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

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.

Genome-wide association study identifies new loci associated with noise-induced tinnitus in Chinese populations

“…Colocalization analysis further showed that the tinnitus-associated SNP rs4149577 is colocalized with eQTL signals for TNFRSF1A in brain tissues (PP0 = 0.040, PP1 = 0.002, PP2 = 0.613, PP3 = 0.057, PP4 = 0.288; Figs. S3 d-f) [ 14 ]. Together, these pieces of evidence suggested a potential role for TNFRSF1A in the development of tinnitus.…”

Exploring the Causality Between Hypothyroidism and Non-alcoholic Fatty Liver: A Mendelian Randomization Study

“…In previous studies, the association between hypothyroidism and NAFLD has been researched from various perspectives, both clinically (Chung et al, 2012;Pagadala et al, 2012;Lee et al, 2015;Ludwig et al, 2015;Mantovani et al, 2018;Hu et al, 2019Hu et al, , 2020Hu et al, , 2021 and biologically (Ferrandino et al, 2017;Gionfra et al, 2019;Lonardo et al, 2019). The causality, however, is still unexplored (Efstathiadou et al, 2018).…”

Single-cell RNA analysis reveals the potential risk of organ-specific cell types vulnerable to SARS-CoV-2 infections

“…M1-like macrophages were grouped into pattern 1 and SPP1 (secreted phosphoprotein 1), NPR2 (Natriuretic Peptide Receptor 2) and CCL (Chemokine ligands) may be possible significant pathways. Moreover, GSVA software was utilized to identify differences in hallmark gene sets of Molecular Signatures Database (MSigDB) across different cell types [ 48 , [52] , [53] , [54] , [55] ]. As shown in Fig.…”