthologous genes, will identify conserved inflammatory and disease-associated molecular pathways.
No new participants, interventions, or biospecimen collection are involved. All analyses will use de-identified datasets in accordance with the NIAGADS Data Use Agreement and NIH Genomic Data Sharing Policy. No formal collaboration with investigators at other institutions is currently planned.

This study aims to better understand how specialized immune cells in the brain, called microglia, contribute to psychiatric and neurological disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer's disease. We will analyze publicly available genetic and gene expression data from donated human brain tissue and compare the findings with data from mouse models previously generated in our laboratory to identify biological mechanisms shared between humans and mice.
We will examine whether these molecular changes differ by sex, brain region, and disease. By identifying common biological pathways involved in brain disorders, this research may improve our understanding of disease mechanisms and support the future development of better diagnostic methods and treatments. This study uses only existing de-identified public datasets and does not involve direct contact with participants, collection of new samples, or any intervention.