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 novel 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 datasets 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.

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

“…Using the same AD biomarkers in CSF as Han et al, Kim et al [54] showed that APOE, LOC100129500, TOMM40, and EPC2 had genome-wide significance. By performing so far the largest GWAS using AD biomarkers in CSF, Cruchaga et al [55] revealed the association of GLIS3 and TREM with AD.…”

Genome-wide association study identifies MAPT locus influencing human plasma tau levels

“…3,4 Enigmatically, despite strong genetic links to tau, CSF tau levels are normal or low in other tauopathies such as PSP and some tau gene (MAPT) mutation carriers. 5,6 The recent development of an ultrasensitive assay for tau in peripheral blood makes it feasible to study the relationship between peripheral tau concentrations and tauopathies.…”

“…3,4 Here, we hypothesized that plasma tau, similar to CSF tau, may constitute a suitable endophenotype for identifying genetic risk factors for tauopathies. Within this context, we conducted a GWAS for plasma tau level and identified a single nucleotide polymorphism (SNP) (rs242557) within the MAPT gene that showed a genome-wide significant association with plasma, but not CSF, tau levels.…”

Genetic risk factors of Alzheimer's disease and cell-to-cell transmission of Tau

“…Another genome-wide association study that used CSF Tau levels as an endophenotype of LOAD identified novel risk variants of the disease, including SNAR-I, GLIS3 and TOMM40, and confirmed the association of APOE and TREM2 with the variability of CSF Tau and phosphoTau levels 36 . These studies clearly indicate that common genetic variants have an impact on the CSF levels of Tau and that this may be associated with the risk of LOAD or rate of disease progression.…”