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

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.

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

“…Gene‐ and pathway‐level mapping of rare eQTL in ADNI blood samples and brain tissue from the Religious Orders Study/Memory and Aging Project (ROSMAP) cohort identified rare and low‐frequency variants involved in inflammation mediated by cytokines and chemokine signaling. 191 These included five genes previously linked to AD ( ALOX5AP, CXCR2, FPR2, GRB2, IFNAR1 ). Rare variants in NLRC3 were associated with neuroinflammation (CSF YKL‐40).…”

Molecular Quantitative Trait Locus Mapping in Human Complex Diseases

“…These rare‐eQTLs have been implicated in disease phenotypes as well, with Patel et al. finding many rare QTLs in genes and pathways implicated in Alzheimer's disease (Patel et al., 2021b).…”

“…Ferraro et al showed that this pattern of rare-variant enrichment in extreme molecular phenotypes was limited to RNA expression alone and found in allelic expression and alternative splicing outliers (Ferraro et al, 2020). These rare-eQTLs have been implicated in disease phenotypes as well, with Patel et al finding many rare QTLs in genes and pathways implicated in Alzheimer's disease (Patel et al, 2021b).…”

Editorial for the Genetics of Alzheimer’s Disease Special Issue: October 2021

“…Specifically, plasma BACE1-AS levels are differentially expressed in the pre-symptomatic phase, indicating long non-coding RNA molecules may be a viable pre-symptomatic diagnostic target. Patel, Zhang [7] demonstrate that rare genetic variants significantly impact gene expression and gene co-expression in Alzheimer's disease, indicating that set-based gene analyses are necessary to fully capture gene dynamics related to disease progression. Those pathway-level analyses confirmed substantial immune and inflammatory expression quantitative trait loci associated with Alzheimer's disease, as suggested in the review published in this Special Issue [1].…”