GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease

Abstract

Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ₄₂ are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10⁻⁹ for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10⁻⁸ and p = 3.22 × 10⁻⁹ for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10⁻⁸ for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10⁻⁴, 0.039, 4.86 × 10⁻⁵, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.

Figure 1. Genome-wide signal intensity (Manhattan) plots showing the individual P values (based on fixed-effects meta-analysis) against genomic position

The results for the association of CSF tau (a), and ptau (b) levels with 5,815,690 SNPs are shown. Within each chromosome, shown on the x axis, the results are plotted left to right from the p-terminal end. Horizontal dashed lines indicate P value thresholds of 1 × 10⁻⁵ and 5 × 10⁻⁸ (genome-wide significance).

Figure 2. Regional plots for associations with CSF tau and ptau at genome-wide significance

Plots are centered on the most significant SNP at a given locus along with the combined-analysis results for SNPs in the region surrounding it (typically ± 400 kb). Symbols are colored according to the LD of the SNP with the top SNP. The light blue line represents the estimated recombination rate. Gene annotations are shown as dark green line.