Tau acts as an independent genetic risk factor in pathologically proven PD

Gavin Charlesworth,Sonia Gandhi,Jose M Bras,Roger A Barker,David J Burn,Patrick F Chinnery,Stephen M Gentleman,Rita Guerreiro,John Hardy,Janice L Holton,Andrew Lees,Karen Morrison,Una-Marie Sheerin,Nigel Williams,Huw Morris,Tamas Revesz,Nicholas W Wood

doi:10.1016/j.neurobiolaging.2011.11.001

Abstract

MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association.

Highlights

To date, several large-scale genome-wide association studies (GWAS) have been completed for Parkinson’s disease (PD), culminating in a recently published metaanalysis that identified 16 loci surpassing the threshold for genome-wide significance (International Parkinson’sDisease Genomics Consortium et al, 2011; International Parkinson’s Disease Genomics Consortium and Wellcome Trust, Case Control Consortium 2, 2011; Satake et al, 2009; Simón-Sánchez et al, 2009; UK Parkinson’s Disease Consortium et al, 2011)
The single nucleotide polymorphisms (SNPs) tested for association in this region were selected on the basis that they had achieved genome-wide significance in the UK samples used in the discovery phase of our GWAS meta-analysis and had been genotyped on the custom-built immunochip used for the replication phase
No proxy in sufficient linkage disequilibrium (r2 Ͼ 0.8) with the H1-specific SNP rs242557, which has previously been implicated in progressive supranuclear palsy (PSP) but not PD, was available for testing (Wider et al, 2010)

Summary

Introduction

Disease Genomics Consortium et al, 2011; International Parkinson’s Disease Genomics Consortium and Wellcome Trust, Case Control Consortium 2, 2011; Satake et al, 2009; Simón-Sánchez et al, 2009; UK Parkinson’s Disease Consortium et al, 2011). Of these 16 loci, some are predictable findings, while others offer the new insights into the pathogenesis of the disease. The detection of variation in MAPT as a risk factor in PD was unexpected, as the relevance of tau aggregation in PD remains unclear. Charlesworth et al / Neurobiology of Aging 33 (2012) 838.e7– 838.e11

Methods

Results

Conclusion