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01-01-2020 | Alzheimer's Disease | Original Paper

The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion

Authors: Zeran Li, Fabiana H. G. Farias, Umber Dube, Jorge L. Del-Aguila, Kathie A. Mihindukulasuriya, Maria Victoria Fernandez, Laura Ibanez, John P. Budde, Fengxian Wang, Allison M. Lake, Yuetiva Deming, James Perez, Chengran Yang, Jorge A. Bahena, Wei Qin, Joseph L. Bradley, Richard Davenport, Kristy Bergmann, John C. Morris, Richard J. Perrin, Bruno A. Benitez, Joseph D. Dougherty, Oscar Harari, Carlos Cruchaga

Published in: Acta Neuropathologica | Issue 1/2020

Abstract

Apart from amyloid β deposition and tau neurofibrillary tangles, Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal loss and astrocytosis in the cerebral cortex. The goal of this study is to investigate genetic factors associated with the neuronal proportion in health and disease. To identify cell-autonomous genetic variants associated with neuronal proportion in cortical tissues, we inferred cellular population structure from bulk RNA-Seq derived from 1536 individuals. We identified the variant rs1990621 located in the TMEM106B gene region as significantly associated with neuronal proportion (p value = 6.40 × 10⁻⁰⁷) and replicated this finding in an independent dataset (p value = 7.41 × 10⁻⁰⁴) surpassing the genome-wide threshold in the meta-analysis (p value = 9.42 × 10⁻⁰⁹). This variant is in high LD with the TMEM106B non-synonymous variant p.T185S (rs3173615; r² = 0.98) which was previously identified as a protective variant for frontotemporal lobar degeneration (FTLD). We stratified the samples by disease status, and discovered that this variant modulates neuronal proportion not only in AD cases, but also several neurodegenerative diseases and in elderly cognitively healthy controls. Furthermore, we did not find a significant association in younger controls or schizophrenia patients, suggesting that this variant might increase neuronal survival or confer resilience to the neurodegenerative process. The single variant and gene-based analyses also identified an overall genetic association between neuronal proportion, AD and FTLD risk. These results suggest that common pathways are implicated in these neurodegenerative diseases, that implicate neuronal survival. In summary, we identified a protective variant in the TMEM106B gene that may have a neuronal protection effect against general aging, independent of disease status, which could help elucidate the relationship between aging and neuronal survival in the presence or absence of neurodegenerative disorders. Our findings suggest that TMEM106B could be a potential target for neuronal protection therapies to ameliorate cognitive and functional deficits.

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Allen M, Carrasquillo MM, Funk C, Heavner BD, Zou F, Younkin CS et al (2016) Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases. Sci Data 3:160089. https://doi.org/10.1038/sdata.2016.89 CrossRefPubMedPubMedCentral

Andrews S (2010) FastQC: a quality control tool for high throughput sequence data. Available: http://www.bioinformatics.babraham.ac.uk/projects/fastqc/

Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J et al (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12:25–31PubMed

Askanas V, Engel WK (2001) Inclusion-body myositis: newest concepts of pathogenesis and relation to aging and Alzheimer disease. J Neuropathol Exp Neurol 60:1–14CrossRefPubMed

Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC et al (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367:795–804CrossRefPubMedCentralPubMed

Battle A, Brown CD, Engelhardt BE, Montgomery SB (2017) Genetic effects on gene expression across human tissues. Nature 550:204–213. https://doi.org/10.1038/nature24277 CrossRefPubMed

Bennett DA, Schneider JA, Arvanitakis Z, Wilson RS (2012) Overview and findings from the religious orders study. Curr Alzheimer Res 9:628–645CrossRefPubMedCentralPubMed

Bennett DA, Schneider JA, Buchman AS, Barnes LL, Boyle PA, Wilson RS (2012) Overview and findings from the rush memory and aging project. Curr Alzheimer Res 9:646–663CrossRefPubMedCentralPubMed

Brady OA, Zheng Y, Murphy K, Huang M, Hu F (2013) The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet 22:685–695. https://doi.org/10.1093/hmg/dds475 CrossRefPubMed

10.

Broad Institute (2017) Picard: A set of command line tools for manipulating high-throughput sequencing data. Available: https://broadinstitute.github.io/picard/

11.

Carmona-Gutierrez D, Hughes AL, Madeo F, Ruckenstuhl C (2016) The crucial impact of lysosomes in aging and longevity. Ageing Res Rev 32:2–12CrossRefPubMedCentralPubMed

12.

Chailangkarn T, Trujillo CA, Freitas BC, Hrvoj-Mihic B, Herai RH, Yu DX et al (2016) A human neurodevelopmental model for Williams syndrome. Nature 536:338–343. https://doi.org/10.1038/nature19067 CrossRefPubMedPubMedCentral

13.

Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4:7CrossRefPubMedCentralPubMed

14.

Chen-Plotkin AS, Unger TL, Gallagher MD, Bill E, Kwong LK, Volpicelli-Daley L et al (2012) TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. J Neurosci 32:11213–11227. https://doi.org/10.1523/jneurosci.0521-12.2012 CrossRefPubMedPubMedCentral

15.

Consortium G (2013) The genotype-tissue expression (GTEx) project. Nat Genet 45:580–585. https://doi.org/10.1038/ng.2653 CrossRef

16.

Cruchaga C, Graff C, Chiang HH, Wang J, Hinrichs AL, Spiegel N et al (2011) Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch Neurol 68:581–586. https://doi.org/10.1001/archneurol.2010.350 CrossRefPubMedPubMedCentral

17.

Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM et al (2013) GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer’s disease. Neuron 78:256–268CrossRefPubMedCentralPubMed

18.

de Leeuw CA, Mooij JM, Heskes T, Posthuma D (2015) MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol 11:e1004219. https://doi.org/10.1371/journal.pcbi.1004219 CrossRefPubMedPubMedCentral

19.

Delaneau O, Marchini J (2014) Integrating sequence and array data to create an improved 1000 genomes project haplotype reference panel. Nat Commun 5:3934. https://doi.org/10.1038/ncomms4934 CrossRefPubMed

20.

Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R et al (2018) The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk. bioRxiv. https://doi.org/10.1101/352179 CrossRef

21.

Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K et al (2017) Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathol 133:839–856CrossRefPubMedCentralPubMed

22.

Deming Y, Xia J, Cai Y, Lord J, Del-Aguila JL, Fernandez MV et al (2016) Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits. Sci Rep. https://doi.org/10.1038/srep18092 CrossRefPubMedCentral

23.

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21. https://doi.org/10.1093/bioinformatics/bts635 CrossRefPubMed

24.

Duan J, Sanders AR, Moy W, Drigalenko EI, Brown EC, Freda J et al (2015) Transcriptome outlier analysis implicates schizophrenia susceptibility genes and enriches putatively functional rare genetic variants. Hum Mol Genet 24:4674–4685. https://doi.org/10.1093/hmg/ddv199 CrossRefPubMedPubMedCentral

25.

Espay AJ, Vizcarra JA, Marsili L, Lang AE, Simon DK, Merola A et al (2019) Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases. Neurology 92:329–337. https://doi.org/10.1212/wnl.0000000000006926 CrossRefPubMedPubMedCentral

26.

Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM (2007) Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol 64:343–349. https://doi.org/10.1001/archneur.64.3.noc60123 CrossRefPubMed

27.

Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JB et al (2014) Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurol 13:686–699. https://doi.org/10.1016/s1474-4422(14)70065-1 CrossRefPubMedPubMedCentral

28.

Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerod L, Fisher EM et al (2007) Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J Cell Biol 179:485–500. https://doi.org/10.1083/jcb.200702115 CrossRefPubMedPubMedCentral

29.

Finch N, Carrasquillo MM, Baker M, Rutherford NJ, Coppola G, Dejesus-Hernandez M et al (2011) TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 76:467–474. https://doi.org/10.1212/WNL.0b013e31820a0e3b CrossRefPubMed

30.

Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM et al (2016) Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci 19:1442–1453. https://doi.org/10.1038/nn.4399 CrossRefPubMedPubMedCentral

31.

Gallagher MD, Posavi M, Huang P, Unger TL, Berlyand Y, Gruenewald AL et al (2017) A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression. Am J Hum Genet 101:643–663. https://doi.org/10.1016/j.ajhg.2017.09.004 CrossRefPubMedPubMedCentral

32.

Garcia-Osta A, Cuadrado-Tejedor M, Garcia-Barroso C, Oyarzabal J, Franco R (2012) Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem Neurosci 3:832–844. https://doi.org/10.1021/cn3000907 CrossRefPubMedPubMedCentral

33.

Gaujoux R, Seoighe C (2013) Cell Mix: a comprehensive toolbox for gene expression deconvolution. Bioinformatics 29:2211–2212. https://doi.org/10.1093/bioinformatics/btt351 CrossRefPubMed

34.

Han B, Eskin E (2012) Interpreting meta-analyses of genome-wide association studies. PLoS Genet 8:e1002555. https://doi.org/10.1371/journal.pgen.1002555 CrossRefPubMedPubMedCentral

35.

Harari O, Cruchaga C, Kauwe JS, Ainscough BJ, Bales K, Pickering EH et al (2014) Phosphorylated tau-Aβ42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer’s disease in multiplex immunoassay panels of cerebrospinal fluid. Biol Psychiatry 75:723–731. https://doi.org/10.1016/j.biopsych.2013.11.032 CrossRefPubMedPubMedCentral

36.

Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356CrossRefPubMed

37.

Holtzman DM, Morris JC, Goate AM (2011) Alzheimer’s disease: the challenge of the second century. Sci Transl Med 3:77sr71

38.

Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR (2012) Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet 44:955–959. https://doi.org/10.1038/ng.2354 CrossRefPubMedPubMedCentral

39.

Infante J, Llorca J, Rodero L, Palacio E, Berciano J, Combarros O (2002) Polymorphism at codon 174 of the prion-like protein gene is not associated with sporadic Alzheimer’s disease. Neurosci Lett 332:213–215CrossRefPubMed

40.

Jentsch TJ (2007) Chloride and the endosomal-lysosomal pathway: emerging roles of CLC chloride transporters. J Physiol 578:633–640. https://doi.org/10.1113/jphysiol.2006.124719 CrossRefPubMed

41.

Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC et al (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21:108–117. https://doi.org/10.1038/mp.2015.23 CrossRefPubMed

42.

Kauwe JS, Bailey MH, Ridge PG, Perry R, Wadsworth ME, Hoyt KL et al (2014) Genome-wide association study of CSF levels of 59 Alzheimer’s disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation. PLoS Genet 10:e1004758CrossRefPubMedCentralPubMed

43.

Keage HA, Hunter S, Matthews FE, Ince PG, Hodges J, Hokkanen SR et al (2014) TDP-43 pathology in the population: prevalence and associations with dementia and age. J Alzheimers Dis 42:641–650. https://doi.org/10.3233/jad-132351 CrossRefPubMed

44.

Kelly MP (2017) A role for phosphodiesterase 11A (PDE11A) in the formation of social memories and the stabilization of mood. Adv Neurobiol 17:201–230. https://doi.org/10.1007/978-3-319-58811-7_8 CrossRefPubMedPubMedCentral

45.

Kelly MP, Adamowicz W, Bove S, Hartman AJ, Mariga A, Pathak G et al (2014) Select 3′,5′-cyclic nucleotide phosphodiesterases exhibit altered expression in the aged rodent brain. Cell Signal 26:383–397. https://doi.org/10.1016/j.cellsig.2013.10.007 CrossRefPubMed

46.

Ko DC, Milenkovic L, Beier SM, Manuel H, Buchanan J, Scott MP (2005) Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann-Pick type C disease. PLoS Genet 1:81–95. https://doi.org/10.1371/journal.pgen.0010007 CrossRefPubMed

47.

Koike M, Shibata M, Ohsawa Y, Nakanishi H, Koga T, Kametaka S et al (2003) Involvement of two different cell death pathways in retinal atrophy of cathepsin D-deficient mice. Mol Cell Neurosci 22:146–161CrossRefPubMed

48.

Koike M, Shibata M, Waguri S, Yoshimura K, Tanida I, Kominami E et al (2005) Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Am J Pathol 167:1713–1728. https://doi.org/10.1016/s0002-9440(10)61253-9 CrossRefPubMedPubMedCentral

49.

Kushima I, Aleksic B, Nakatochi M, Shimamura T, Okada T, Uno Y et al (2018) Comparative analyses of copy-number variation in autism spectrum disorder and schizophrenia reveal etiological overlap and biological insights. Cell Rep 24:2838–2856. https://doi.org/10.1016/j.celrep.2018.08.022 CrossRefPubMed

50.

Kypri E, Schmauch C, Maniak M, De Lozanne A (2007) The BEACH protein LvsB is localized on lysosomes and postlysosomes and limits their fusion with early endosomes. Traffic (Copenhagen, Denmark) 8:774–783. https://doi.org/10.1111/j.1600-0854.2007.00567.x CrossRef

51.

Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458. https://doi.org/10.1038/ng.2802 CrossRefPubMedPubMedCentral

52.

Lang CM, Fellerer K, Schwenk BM, Kuhn PH, Kremmer E, Edbauer D et al (2012) Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. J Biol Chem 287:19355–19365. https://doi.org/10.1074/jbc.M112.365098 CrossRefPubMedPubMedCentral

53.

Laszlo L, Lowe J, Self T, Kenward N, Landon M, McBride T et al (1992) Lysosomes as key organelles in the pathogenesis of prion encephalopathies. J Pathol 166:333–341. https://doi.org/10.1002/path.1711660404 CrossRefPubMed

54.

Lee JA, Beigneux A, Ahmad ST, Young SG, Gao FB (2007) ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr Biol 17:1561–1567. https://doi.org/10.1016/j.cub.2007.07.029 CrossRefPubMed

55.

Leidal AM, Levine B, Debnath J (2018) Autophagy and the cell biology of age-related disease. Nat Cell Biol 20:1338–1348. https://doi.org/10.1038/s41556-018-0235-8 CrossRefPubMed

56.

Li Z, Del-Aguila JL, Dube U, Budde J, Martinez R, Black K et al (2018) Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure. Genome Med 10:43. https://doi.org/10.1186/s13073-018-0551-4 CrossRefPubMedPubMedCentral

57.

Murray ME, Cannon A, Graff-Radford NR, Liesinger AM, Rutherford NJ, Ross OA et al (2014) Differential clinicopathologic and genetic features of late-onset amnestic dementias. Acta Neuropathol 128:411–421. https://doi.org/10.1007/s00401-014-1302-2 CrossRefPubMedPubMedCentral

58.

Murray ME, Dickson DW (2014) Is pathological aging a successful resistance against amyloid-beta or preclinical Alzheimer’s disease? Alzheimers Res Ther 6:24. https://doi.org/10.1186/alzrt254 CrossRefPubMedPubMedCentral

59.

Newman AM, Steen CB, Liu CL, Gentles AJ, Chaudhuri AA, Scherer F et al (2019) Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol 37:773–782. https://doi.org/10.1038/s41587-019-0114-2 CrossRefPubMedPubMedCentral

60.

Nicholson AM, Finch NA, Wojtas A, Baker MC, Perkerson RB 3rd, Castanedes-Casey M et al (2013) TMEM106B p. T185S regulates TMEM106B protein levels: implications for frontotemporal dementia. J Neurochem 126:781–791. https://doi.org/10.1111/jnc.12329 CrossRefPubMedPubMedCentral

61.

Nixon RA (2005) Endosome function and dysfunction in Alzheimer’s disease and other neurodegenerative diseases. Neurobiol Aging 26:373–382. https://doi.org/10.1016/j.neurobiolaging.2004.09.018 CrossRefPubMed

62.

Nixon RA, Yang DS, Lee JH (2008) Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 4:590–599CrossRefPubMed

63.

Pacheco CD, Kunkel R, Lieberman AP (2007) Autophagy in Niemann-Pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects. Hum Mol Genet 16:1495–1503. https://doi.org/10.1093/hmg/ddm100 CrossRefPubMed

64.

Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C (2017) Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods 14:417–419. https://doi.org/10.1038/nmeth.4197 CrossRefPubMedPubMedCentral

65.

Piccio L, Deming Y, Del-Aguila JL, Ghezzi L, Holtzman DM, Fagan AM et al (2016) Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol 131:925–933. https://doi.org/10.1007/s00401-016-1533-5 CrossRefPubMedPubMedCentral

66.

Premi E, Grassi M, van Swieten J, Galimberti D, Graff C, Masellis M et al (2017) Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study. Brain 140:1784–1791. https://doi.org/10.1093/brain/awx103 CrossRefPubMedPubMedCentral

67.

Ramasamy A, Trabzuni D, Guelfi S, Varghese V, Smith C, Walker R et al (2014) Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci 17:1418–1428. https://doi.org/10.1038/nn.3801 CrossRefPubMedPubMedCentral

68.

Reid E, Connell J, Edwards TL, Duley S, Brown SE, Sanderson CM (2005) The hereditary spastic paraplegia protein spastin interacts with the ESCRT-III complex-associated endosomal protein CHMP1B. Hum Mol Genet 14:19–38. https://doi.org/10.1093/hmg/ddi003 CrossRefPubMed

69.

Rhinn H, Abeliovich A (2017) Differential aging analysis in human cerebral cortex identifies variants in TMEM106B and GRN that regulate aging phenotypes. Cell Syst 4:404–415.e5. https://doi.org/10.1016/j.cels.2017.02.009 CrossRefPubMed

70.

Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC (2007) Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 282:5641–5652. https://doi.org/10.1074/jbc.M609532200 CrossRefPubMed

71.

Schroder B, Franz B, Hempfling P, Selbert M, Jurgens T, Kretzschmar HA et al (2001) Polymorphisms within the prion-like protein gene (Prnd) and their implications in human prion diseases, Alzheimer’s disease and other neurological disorders. Hum Genet 109:319–325. https://doi.org/10.1007/s004390100591 CrossRefPubMed

72.

Schwenk BM, Lang CM, Hogl S, Tahirovic S, Orozco D, Rentzsch K et al (2014) The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO J 33:450–467. https://doi.org/10.1002/embj.201385857 CrossRefPubMed

73.

Shirk AJ, Anderson SK, Hashemi SH, Chance PF, Bennett CL (2005) SIMPLE interacts with NEDD4 and TSG101: evidence for a role in lysosomal sorting and implications for Charcot–Marie–Tooth disease. J Neurosci Res 82:43–50. https://doi.org/10.1002/jnr.20628 CrossRefPubMed

74.

Stagi M, Klein ZA, Gould TJ, Bewersdorf J, Strittmatter SM (2014) Lysosome size, motility and stress response regulated by fronto-temporal dementia modifier TMEM106B. Mol Cell Neurosci 61:226–240. https://doi.org/10.1016/j.mcn.2014.07.006 CrossRefPubMedPubMedCentral

75.

Suárez-Calvet M, Capell A, Caballero MÁA, Morenas-Rodríguez E, Fellerer K, Franzmeier N et al (2018) CSF progranulin increases in the course of Alzheimer’s disease and is associated with sTREM2, neurodegeneration and cognitive decline. EMBO Mol Med 10:e9712CrossRefPubMedCentralPubMed

76.

Sul JH, Han B, Ye C, Choi T, Eskin E (2013) Effectively identifying eQTLs from multiple tissues by combining mixed model and meta-analytic approaches. PLoS Genet 9:e1003491. https://doi.org/10.1371/journal.pgen.1003491 CrossRefPubMedPubMedCentral

77.

Toledo JB, Cairns NJ, Da X, Chen K, Carter D, Fleisher A et al (2013) Clinical and multimodal biomarker correlates of ADNI neuropathological findings. Acta Neuropathol Commun 1:65. https://doi.org/10.1186/2051-5960-1-65 CrossRefPubMedPubMedCentral

78.

Turner SD (2014) qqman: an R package for visualizing GWAS results using Q–Q and manhattan plots. bioRxiv. https://doi.org/10.1101/005165 CrossRef

79.

Uchino A, Takao M, Hatsuta H, Sumikura H, Nakano Y, Nogami A et al (2015) Incidence and extent of TDP-43 accumulation in aging human brain. Acta Neuropathol Commun 3:35. https://doi.org/10.1186/s40478-015-0215-1 CrossRefPubMedPubMedCentral

80.

Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR et al (2010) Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42:234–239. https://doi.org/10.1038/ng.536 CrossRefPubMedPubMedCentral

81.

Vass R, Ashbridge E, Geser F, Hu WT, Grossman M, Clay-Falcone D et al (2011) Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis. Acta Neuropathol 121:373–380. https://doi.org/10.1007/s00401-010-0782-y CrossRefPubMed

82.

Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57:369–384CrossRefPubMed

83.

Wang D, Liu S, Warrell J, Won H, Shi X, Navarro FCP et al (2018) Comprehensive functional genomic resource and integrative model for the human brain. Science. https://doi.org/10.1126/science.aat8464 CrossRefPubMedPubMedCentral

84.

Wang L, Nie J, Sicotte H, Li Y, Eckel-Passow JE, Dasari S et al (2016) Measure transcript integrity using RNA-seq data. BMC Bioinform 17:58. https://doi.org/10.1186/s12859-016-0922-z CrossRef

85.

Wang M, Beckmann ND, Roussos P, Wang E, Zhou X, Wang Q et al (2018) The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer’s disease. Sci Data 5:180185. https://doi.org/10.1038/sdata.2018.185 CrossRefPubMedPubMedCentral

86.

Watanabe K, Taskesen E, van Bochoven A, Posthuma D (2017) Functional mapping and annotation of genetic associations with FUMA. Nat Commun 8:1826. https://doi.org/10.1038/s41467-017-01261-5 CrossRefPubMedPubMedCentral

87.

Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009–25013. https://doi.org/10.1074/jbc.M300227200 CrossRefPubMed

88.

Wennberg AM, Whitwell JL, Tosakulwong N, Weigand SD, Murray ME, Machulda MM et al (2019) The influence of tau, amyloid, alpha-synuclein, TDP-43, and vascular pathology in clinically normal elderly individuals. Neurobiol Aging 77:26–36. https://doi.org/10.1016/j.neurobiolaging.2019.01.008 CrossRefPubMedPubMedCentral

89.

White CC, Yang HS, Yu L, Chibnik LB, Dawe RJ, Yang J et al (2017) Identification of genes associated with dissociation of cognitive performance and neuropathological burden: multistep analysis of genetic, epigenetic, and transcriptional data. PLoS Med 14:e1002287. https://doi.org/10.1371/journal.pmed.1002287 CrossRefPubMedPubMedCentral

90.

Yang J, Lee SH, Goddard ME, Visscher PM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88:76–82. https://doi.org/10.1016/j.ajhg.2010.11.011 CrossRefPubMedPubMedCentral

91.

Zhou X, Sun L, Brady OA, Murphy KA, Hu F (2017) Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency. Acta Neuropathol Commun 5:9. https://doi.org/10.1186/s40478-017-0412-1 CrossRefPubMedPubMedCentral

Title: The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion
Authors: Zeran Li
Fabiana H. G. Farias
Umber Dube
Jorge L. Del-Aguila
Kathie A. Mihindukulasuriya
Maria Victoria Fernandez
Laura Ibanez
John P. Budde
Fengxian Wang
Allison M. Lake
Yuetiva Deming
James Perez
Chengran Yang
Jorge A. Bahena
Wei Qin
Joseph L. Bradley
Richard Davenport
Kristy Bergmann
John C. Morris
Richard J. Perrin
Bruno A. Benitez
Joseph D. Dougherty
Oscar Harari
Carlos Cruchaga
Publication date: 01-01-2020
Publisher: Springer Berlin Heidelberg
Keywords: Alzheimer's Disease
Alzheimer's Disease
Published in: Acta Neuropathologica / Issue 1/2020
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02066-0

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The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion

Abstract

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Abstract

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FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas

Proteomics in cerebrospinal fluid and spinal cord suggests UCHL1, MAP2 and GPNMB as biomarkers and underpins importance of transcriptional pathways in amyotrophic lateral sclerosis

Evidence of corticofugal tau spreading in patients with frontotemporal dementia

Correction to: 4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration

4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration

Poly-glycine–alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3