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

BMC Medicine - 2021
Yang Hu1, Jing-yi Sun2, Yan Zhang3, Haihua Zhang4, Shan Gao4, Tao Wang5,6, Zhifa Han7,8,9, Longcai Wang10, Bao-liang Sun11, Guiyou Liu4,12,13,6,11
1School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
2Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
3Department of Pathology, The Affiliated Hospital of Weifang Medical University, Weifang, China
4Beijing Institute for Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
5Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
6Chinese Institute for Brain Research, Beijing, China
7Department of Pathophysiology, Peking Union Medical College, Beijing, China
8State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China
9School of Medicine, School of Pharmaceutical Sciences, THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China
10Department of Anesthesiology, The Affiliated Hospital of Weifang Medical University, Weifang, China
11Key Laboratory of Cerebral Microcirculation in Universities of Shandong; Department of Neurology, Second Affiliated Hospital; Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, China
12National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, Beijing, China
13Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China

Tóm tắt

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. 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. 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. 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.

Từ khóa


Tài liệu tham khảo

Zhou X, Nicholson AM, Ren Y, Brooks M, Jiang P, Zuberi A, Phuoc HN, Perkerson RB, Matchett B, Parsons TM, et al. Loss of TMEM106B leads to myelination deficits: implications for frontotemporal dementia treatment strategies. Brain. 2020;143(6):1905–19. Nicholson AM, Rademakers R. What we know about TMEM106B in neurodegeneration. Acta Neuropathol. 2016;132(5):639–51. Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Grossman M, et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet. 2010;42(3):234–9. Li Z, Farias FHG, Dube U, Del-Aguila JL, Mihindukulasuriya KA, Fernandez MV, Ibanez L, Budde JP, Wang F, Lake AM, et al. The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion. Acta Neuropathol. 2020;139(1):45–61. Yang HS, White CC, Klein HU, Yu L, Gaiteri C, Ma Y, Felsky D, Mostafavi S, Petyuk VA, Sperling RA, et al. Genetics of gene expression in the aging human brain reveal TDP-43 proteinopathy pathophysiology. Neuron. 2020;107(3):496–508 e496. Ren Y, van Blitterswijk M, Allen M, Carrasquillo MM, Reddy JS, Wang X, Beach TG, Dickson DW, Ertekin-Taner N, Asmann YW, et al. TMEM106B haplotypes have distinct gene expression patterns in aged brain. Mol Neurodegener. 2018;13(1):35. Tropea TF, Mak J, Guo MH, Xie SX, Suh E, Rick J, Siderowf A, Weintraub D, Grossman M, Irwin D, et al. TMEM106B effect on cognition in Parkinson disease and frontotemporal dementia. Ann Neurol. 2019;85(6):801–11. Ng B, White CC, Klein HU, Sieberts SK, McCabe C, Patrick E, Xu J, Yu L, Gaiteri C, Bennett DA, et al. An xQTL map integrates the genetic architecture of the human brain’s transcriptome and epigenome. Nat Neurosci. 2017;20(10):1418–26. Satoh J, Kino Y, Kawana N, Yamamoto Y, Ishida T, Saito Y, Arima K. TMEM106B expression is reduced in Alzheimer’s disease brains. Alzheimers Res Ther. 2014;6(2):17. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet. 2019;51(3):414–30. Marioni RE, Harris SE, Zhang Q, McRae AF, Hagenaars SP, Hill WD, Davies G, Ritchie CW, Gale CR, Starr JM, et al. GWAS on family history of Alzheimer’s disease. Transl Psychiatry. 2018;8(1):99. Ramasamy A, Trabzuni D, Guelfi S, Varghese V, Smith C, Walker R, De T, Coin L, de Silva R, Cookson MR, et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci. 2014;17(10):1418–28. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348(6235):648–60. Liu G, Wang T, Tian R, Hu Y, Han Z, Wang P, Zhou W, Ren P, Zong J, Jin S, et al. Alzheimer’s disease risk variant rs2373115 regulates GAB2 and NARS2 expression in human brain tissues. J Mol Neurosci. 2018;66(1):37–43. Zhang Y, Wang L, Jia H, Liao M, Chen X, Xu J, Bao Y, Liu G. Genetic variants regulate NR1H3 expression and contribute to multiple sclerosis risk. J Neurol Sci. 2018;390:162–5. Liu G, Zhang H, Liu B, Wang T, Han Z, Ji X. rs4147929 variant minor allele increases ABCA7 gene expression and ABCA7 shows increased gene expression in Alzheimer’s disease patients compared with controls. Acta Neuropathol. 2020;139(5):937–40. Liu G, Zhang H, Liu B, Ji X. Rs2293871 regulates HTRA1 expression and affects cerebral small vessel stroke and Alzheimer’s disease. Brain. 2019;142(11):e61. Liu G, Hu Y, Han Z, Jin S, Jiang Q. Genetic variant rs17185536 regulates SIM1 gene expression in human brain hypothalamus. Proc Natl Acad Sci U S A. 2019;116(9):3347–8. Liu G, Jin S, Hu Y, Jiang Q. Disease status affects the association between rs4813620 and the expression of Alzheimer’s disease susceptibility gene TRIB3. Proc Natl Acad Sci U S A. 2018;115(45):E10519–20. Zou F, Chai HS, Younkin CS, Allen M, Crook J, Pankratz VS, Carrasquillo MM, Rowley CN, Nair AA, Middha S, et al. Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. PLoS Genet. 2012;8(6):e1002707. Liu G, Bao X, Jiang Y, Liao M, Jiang Q, Feng R, Zhang L, Ma G, Chen Z, Wang G, et al. Identifying the association between Alzheimer’s disease and Parkinson’s disease using genome-wide association studies and protein-protein interaction network. Mol Neurobiol. 2015;52(3):1629–36. Liu G, Jiang Y, Chen X, Zhang R, Ma G, Feng R, Zhang L, Liao M, Miao Y, Chen Z, et al. Measles contributes to rheumatoid arthritis: evidence from pathway and network analyses of genome-wide association studies. Plos One. 2013;8(10):e75951. Hu Y, Zheng L, Cheng L, Zhang Y, Bai W, Zhou W, Wang T, Han Z, Zong J, Jin S, et al. GAB2 rs2373115 variant contributes to Alzheimer’s disease risk specifically in European population. J Neurol Sci. 2017;375:18–22. Liu G, Sun JY, Xu M, Yang XY, Sun BL. SORL1 variants show different association with early-onset and late-onset Alzheimer’s disease risk. J Alzheimers Dis. 2017;58(4):1121–8. Liao M, Wang G, Quan B, Qi X, Yu Z, Feng R, Zhang L, Jiang Y, Zhang Y, Liu G. Analyzing large-scale samples confirms the association between rs16892766 polymorphism and colorectal cancer susceptibility. Sci Rep. 2015;5:7957. Hu Y, Cheng L, Zhang Y, Bai W, Zhou W, Wang T, Han Z, Zong J, Jin S, Zhang J, et al. Rs4878104 contributes to Alzheimer’s disease risk and regulates DAPK1 gene expression. Neurol Sci. 2017;38(7):1255–62. Battle A, Brown CD, Engelhardt BE, Montgomery SB. Genetic effects on gene expression across human tissues. Nature. 2017;550(7675):204–13. Giambartolomei C, Vukcevic D, Schadt EE, Franke L, Hingorani AD, Wallace C, Plagnol V. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. Plos Genet. 2014;10(5):e1004383. Wallace C. Eliciting priors and relaxing the single causal variant assumption in colocalisation analyses. PLoS Genet. 2020;16(4):e1008720. White CC, Yang HS, Yu L, Chibnik LB, Dawe RJ, Yang J, Klein HU, Felsky D, Ramos-Miguel A, Arfanakis K, et al. Identification of genes associated with dissociation of cognitive performance and neuropathological burden: multistep analysis of genetic, epigenetic, and transcriptional data. Plos Med. 2017;14(4):e1002287. Rhinn H, Abeliovich A. Differential aging analysis in human cerebral cortex identifies variants in TMEM106B and GRN that regulate aging phenotypes. Cell Syst. 2017;4(4):404–15 e405. Katsumata Y, Nelson PT, Ellingson SR, Fardo DW. Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2. Neurobiol Aging. 2017;53:193 e117–25. Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC, Kunkle BW, Wang LS, Bis JC, Bellenguez C, et al. A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry. 2016;21(1):108–17. Hu T, Chen Y, Ou R, Wei Q, Cao B, Zhao B, Wu Y, Song W, Chen X, Shang HF. Association analysis of polymorphisms in VMAT2 and TMEM106B genes for Parkinson’s disease, amyotrophic lateral sclerosis and multiple system atrophy. J Neurol Sci. 2017;377:65–71. GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369(6509):1318–1330. Yau AC, Houtman M, Padyukov L, Holmdahl R. Reply to Liu et al.: translation of rat congenic data to humans on a conserved MHC-III haplotype associated with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016;113(42):E6323–4. Gratuze M, Leyns CEG, Holtzman DM. New insights into the role of TREM2 in Alzheimer’s disease. Mol Neurodegener. 2018;13(1):66. Karch CM, Ezerskiy LA, Bertelsen S, Goate AM. Alzheimer’s disease risk polymorphisms regulate gene expression in the ZCWPW1 and the CELF1 loci. Plos One. 2016;11(2):e0148717. Blauwendraat C, Francescatto M, Gibbs JR, Jansen IE, Simon-Sanchez J, Hernandez DG, Dillman AA, Singleton AB, Cookson MR, Rizzu P, et al. Comprehensive promoter level expression quantitative trait loci analysis of the human frontal lobe. Genome Med. 2016;8(1):65. Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011;43(7):699–705. Bhalala OG, Nath AP, Inouye M, Sibley CR. Identification of expression quantitative trait loci associated with schizophrenia and affective disorders in normal brain tissue. Plos Genet. 2018;14(8):e1007607. O'Brien HE, Hannon E, Hill MJ, Toste CC, Robertson MJ, Morgan JE, McLaughlin G, Lewis CM, Schalkwyk LC, Hall LS, et al. Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders. Genome Biol. 2018;19(1):194. Pierce S, Coetzee GA. Parkinson’s disease-associated genetic variation is linked to quantitative expression of inflammatory genes. Plos One. 2017;12(4):e0175882. Akkouh IA, Skrede S, Holmgren A, Ersland KM, Hansson L, Bahrami S, Andreassen OA, Steen VM, Djurovic S, Hughes T. Exploring lithium’s transcriptional mechanisms of action in bipolar disorder: a multi-step study. Neuropsychopharmacology. 2020;45(6):947–55. Chung J, Zhang X, Allen M, Wang X, Ma Y, Beecham G, Montine TJ, Younkin SG, Dickson DW, Golde TE, et al. Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease. Alzheimers Res Ther. 2018;10(1):22. Sieberts SK, Perumal TM, Carrasquillo MM, Allen M, Reddy JS, Hoffman GE, Dang KK, Calley J, Ebert PJ, Eddy J, et al. Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions. Sci Data. 2020;7(1):340. Hu Y, Jin S, Cheng L, Liu G, Jiang Q. Autoimmune disease variants regulate GSDMB gene expression in human immune cells and whole blood. Proc Natl Acad Sci U S A. 2017;114(38):E7860–2. Soldner F, Stelzer Y, Shivalila CS, Abraham BJ, Latourelle JC, Barrasa MI, Goldmann J, Myers RH, Young RA, Jaenisch R. Parkinson-associated risk variant in distal enhancer of alpha-synuclein modulates target gene expression. Nature. 2016;533(7601):95–9. Liu G, Hu Y, Jin S, Jiang Q. Genetic variant rs763361 regulates multiple sclerosis CD226 gene expression. Proc Natl Acad Sci U S A. 2017;114(6):E906–7. Liu G, Hu Y, Jin S, Zhang F, Jiang Q, Hao J. Cis-eQTLs regulate reduced LST1 gene and NCR3 gene expression and contribute to increased autoimmune disease risk. Proc Natl Acad Sci U S A. 2016;113(42):E6321–2. Peters JE, Lyons PA, Lee JC, Richard AC, Fortune MD, Newcombe PJ, Richardson S, Smith KG. Insight into genotype-phenotype associations through eQTL mapping in multiple cell types in health and immune-mediated disease. Plos Genet. 2016;12(3):e1005908. Liu G, Hu Y, Jiang Q. Population difference and disease status affect the association between genetic variants and gene expression. Gastroenterology. 2019;157(3):894–6. Oliva M, Munoz-Aguirre M, Kim-Hellmuth S, Wucher V, Gewirtz ADH, Cotter DJ, Parsana P, Kasela S, Balliu B, Vinuela A et al. The impact of sex ongene expression across human tissues. Science. 2020;369(6509):eaba3066.
Thông tin
Thông tin xuất bản

BMC Medicine

Thông tin tác giả