Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Oct 25:11:297.
doi: 10.3389/fnagi.2019.00297. eCollection 2019.

Genome-Wide Association Studies for Cerebrospinal Fluid Soluble TREM2 in Alzheimer's Disease

Changan Liu  1 , Jun Yu  2
Affiliations

Genome-Wide Association Studies for Cerebrospinal Fluid Soluble TREM2 in Alzheimer's Disease

Changan Liu et al. Front Aging Neurosci. .

Abstract

Alzheimer's disease (AD) is the most common form of dementia. Rare variants in triggering receptor expressed on myeloid cells 2 (TREM2) have been identified as risk factors for AD. Soluble TREM2 (sTREM2) in the cerebrospinal fluid (CSF) is a potential and novel biomarker of neuroinflammation implicated in the onset and progression of AD. To explore the roles of CSF sTREM2 on the pathogenesis of AD, we performed genome-wide association studies (GWAS) by using the data from Alzheimer's Disease Neuroimaging Initiative (ADNI). We found CSF sTREM2 levels were elevated with the disease stages, but there was no significant difference between that of AD patients and normal participants. CSF sTREM2 was positively correlated with CSF total tau and phosphorylated-tau levels (ρ > 0.35, p < 1e-06; ρ > 0.32, p < 1e-05, respectively) for all disease states. We identified the most significant CSF sTREM2 related locus was rs7232 (FDR = 3.01e-08), a missense variant in MS4A6A gene of chromosome 11. Moreover, we also detected rs7232 was highly associated with MS4A6A gene expression (FDR = 1.37e-18). In addition, our pathway analysis for our significant GWAS results showed that biological processes for regulation of viruses and immune response were highly overrepresented or enriched. Our study suggests that CSF sTREM2 plays an informative role in AD progression. Moreover, CSF sTREM2 and AD is highly related to viral infections and immune response.

Keywords: Alzheimer’s disease; GWAS; SNP; cerebrospinal fluid; immune; soluble TREM2.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Cerebrospinal fluid sTREM2 levels in the five clinical disease stages and the correlation between sTREM2 and other AD biomarkers. (A) Violin plots with boxplots for the comparison of CSF sTREM2 levels in disease states. Statistical significance was determined by Wilcoxon rank sum test. +: mean. ∗p < 0.05. The correlation plots between log transformed CSF sTREM2 and (B) log transformed TREM2 gene expression in blood samples, (C) log transformed CSF Aβ42, (D) log transformed CSF tau, (E) log transformed CSF p-tau, and (F) log transformed ADAS13 scores for each group. Black straight lines are the regression lines. Shaded areas around regression lines represent the pointwise 95% confidence intervals (CI). ρ: Spearman’s rank correlation coefficient (rho).
FIGURE 2
FIGURE 2
Manhattan plot and regional plot of the results from QTL analysis for CSF sTREM2 levels. (A) Manhattan plot of –log10 (p-value) from the results of QTL analysis. (B) Regional plot for the most significant SNP rs7232 identified by the QTL analysis. The r2 measures the linkage disequilibrium of each SNP with the most significant SNP rs7232 according to hg19/1000 Genomes Nov 2014 AMR population. Points with gray color indicates that their r2 values were not available in the reference genome.
FIGURE 3
FIGURE 3
The linkage disequilibrium pattern for the identified SNPs close to rs7232 in our study. Here the LD measure is r2.
FIGURE 4
FIGURE 4
Bar plot for enriched gene ontology categories with FDR < 0.25 from GSEA of our eQTL analysis results. The numbers on the bars are the normalized enrichment scores for the corresponding gene ontology categories. NES: normalized enrichment score.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Balin B. J., Hudson A. P. (2018). Herpes viruses and Alzheimer’s disease: new evidence in the debate. Lancet Neurol. 17 839–841. 10.1016/s1474-4422(18)30316-8 - DOI - PubMed
    1. Ball M. J. (1982). Limbic predilection in Alzheimer Dementia: is reactivated herpesvirus involved? Can. J. Neurol. Sci. J. Can. Sci. Neurol. 9 303–306. 10.1017/S0317167100044115 - DOI - PubMed
    1. Bertram L., Lill C. M., Tanzi R. E. (2010). The genetics of Alzheimer Disease: back to the future. Neuron 68 270–281. 10.1016/j.neuron.2010.10.013 - DOI - PubMed
    1. Blennow K., Hampel H., Weiner M., Zetterberg H. (2010). Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat. Rev. Neurol. 6 131–144. 10.1038/nrneurol.2010.4 - DOI - PubMed
    1. Clayton D. (2012). Snpstats: SnpMatrix and XSnpMatrix Classes and Methods. R Package.

LinkOut - more resources