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

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.

Figure 1

(a) Association results for 1q25.3 STX6. (b) Association results for 2p11.2 EIF2AK3. (c) Association results for 3p22.1 MOBP regions. –log10 P values are shown for Stages 1 and 2 and the joint analyses. Recombination rate, calculated from the linkage disequilibrium (LD) structure of the region, is derived from Hapmap3 data. LD, encoded by intensity of the colors, is the pairwise LD of the most highly associated SNP at Stage 1 with each of the SNPs in the region. Transcript positions are shown below each graph.

Figure 2

(a) Association results for the 17q21.31 H1/H2 inversion polymorphism (40,974,015 – 41,926,692 Kb) and flanking segments. (b) Association results for 17q21.31 controlling for H1/H2. Results are shown for Stages 1 and 2 and the joint analyses. Recombination rate, calculated from the linkage disequilibrium (LD) structure of the region, is derived from Hapmap3 data. LD, encoded by intensity of the colors, is the pairwise LD of the most highly associated SNP at Stage 1 with each of the SNPs in the region.

Figure 3

(a) Association results for the relationship between SNP genotypes and mRNA transcripts from the cerebellum and frontal cortex for the SLC25S38/MOBP region. (b) Association results for the relationship between SNP genotypes and mRNA transcripts from the cerebellum and frontal cortex for the H1/H2 inversion polymorphism region. (c) Association results for the relationship between SNP genotypes and mRNA transcripts from the cerebellum and frontal cortex for the H1/H2 inversion polymorphism region controlling for H1/H2. The color of the circle corresponds to the color assigned each gene and each SNP is tested against multiple cis transcripts. The data presented here are independent samples from those used previously by Simon-Sanchez et al..