Ascertaining perturbations in microglial expression profiles using single‐nuclei RNA‐seq from human brains: Genetics/genetic factors of Alzheimer's disease. (7th December 2020)

• Record Type: Journal Article
• Authors: Brase, Logan; Del‐Aguila, Jorge L.; Benitez, Bruno A.; Karch, Celeste M.; Cruchaga, Carlos; Harari, Oscar
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.046024
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Alzheimer's disease (AD) is a complex and heterogeneous trait in which multiple molecular pathways are disrupted in different cell‐types culminating in disease. Genetic variants in TREM2, a gene expressed in microglia, have been associated with high‐risk with AD, and similarly soluble TREM2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with AD. In a previous Genome‐wide association study (GWAS) of CSF sTREM2 levels, a genetic variant near the MS4A gene cluster accounted for 6 percent of the protein's variance (rs1582763 p = 1.15 × 10−15). This finding suggests that TREM2 is involved in AD risk in the general population, beyond TREM2 risk‐variant carriers, as the minor allele frequency of rs1582763 > 0.30. rs1582763 is also a cis‐eQTL for both MS4A4A and MS4A6A genes in bulk RNA‐seq of blood. Method: We generated unsorted single‐nuclei RNA‐seq from human brain tissue from the Knight‐ADRC brain bank. We collected the parietal lobe for 30 AD brains (19 are carriers of the rs1582763 minor allele), 18 autosomal dominant AD brains (ADAD) (9 carriers) and 7 neuropath‐free (6 carriers) for a total of 55 brains (34 carriers). Using the 10X Chromium 3' chemistry v3 we generated high quality data for over 287, 000 nuclei from 54 brains (after QC) to identify the transcriptomic effects of this variant at a cell specific resolution. We identified 13, 880 microglial nuclei to analyze microglial subtypes, activation states, cell‐type specific eQTLs, and differential gene expression between carriers and non‐carriers of rs1582763. Result: We identified microglia expression states that are specific to ADAD subjects, an increased proportion of total microglia on controls, and a shift in microglia expression state for AD subjects that are carriers of rs1582763. Using linear mixed models to account for subject of origin, we will analyze these nuclei to determine which subset of genes are differentially expressed. Conclusion: Both ADAD status and rs1582763 status in AD subjects alter microglia gene expression states.