Yang Hu1, Jing-Yi Sun2, Yan Zhang3, Haihua Zhang4, Shan Gao4, Tao Wang5,6, Zhifa Han7,8,9, Longcai Wang10, Bao-Liang Sun11, Guiyou Liu12,13,14,15,16. 1. School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150080, China. 2. Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250021, China. 3. Department of Pathology, The Affiliated Hospital of Weifang Medical University, Weifang, 261053, China. 4. Beijing Institute for Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China. 5. Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. 6. Chinese Institute for Brain Research, Beijing, China. 7. School of Medicine, School of Pharmaceutical Sciences, THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China. 8. State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China. 9. Department of Pathophysiology, Peking Union Medical College, Beijing, China. 10. Department of Anesthesiology, The Affiliated Hospital of Weifang Medical University, Weifang, 261053, China. 11. Key Laboratory of Cerebral Microcirculation in Universities of Shandong; Department of Neurology, Second Affiliated Hospital; Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, Shandong, China. 12. Beijing Institute for Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China. liuguiyou1981@163.com. 13. Chinese Institute for Brain Research, Beijing, China. liuguiyou1981@163.com. 14. Key Laboratory of Cerebral Microcirculation in Universities of Shandong; Department of Neurology, Second Affiliated Hospital; Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, Shandong, China. liuguiyou1981@163.com. 15. National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China. liuguiyou1981@163.com. 16. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China. liuguiyou1981@163.com.
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.
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 FTDrs1990622 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.
Entities:
Keywords:
Alzheimer’s disease; Genome-wide association study; Neurological diseases; TMEM106B; eQTLs
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