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 Sep 13;22(18):9865. doi: 10.3390/ijms22189865.


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.

Keywords: Alzheimer’s disease; TREM2; aggregation of low-frequency variants; alternative splicing; low-frequency variant.

MeSH terms

  • Aged
  • Alternative Splicing / genetics*
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Brain / metabolism
  • Brain / pathology
  • Exons / genetics
  • Female
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease*
  • Genetic Variation / genetics
  • Humans
  • Male
  • Membrane Glycoproteins / genetics*
  • RNA Splicing / genetics
  • RNA-Seq
  • Receptors, Immunologic / genetics*
  • Regulatory Sequences, Nucleic Acid / genetics
  • Whole Genome Sequencing


  • Membrane Glycoproteins
  • Receptors, Immunologic
  • TREM2 protein, human