Identification of Common Variants Influencing Risk of the Tauopathy Progressive Supranuclear Palsy

Overview

Journal Nat Genet

Specialty Genetics

Date 2011 Jun 21

PMID 21685912

Citations 330

Authors

Gunter U Hoglinger

Nadine M Melhem

Dennis W Dickson

Patrick M A Sleiman

Li-San Wang

Lambertus Klei

Rosa Rademakers

Rohan de Silva

Irene Litvan

David E Riley

John C Van Swieten

Peter Heutink

Zbigniew K Wszolek

Ryan J Uitti

Jana Vandrovcova

Howard I Hurtig

Rachel G Gross

Walter Maetzler

Stefano Goldwurm

Eduardo Tolosa

Barbara Borroni

Pau Pastor

Laura B Cantwell

Mi Ryung Han

Allissa Dillman

Marcel P van der Brug

J Raphael Gibbs

Mark R Cookson

Dena G Hernandez

Andrew B Singleton

Matthew J Farrer

Chang-En Yu

Lawrence I Golbe

Tamas Revesz

John Hardy

Andrew J Lees

Bernie Devlin

Hakon Hakonarson

Ulrich Muller

Gerard D Schellenberg

Affiliations

Soon will be listed here.

Abstract

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

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References

Jahn R, Scheller R . SNAREs--engines for membrane fusion. Nat Rev Mol Cell Biol. 2006; 7(9):631-43. DOI: 10.1038/nrm2002. View

Hauw J, Daniel S, Dickson D, Horoupian D, Jellinger K, Lantos P . Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology. 1994; 44(11):2015-9. DOI: 10.1212/wnl.44.11.2015. View

Zody M, Jiang Z, Fung H, Antonacci F, Hillier L, Cardone M . Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat Genet. 2009; 40(9):1076-83. PMC: 2684794. DOI: 10.1038/ng.193. View

Gibbs J, van der Brug M, Hernandez D, Traynor B, Nalls M, Lai S . Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 2010; 6(5):e1000952. PMC: 2869317. DOI: 10.1371/journal.pgen.1000952. View

Golbe L, Rubin R, Cody R, Belsh J, Duvoisin R, Grosmann C . Follow-up study of risk factors in progressive supranuclear palsy. Neurology. 1996; 47(1):148-54. DOI: 10.1212/wnl.47.1.148. View

Montague P, McCallion A, Davies R, Griffiths I . Myelin-associated oligodendrocytic basic protein: a family of abundant CNS myelin proteins in search of a function. Dev Neurosci. 2006; 28(6):479-87. DOI: 10.1159/000095110. View

Dickson D, Bergeron C, Chin S, Duyckaerts C, Horoupian D, Ikeda K . Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol. 2002; 61(11):935-46. DOI: 10.1093/jnen/61.11.935. View

Houlden H, Baker M, Morris H, Macdonald N, Pickering-Brown S, Adamson J . Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology. 2001; 56(12):1702-6. DOI: 10.1212/wnl.56.12.1702. View

Wendler F, Tooze S . Syntaxin 6: the promiscuous behaviour of a SNARE protein. Traffic. 2001; 2(9):606-11. DOI: 10.1034/j.1600-0854.2001.20903.x. View

10.

Tian C, Plenge R, Ransom M, Lee A, Villoslada P, Selmi C . Analysis and application of European genetic substructure using 300 K SNP information. PLoS Genet. 2008; 4(1):e4. PMC: 2211544. DOI: 10.1371/journal.pgen.0040004. View

11.

Lee A, Luca D, Klei L, Devlin B, Roeder K . Discovering genetic ancestry using spectral graph theory. Genet Epidemiol. 2009; 34(1):51-9. PMC: 4610359. DOI: 10.1002/gepi.20434. View

12.

Naj A, Jun G, Beecham G, Wang L, Vardarajan B, Buros J . Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011; 43(5):436-41. PMC: 3090745. DOI: 10.1038/ng.801. View

13.

Dickson D, Rademakers R, Hutton M . Progressive supranuclear palsy: pathology and genetics. Brain Pathol. 2007; 17(1):74-82. PMC: 8095545. DOI: 10.1111/j.1750-3639.2007.00054.x. View

14.

Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin R . Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology. 1996; 47(1):1-9. DOI: 10.1212/wnl.47.1.1. View

15.

Myers A, Pittman A, Zhao A, Rohrer K, Kaleem M, Marlowe L . The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol Dis. 2006; 25(3):561-70. DOI: 10.1016/j.nbd.2006.10.018. View

16.

Hoozemans J, van Haastert E, Eikelenboom P, de Vos R, Rozemuller J, Scheper W . Activation of the unfolded protein response in Parkinson's disease. Biochem Biophys Res Commun. 2007; 354(3):707-11. DOI: 10.1016/j.bbrc.2007.01.043. View

17.

Farrer L, Cupples L, Haines J, Hyman B, Kukull W, Mayeux R . Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997; 278(16):1349-56. View

18.

Nalls M, Plagnol V, Hernandez D, Sharma M, Sheerin U, Saad M . Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet. 2011; 377(9766):641-9. PMC: 3696507. DOI: 10.1016/S0140-6736(10)62345-8. View

19.

Hoozemans J, van Haastert E, Nijholt D, Rozemuller A, Eikelenboom P, Scheper W . The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus. Am J Pathol. 2009; 174(4):1241-51. PMC: 2671357. DOI: 10.2353/ajpath.2009.080814. View

20.

Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J . Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet. 1999; 8(4):711-5. DOI: 10.1093/hmg/8.4.711. View