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. 2021 Jan 19;19(1):11.
doi: 10.1186/s12916-020-01883-5.

rs1990622 variant associates with Alzheimer's disease and regulates TMEM106B expression in human brain tissues

Yang Hu  1 , Jing-Yi Sun  2 , Yan Zhang  3 , Haihua Zhang  4 , Shan Gao  4 , Tao Wang  5   6 , Zhifa Han  7   8   9 , Longcai Wang  10 , Bao-Liang Sun  11 , Guiyou Liu  12   13   14   15   16
Affiliations

rs1990622 variant associates with Alzheimer's disease and regulates TMEM106B expression in human brain tissues

Yang Hu et al. BMC Med. .

Abstract

Background: It has been well established that the TMEM106B gene rs1990622 variant was a frontotemporal dementia (FTD) risk factor. Until recently, growing evidence highlights the role of TMEM106B in Alzheimer's disease (AD). However, it remains largely unclear about the role of rs1990622 variant in AD.

Methods: Here, we conducted comprehensive analyses including genetic association study, gene expression analysis, eQTLs analysis, and colocalization analysis. In stage 1, we conducted a genetic association analysis of rs1990622 using large-scale genome-wide association study (GWAS) datasets from International Genomics of Alzheimer's Project (21,982 AD and 41,944 cognitively normal controls) and UK Biobank (314,278 participants). In stage 2, we performed a gene expression analysis of TMEM106B in 49 different human tissues using the gene expression data in GTEx. In stage 3, we performed an expression quantitative trait loci (eQTLs) analysis using multiple datasets from UKBEC, GTEx, and Mayo RNAseq Study. In stage 4, we performed a colocalization analysis to provide evidence of the AD GWAS and eQTLs pair influencing both AD and the TMEM106B expression at a particular region.

Results: We found (1) rs1990622 variant T allele contributed to AD risk. A sex-specific analysis in UK Biobank further indicated that rs1990622 T allele only contributed to increased AD risk in females, but not in males; (2) TMEM106B showed different expression in different human brain tissues especially high expression in cerebellum; (3) rs1990622 variant could regulate the expression of TMEM106B in human brain tissues, which vary considerably in different disease statuses, the mean ages at death, the percents of females, and the different descents of the selected donors; (4) colocalization analysis provided suggestive evidence that the same variant contributed to AD risk and TMEM106B expression in cerebellum.

Conclusion: Our comprehensive analyses highlighted the role of FTD rs1990622 variant in AD risk. This cross-disease approach may delineate disease-specific and common features, which will be important for both diagnostic and therapeutic development purposes. Meanwhile, these findings highlight the importance to better understand TMEM106B function and dysfunction in the context of normal aging and neurodegenerative diseases.

Keywords: Alzheimer’s disease; Genome-wide association study; Neurological diseases; TMEM106B; eQTLs.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The box plots for the expression of TMEM106B in different tissues in GTEx. The gene expression values are shown in transcripts per million (TPM). The gene expression level was quantified by TPM based on the GENCODE 26 annotation, collapsed to a single transcript model for each gene using a custom isoform collapsing procedure [27]
Fig. 2
Fig. 2
Colocalization analysis of genetic variants associated with TMEM106B expression in GTEx cerebellum and AD risk. Created using locuscomparer R package. Coloc PP0 = 0.031, PP1 = 0.002, PP2 = 0.735, PP3 = 0.037, and PP4 = 0.196. The eQTLs dataset is from GTEx cerebellum (n = 209). The AD GWAS dataset is from the IGAP including 21,982 AD and 41,944 cognitively normal controls
See this image and copyright information in PMC

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