Alternative splicing regulation of low-frequency genetic variants in exon 2 of trem2 in alzheimer’s disease by splicing-based aggregationopen access
- Authors
- Han, Seonggyun; Na, Yirang; Koh, Insong; Nho, Kwangsik; Lee, Younghee
- Issue Date
- Sep-2021
- Publisher
- MDPI
- Keywords
- Aggregation of low-frequency variants; Alternative splicing; Alzheimer’s disease; Low-frequency variant; TREM2
- Citation
- International Journal of Molecular Sciences, v.22, no.18, pp.1 - 12
- Indexed
- SCIE
SCOPUS
- Journal Title
- International Journal of Molecular Sciences
- Volume
- 22
- Number
- 18
- Start Page
- 1
- End Page
- 12
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/141022
- DOI
- 10.3390/ijms22189865
- ISSN
- 1661-6596
- 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.
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