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. 2021 Mar 15;12(3):419.
doi: 10.3390/genes12030419.

Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants

Devanshi Patel  1   2 , Xiaoling Zhang  2 , John J Farrell  2 , Kathryn L Lunetta  3 , Lindsay A Farrer  1   2   3   4   5   6
Affiliations

Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants

Devanshi Patel et al. Genes (Basel). .

Abstract

Because studies of rare variant effects on gene expression have limited power, we investigated set-based methods to identify rare expression quantitative trait loci (eQTL) related to Alzheimer disease (AD). Gene-level and pathway-level cis rare-eQTL mapping was performed genome-wide using gene expression data derived from blood donated by 713 Alzheimer's Disease Neuroimaging Initiative participants and from brain tissues donated by 475 Religious Orders Study/Memory and Aging Project participants. The association of gene or pathway expression with a set of all cis potentially regulatory low-frequency and rare variants within 1 Mb of genes was evaluated using SKAT-O. A total of 65 genes expressed in the brain were significant targets for rare expression single nucleotide polymorphisms (eSNPs) among which 17% (11/65) included established AD genes HLA-DRB1 and HLA-DRB5. In the blood, 307 genes were significant targets for rare eSNPs. In the blood and the brain, GNMT, LDHC, RBPMS2, DUS2, and HP were targets for significant eSNPs. Pathway enrichment analysis revealed significant pathways in the brain (n = 9) and blood (n = 16). Pathways for apoptosis signaling, cholecystokinin receptor (CCKR) signaling, and inflammation mediated by chemokine and cytokine signaling were common to both tissues. Significant rare eQTLs in inflammation pathways included five genes in the blood (ALOX5AP, CXCR2, FPR2, GRB2, IFNAR1) that were previously linked to AD. This study identified several significant gene- and pathway-level rare eQTLs, which further confirmed the importance of the immune system and inflammation in AD and highlighted the advantages of using a set-based eQTL approach for evaluating the effect of low-frequency and rare variants on gene expression.

Keywords: ADNI; Alzheimer disease; ROSMAP; SKAT-O; expression quantitative trait loci (eQTL); immune system; inflammation; pathways; rare variants; set-based eQTL.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of set-based rare expression quantitative trait loci (eQTL) analysis. Gene-level tests were performed for each protein-coding gene using an aggregate of all potentially regulatory single nucleotide polymorphisms (SNPs) with minor allele frequency ≤0.05 within 1 Mb of each gene. Pathway-level analysis was carried out in two steps. First, the weighted gene co-expression network analysis (WCGNA) method was applied to identify co-expressed gene modules. Next, pathway enrichment analysis was conducted using the Protein Analysis Through Evolutionary Relationships (PANTHER) tool to identify significantly enriched pathways in these gene modules, and pathway-level tests were then performed on each enriched pathway, including the aggregated SNPs for each gene in the module. Results were considered significant (p < 0.05) after applying a Bonferroni correction.
Figure 2
Figure 2
Overlap of significant genes in rare gene-level and common eQTLs in (A) the blood and (B) the brain.
See this image and copyright information in PMC

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