Abstract
TREM2 is among the most well-known Alzheimer’s disease (AD) risk genes; however, the functional roles of its AD-associated variants remain to be elucidated, and most known risk alleles are low-frequency variants whose investigation is challenging. Here, we utilized a splicing-guided aggregation method in which multiple low-frequency TREM2 variants were bundled together to investigate the functional impact of those variants on alternative splicing in AD. We analyzed whole genome sequencing (WGS) and RNA-seq data generated from cognitively normal elderly controls (CN) and AD patients in two independent cohorts, representing three regions in the frontal lobe of the human brain: the dorsolateral prefrontal cortex (CN = 213 and AD = 376), frontal pole (CN = 72 and AD = 175), and inferior frontal (CN = 63 and AD = 157). We observed an exon skipping event in the second exon of TREM2, with that exon tending to be more frequently skipped (p = 0.0012) in individuals having at least one low-frequency variant that caused loss-of-function for a splicing regulatory element. In addition, genes differentially expressed between AD patients with high vs. low skipping of the second exon (i.e., loss of a TREM2 functional domain) were significantly enriched in immune-related pathways. Our splicing-guided aggregation method thus provides new insight into the regulation of alternative splicing of the second exon of TREM2 by low-frequency variants and could be a useful tool for further exploring the potential molecular mechanisms of multiple, disease-associated, low-frequency variants.
Highlights
Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders leading to cognitive impairment in the elderly
The triggering receptor expressed in myeloid cells 2 (TREM2) has become one of the most wellknown genes implicated in increased risk of late-onset AD [5]
Since it has been reported that cognitively normal older adults (CN) and AD patients differ significantly in TREM2 protein structure [26], we evaluated whether skipping of
Summary
Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders leading to cognitive impairment in the elderly. TREM2 encodes a membrane protein that features an immunoglobulin extracellular domain expressed in myeloid cells, including microglia in the brain [6] It mediates the phagocytosis of apoptotic neurons, inflammatory responses, and microglia proliferation [5,7,8,9,10], and so strongly affects risk of AD. A neuropathological study of rs75932628 validated that it increases the risk of developing late-onset AD by almost three times, which is similar to having one copy of the APOE ε4 allele [19,21] Another variant, TREM2 R47H (i.e., rs75932628), has been shown to result in a loss-of-function phenotype [22,23] and decreased Trem mRNA and protein levels in mice [24]. Three frontal brain regions were represented in this data: the dorsolateral prefrontal cortex (DLPFC), frontal pole (FP), and inferior frontal (IF)
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