Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy.

TitleIdentification of common variants influencing risk of the tauopathy progressive supranuclear palsy.
Publication TypeJournal Article
Year of Publication2011
AuthorsHöglinger GU, Melhem NM, Dickson DW, Sleiman PMA, San Wang L-, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P, Cantwell LB, Han MRyung, Dillman A, van der Brug MP, J Gibbs R, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu C-E, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Müller U, Schellenberg GD
Corporate AuthorsPSP Genetics Study Group
JournalNat Genet
Volume43
Issue7
Pagination699-705
Date Published2011 Jun 19
ISSN1546-1718
KeywordsCase-Control Studies, Chromosomes, Human, Cohort Studies, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Prognosis, Risk Factors, Supranuclear Palsy, Progressive, tau Proteins, Tauopathies
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.

DOI10.1038/ng.859
Alternate JournalNat. Genet.
PubMed ID21685912
PubMed Central IDPMC3125476
Grant ListK01 MH077930 / MH / NIMH NIH HHS / United States
K01 MH077930-05 / MH / NIMH NIH HHS / United States
1RC2NS070276 / NS / NINDS NIH HHS / United States
R01 NS057567 / NS / NINDS NIH HHS / United States
U01HG004438 / HG / NHGRI NIH HHS / United States
U01 HG004438 / HG / NHGRI NIH HHS / United States
G0501560 / / Medical Research Council / United Kingdom
R37 MH057881 / MH / NIMH NIH HHS / United States
P50 NS72187 / NS / NINDS NIH HHS / United States
D1A RH00025 / / PHS HHS / United States
R37 AG 11762 / AG / NIA NIH HHS / United States
MH077930 / MH / NIMH NIH HHS / United States
P01 AG017586 / AG / NIA NIH HHS / United States
G0701075 / / Medical Research Council / United Kingdom
NS057567 / NS / NINDS NIH HHS / United States
U01 HG004603-01 / HG / NHGRI NIH HHS / United States
P50NS072187 / NS / NINDS NIH HHS / United States
U01 HG004603 / HG / NHGRI NIH HHS / United States
P01 AG17216 / AG / NIA NIH HHS / United States
P50 NS072187-01 / NS / NINDS NIH HHS / United States
G0400074 / / Medical Research Council / United Kingdom
R01 MH057881 / MH / NIMH NIH HHS / United States
G0900652 / / Medical Research Council / United Kingdom
R37 AG011762-17 / AG / NIA NIH HHS / United States
G0501560(76517) / / Medical Research Council / United Kingdom
R37 AG011762 / AG / NIA NIH HHS / United States
/ / Intramural NIH HHS / United States
G0502157 / / Medical Research Council / United Kingdom
R01 NS057567-04 / NS / NINDS NIH HHS / United States
G0701441 / / Medical Research Council / United Kingdom
R01 MH057881-13 / MH / NIMH NIH HHS / United States
GTB07001 / / Telethon / Italy
P50 NS072187 / NS / NINDS NIH HHS / United States
U01HG004608 / HG / NHGRI NIH HHS / United States
RC2 NS070276-02S1 / NS / NINDS NIH HHS / United States
P01 AG017216-05 / AG / NIA NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
RC2 NS070276 / NS / NINDS NIH HHS / United States
MH057881 / MH / NIMH NIH HHS / United States
U01HG004603 / HG / NHGRI NIH HHS / United States
P50 NS038377 / NS / NINDS NIH HHS / United States
U01 HG004608-04 / HG / NHGRI NIH HHS / United States
P01 AG017216 / AG / NIA NIH HHS / United States
081864 / / Wellcome Trust / United Kingdom
/ / Wellcome Trust / United Kingdom
R01 PAS-03-092 / / PHS HHS / United States
U01 HG004608 / HG / NHGRI NIH HHS / United States
G0600676 / / Medical Research Council / United Kingdom
G0700943 / / Medical Research Council / United Kingdom
MC_G1000734 / / Medical Research Council / United Kingdom