Integrative omics studies to discover genetic determinants of brain cell type proportions

• DOI: 10.1002/alz.080786
• Publication Date: 2023-12-25T09:32:58Z
• Authors: Joseph S. Reddy; Mariet Allen; Tulsi Patel; Zachary Quicksall; Xue Wang; Troy Carnwath; Yuhao Min; Todd E Golde; Nilufer Ertekin‐T...
• Keywords: Neuropathology; Genome-wide Association Study; Cell type; Brain Cell; Genetic Association

Abstract Background Neurodegenerative disorders affect different brain regions at time points and to varying degrees, although the underlying reasons for this variability in regional susceptibility is unknown. Brain have proportions of cell types. This proportion may be further influenced by presence degree disorders, including neurodegenerative diseases. We postulate that genetic other factors influence type also provide insights into Methods Utilizing bulk transcriptomics data from 7 obtained 3 cohorts corresponding whole genome sequencing (WGS) data, variants were evaluated association with across regions. specific marker genes deconvolution provided McKenzie et.al, we estimated surrogate variables (SVP) various types using BRETIGEA. then relationship between SVP AD as well Age, Sex, APOE ε4 neuropathology measures. Genetic WGS tested identify distinct conserved patterns 6 Results Analysis diagnosis, sex, age, measures identified significant differences GWAS 134 loci reached genome‐wide significance (5e‐8). After conservative adjustment multiple testing (6 regions; 42 tests), proximal SYNPR VENTXP7 remained (p‐value<1.19E‐09). Variants associated increased oligodendrocytes cerebellum whereas near reduced astrocytes DLPFC. previously been neurofibrillary tangles diffuse plaque measurements while measurement tangles, cognitive decline, unipolar depression, bipolar disorder. Conclusions It likely there are brain, vary region, others act more broadly. Identification affected cells vulnerabilities.