Abstract
Background
Identifying the genes and biological pathways involved in Alzheimer disease (AD) is critical in the effort to develop effective therapies. Significant work has identified genetic variants conferring risk and protection for AD in individuals of diverse ancestries, but identification of downstream functional effects including modulation of gene regulation is lacking, particularly in individuals of diverse ancestries. Therefore, to explore transcriptional changes between clinically diagnosed AD and cognitively intact age‐matched controls, herein we analyzed RNA sequencing data from peripheral blood collected from individuals of admixed genetic backgrounds.
Method
Total RNA was extracted from peripheral whole blood stored in PAXGene tubes from 47 Cubans (22 AD and 25 controls), 85 Peruvians (41 AD and 44 controls), and 168 Puerto Ricans (88 AD and 80 controls). PolyA selected mRNA was sequenced to more than 40 million paired end read per sample on the Illumina NovaSeq 6000. The bioinformatic pipeline included mapping to the human reference genome (GRCh38), gene quantifications against the GENCODE v35 annotation set, and differential expression was calculated using DESeq2 with sex, age at blood draw, and count of APOEe4 alleles as covariates. Functional categorization was performed by gene set enrichment of gene ontology and KEGG pathways.
Result
Across the cohorts, a total of 358 protein‐coding genes (FDR ≤ 0.05, Fold change ≥ 1.25) were differentially expressed with 238 down‐regulated and 120 up‐regulated in AD relative to controls. Despite the few genes overlapping between ethnicities, pathway analysis revealed common pathways including up‐regulation of genes involved in inflammation and RNA processing and down‐regulation of genes involved in cellular detoxification and lipid transport, among others. Interestingly, while few specific genes overlap in differential expression overlap with a published set of genes from non‐Hispanic Europeans and African Americans (Griswold et al, 2018), the pathways identified are similar.
Conclusion
Our analysis reveals a signature of gene expression that implicates increased inflammation and decreased cellular detoxification based on gene expression analysis in admixed Latinx AD. Convergence of pathways across these and African American and European cohorts supports the idea of distinct genes but similar underlying pathological processes contributing to AD across individuals of diverse ancestries.