Top

Published in:

01-08-2016 | Original Paper

Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci

Authors: Mariet Allen, Jeremy D. Burgess, Travis Ballard, Daniel Serie, Xue Wang, Curtis S. Younkin, Zhifu Sun, Naomi Kouri, Saurabh Baheti, Chen Wang, Minerva M. Carrasquillo, Thuy Nguyen, Sarah Lincoln, Kimberly Malphrus, Melissa Murray, Todd E. Golde, Nathan D. Price, Steven G. Younkin, Gerard D. Schellenberg, Yan Asmann, Tamas Ordog, Julia Crook, Dennis Dickson, Nilüfer Ertekin-Taner

Published in: Acta Neuropathologica | Issue 2/2016

Abstract

To determine the effects of single nucleotide polymorphisms (SNPs) identified in a genome-wide association study of progressive supranuclear palsy (PSP), we tested their association with brain gene expression, CpG methylation and neuropathology. In 175 autopsied PSP subjects, we performed associations between seven PSP risk variants and temporal cortex levels of 20 genes in-cis, within ±100 kb. Methylation measures were collected using reduced representation bisulfite sequencing in 43 PSP brains. To determine whether SNP/expression associations are due to epigenetic modifications, CpG methylation levels of associated genes were tested against relevant variants. Quantitative neuropathology endophenotypes were tested for SNP associations in 422 PSP subjects. Brain levels of LRRC37A4 and ARL17B were associated with rs8070723; MOBP with rs1768208 and both ARL17A and ARL17B with rs242557. Expression associations for LRRC37A4 and MOBP were available in an additional 100 PSP subjects. Meta-analysis revealed highly significant associations for PSP risk alleles of rs8070723 and rs1768208 with higher LRRC37A4 and MOBP brain levels, respectively. Methylation levels of one CpG in the 3′ region of ARL17B associated with rs242557 and rs8070723. Additionally, methylation levels of an intronic ARL17A CpG associated with rs242557 and that of an intronic MOBP CpG with rs1768208. MAPT and MOBP region risk alleles also associated with higher levels of neuropathology. Strongest associations were observed for rs242557/coiled bodies and tufted astrocytes; and for rs1768208/coiled bodies and tau threads. These findings suggest that PSP variants at MAPT and MOBP loci may confer PSP risk via influencing gene expression and tau neuropathology. MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes. Our findings have implications for the mechanism of action of variants at some of the top PSP risk loci.

Available only for authorised users

Allen M, Kachadoorian M, Quicksall Z, Zou F, Chai HS, Younkin C et al (2014) Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels. Alzheimers Res Ther 6:39. doi:10.1186/alzrt268 CrossRefPubMedPubMedCentral

Allen M, Kachadoorian M, Carrasquillo MM, Karhade A, Manly L, Burgess JD et al (2015) Late-onset Alzheimer disease risk variants mark brain regulatory loci. Neurol Genet 1:e15CrossRefPubMedPubMedCentral

Bekpen C, Tastekin I, Siswara P, Akdis CA, Eichler EE (2012) Primate segmental duplication creates novel promoters for the LRRC37 gene family within the 17q21.31 inversion polymorphism region. Genome Res 22:1050–1058. doi:10.1101/gr.134098.111 CrossRefPubMedPubMedCentral

Bennett DA, Yu L, Yang J, Srivastava GP, Aubin C, De Jager PL (2015) Epigenomics of Alzheimer’s disease. Transl Res 165:200–220. doi:10.1016/j.trsl.2014.05.006 CrossRefPubMed

Boettger LM, Handsaker RE, Zody MC, McCarroll SA (2012) Structural haplotypes and recent evolution of the human 17q21.31 region. Nat Genet 44:881–885. doi:10.1038/ng.2334 CrossRefPubMedPubMedCentral

Bollen KA (2002) Latent variables in psychology and the social sciences. Annu Rev Psychol 53:605–634. doi:10.1146/annurev.psych.53.100901.135239 CrossRefPubMed

Carrasquillo MM, Zou F, Pankratz VS, Wilcox SL, Ma L, Walker LP et al (2009) Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease. Nat Genet 41:192–198. doi:10.1038/ng.305 CrossRefPubMedPubMedCentral

Coupland KG, Mellick GD, Silburn PA, Mather K, Armstrong NJ, Sachdev PS et al (2014) DNA methylation of the MAPT gene in Parkinson’s disease cohorts and modulation by vitamin E in vitro. Mov Disord 29:1606–1614. doi:10.1002/mds.25784 CrossRefPubMed

De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L et al (2014) Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 17:1156–1163. doi:10.1038/nn.3786 CrossRefPubMedPubMedCentral

10.

de Jong S, Chepelev I, Janson E, Strengman E, van den Berg LH, Veldink JH et al (2012) Common inversion polymorphism at 17q21.31 affects expression of multiple genes in tissue-specific manner. BMC Genom 13:458. doi:10.1186/1471-2164-13-458 CrossRef

11.

Desikan RS, Schork AJ, Wang Y, Witoelar A, Sharma M, McEvoy LK et al (2015) Genetic overlap between Alzheimer’s disease and Parkinson’s disease at the MAPT locus. Mol Psychiatry 20:1588–1595. doi:10.1038/mp.2015.6 CrossRefPubMedPubMedCentral

12.

Dickson DW, Rademakers R, Hutton ML (2007) Progressive supranuclear palsy: pathology and genetics. Brain Pathol 17:74–82. doi:10.1111/j.1750-3639.2007.00054.x CrossRefPubMed

13.

Donker Kaat L, Boon AJ, Azmani A, Kamphorst W, Breteler MM, Anar B et al (2009) Familial aggregation of parkinsonism in progressive supranuclear palsy. Neurology 73:98–105. doi:10.1212/WNL.0b013e3181a92bcc CrossRefPubMed

14.

Du P, Kibbe WA, Lin SM (2008) lumi: a pipeline for processing Illumina microarray. Bioinformatics 24:1547–1548. doi:10.1093/bioinformatics/btn224 CrossRefPubMed

15.

Ertekin-Taner N, De Jager PL, Yu L, Bennett DA (2013) Alternative approaches in gene discovery and characterization in Alzheimer’s disease. Curr Genet Med Rep 1:39–51. doi:10.1007/s40142-013-0007-5 CrossRefPubMedPubMedCentral

16.

Ferrari R, Ryten M, Simone R, Trabzuni D, Nicolaou N, Hondhamuni G et al (2014) Assessment of common variability and expression quantitative trait loci for genome-wide associations for progressive supranuclear palsy. Neurobiol Aging 35(1514):e1511–e1512. doi:10.1016/j.neurobiolaging.2014.01.010

17.

Goedert M (2015) Neurodegeneration. Alzheimer’s and Parkinson’s diseases: the prion concept in relation to assembled Abeta, tau, and alpha-synuclein. Science 349:1255555. doi:10.1126/science.1255555

18.

Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL et al (1994) Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 44:2015–2019CrossRefPubMed

19.

Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L et al (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699–705. doi:10.1038/ng.859 CrossRefPubMedPubMedCentral

20.

Im SY, Kim YE, Kim YJ (2015) Genetics of progressive supranuclear palsy. J Mov Disord 8:122–129. doi:10.14802/jmd.15033 CrossRefPubMedPubMedCentral

21.

Iwata A, Nagata K, Hatsuta H, Takuma H, Bundo M, Iwamoto K et al (2014) Altered CpG methylation in sporadic Alzheimer’s disease is associated with APP and MAPT dysregulation. Hum Mol Genet 23:648–656. doi:10.1093/hmg/ddt451 CrossRefPubMed

22.

Jowaed A, Schmitt I, Kaut O, Wullner U (2010) Methylation regulates alpha-synuclein expression and is decreased in Parkinson’s disease patients’ brains. J Neurosci 30:6355–6359. doi:10.1523/JNEUROSCI.6119-09.2010 CrossRefPubMed

23.

Kett LR, Dauer WT (2012) Leucine-rich repeat kinase 2 for beginners: six key questions. Cold Spring Harb Perspect Med 2:a009407. doi:10.1101/cshperspect.a009407 CrossRefPubMedPubMedCentral

24.

Kouri N, Ross OA, Dombroski B, Younkin CS, Serie DJ, Soto-Ortolaza A et al (2015) Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat Commun 6:7247. doi:10.1038/ncomms8247 CrossRefPubMedPubMedCentral

25.

Li Y, Chen JA, Sears RL, Gao F, Klein ED, Karydas A et al (2014) An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy. PLoS Genet 10:e1004211. doi:10.1371/journal.pgen.1004211 CrossRefPubMedPubMedCentral

26.

Lincoln S, Allen M, Cox CL, Walker LP, Malphrus K, Qiu Y et al (2013) LRRTM3 interacts with APP and BACE1 and has variants associating with late-onset Alzheimer’s disease (LOAD). PLoS One 8:e64164. doi:10.1371/journal.pone.0064164 CrossRefPubMedPubMedCentral

27.

Lunnon K, Mill J (2013) Epigenetic studies in Alzheimer’s disease: current findings, caveats, and considerations for future studies. Am J Med Genet B Neuropsychiatr Genet 162B:789–799. doi:10.1002/ajmg.b.32201 CrossRefPubMed

28.

Majercak J, Ray WJ, Espeseth A, Simon A, Shi XP, Wolffe C et al (2006) LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer’s disease. Proc Natl Acad Sci 103:17967–17972. doi:10.1073/pnas.0605461103 CrossRefPubMedPubMedCentral

29.

Myers AJ, Pittman AM, Zhao AS, Rohrer K, Kaleem M, Marlowe L et al (2007) The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol Dis 25:561–570. doi:10.1016/j.nbd.2006.10.018 CrossRefPubMed

30.

Ng CW, Yildirim F, Yap YS, Dalin S, Matthews BJ, Velez PJ et al (2013) Extensive changes in DNA methylation are associated with expression of mutant huntingtin. Proc Natl Acad Sci 110:2354–2359. doi:10.1073/pnas.1221292110 CrossRefPubMedPubMedCentral

31.

Pastor P, Moreno F, Clarimon J, Ruiz A, Combarros O, Calero M et al (2015) MAPT H1 haplotype is associated with late-onset Alzheimer’s disease risk in APOEvarepsilon4 noncarriers: results from the Dementia Genetics Spanish Consortium. J Alzheimers Dis 49:343–352. doi:10.3233/JAD-150555 CrossRefPubMed

32.

Patterson N, Price AL, Reich D (2006) Population structure and eigenanalysis. PLoS Genet 2:e190. doi:10.1371/journal.pgen.0020190 CrossRefPubMedPubMedCentral

33.

Pittman AM, Myers AJ, Abou-Sleiman P, Fung HC, Kaleem M, Marlowe L et al (2005) Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J Med Genet 42:837–846. doi:10.1136/jmg.2005.031377 CrossRefPubMedPubMedCentral

34.

Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909. doi:10.1038/ng1847 CrossRefPubMed

35.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575. doi:10.1086/519795 CrossRefPubMedPubMedCentral

36.

Rademakers R, Melquist S, Cruts M, Theuns J, Del-Favero J, Poorkaj P et al (2005) High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet 14:3281–3292. doi:10.1093/hmg/ddi361 CrossRefPubMed

37.

Rizopoulos D (2006) ltm: an R Package for latent variable modeling and item response theory analyses. J Stat Softw 17:1–25CrossRef

38.

Rojo A, Pernaute RS, Fontan A, Ruiz PG, Honnorat J, Lynch T et al (1999) Clinical genetics of familial progressive supranuclear palsy. Brain 122(Pt 7):1233–1245CrossRefPubMed

39.

Seixas E, Barros M, Seabra MC, Barral DC (2013) Rab and Arf proteins in genetic diseases. Traffic 14:871–885. doi:10.1111/tra.12072 CrossRefPubMed

40.

Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D et al (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41:1308–1312. doi:10.1038/ng.487 CrossRefPubMedPubMedCentral

41.

Steinberg KM, Antonacci F, Sudmant PH, Kidd JM, Campbell CD, Vives L et al (2012) Structural diversity and African origin of the 17q21.31 inversion polymorphism. Nat Genet 44:872–880. doi:10.1038/ng.2335 CrossRefPubMedPubMedCentral

42.

Stranger BE, Forrest MS, Clark AG, Minichiello MJ, Deutsch S, Lyle R et al (2005) Genome-wide associations of gene expression variation in humans. PLoS Genet 1:e78. doi:10.1371/journal.pgen.0010078 CrossRefPubMedPubMedCentral

43.

Sun Z, Baheti S, Middha S, Kanwar R, Zhang Y, Li X et al (2012) SAAP-RRBS: streamlined analysis and annotation pipeline for reduced representation bisulfite sequencing. Bioinformatics 28:2180–2181. doi:10.1093/bioinformatics/bts337 CrossRefPubMedPubMedCentral

44.

Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–2191. doi:10.1093/bioinformatics/btq340 CrossRefPubMedPubMedCentral

45.

Yamamoto Y, Mizuno R, Nishimura T, Ogawa Y, Yoshikawa H, Fujimura H et al (1994) Cloning and expression of myelin-associated oligodendrocytic basic protein. A novel basic protein constituting the central nervous system myelin. J Biol Chem 269:31725–31730PubMed

46.

Zhang H, Zhang YW, Chen Y, Huang X, Zhou F, Wang W et al (2012) Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration. J Neurosci 32:15565–15576. doi:10.1523/JNEUROSCI.3668-12.2012 CrossRefPubMedPubMedCentral

47.

Zhao Y, Tseng IC, Heyser CJ, Rockenstein E, Mante M, Adame A et al (2015) Appoptosin-mediated caspase cleavage of tau contributes to progressive supranuclear palsy pathogenesis. Neuron 87:963–975. doi:10.1016/j.neuron.2015.08.020 CrossRefPubMed

48.

Zou F, Chai HS, Younkin CS, Allen M, Crook J, Pankratz VS et al (2012) Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. PLoS Genet 8:e1002707. doi:10.1371/journal.pgen.1002707 CrossRefPubMedPubMedCentral

Title: Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci
Authors: Mariet Allen
Jeremy D. Burgess
Travis Ballard
Daniel Serie
Xue Wang
Curtis S. Younkin
Zhifu Sun
Naomi Kouri
Saurabh Baheti
Chen Wang
Minerva M. Carrasquillo
Thuy Nguyen
Sarah Lincoln
Kimberly Malphrus
Melissa Murray
Todd E. Golde
Nathan D. Price
Steven G. Younkin
Gerard D. Schellenberg
Yan Asmann
Tamas Ordog
Julia Crook
Dennis Dickson
Nilüfer Ertekin-Taner
Publication date: 01-08-2016
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 2/2016
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-016-1576-7

At a glance: The STEP trials

Springer Medicine

Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2016

Inside out: the role of nucleocytoplasmic transport in ALS and FTLD

A rapidly progressive dementia case with pathological diagnosis of FTLD-UPS

Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology

Significant association of cadaveric dura mater grafting with subpial Aβ deposition and meningeal amyloid angiopathy

Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease

The importance of nerve microenvironment for schwannoma development