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Article

Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 of TREM2 in Alzheimer’s Disease by Splicing-Based Aggregation

1
Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA
2
Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul 03080, Korea
3
Department of Physiology, Hanyang University, Seoul 04763, Korea
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Department of Radiology and Imaging Sciences, Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
5
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Anna Atlante
Int. J. Mol. Sci. 2021, 22(18), 9865; https://doi.org/10.3390/ijms22189865
Received: 30 June 2021 / Revised: 26 August 2021 / Accepted: 8 September 2021 / Published: 13 September 2021
(This article belongs to the Special Issue Molecular Genetic of Alzheimer's Disease 2.0)
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. View Full-Text
Keywords: TREM2; Alzheimer’s disease; alternative splicing; low-frequency variant; aggregation of low-frequency variants TREM2; Alzheimer’s disease; alternative splicing; low-frequency variant; aggregation of low-frequency variants
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MDPI and ACS Style

Han, S.; Na, Y.; Koh, I.; Nho, K.; Lee, Y. Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 of TREM2 in Alzheimer’s Disease by Splicing-Based Aggregation. Int. J. Mol. Sci. 2021, 22, 9865. https://doi.org/10.3390/ijms22189865

AMA Style

Han S, Na Y, Koh I, Nho K, Lee Y. Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 of TREM2 in Alzheimer’s Disease by Splicing-Based Aggregation. International Journal of Molecular Sciences. 2021; 22(18):9865. https://doi.org/10.3390/ijms22189865

Chicago/Turabian Style

Han, Seonggyun, Yirang Na, Insong Koh, Kwangsik Nho, and Younghee Lee. 2021. "Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 of TREM2 in Alzheimer’s Disease by Splicing-Based Aggregation" International Journal of Molecular Sciences 22, no. 18: 9865. https://doi.org/10.3390/ijms22189865

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