Genome-wide meta-analysis of CSF biomarkers in Alzheimer's disease and Parkinson's disease cohorts

BackgroundAmyloid beta (A{beta}), phosphorylated tau (p-tau), and total tau (t-tau) in cerebrospinal fluid are established biomarkers for Alzheimers disease (AD). In other neurodegenerative diseases, such as Parkinsons disease (PD), these biomarkers have also been found to be altered, and the molecular mechanisms responsible for these alterations are still under investigation. Moreover, the interplay between these mechanisms and the diverse underlying disease states remains to be elucidated. ObjectivesTo investigate genetic contributions to the AD biomarkers and assess the commonality and heterogeneity of the associations per underlying disease status. MethodsWe conducted GWAS for the AD biomarkers on subjects from the Parkinsons Progression Markers Initiative (PPMI), the Fox Investigation for New Discovery of Biomarkers (BioFIND), and the Alzheimers Disease Neuroimaging Initiative (ADNI) and meta-analyzed with the largest AD GWAS.[7] We tested heterogeneity of associations of interest between different disease statuses (AD, PD, and control). ResultsWe observed three GWAS signals: the APOE locus for A{beta}, the 3q28 locus between GEMC1 and OSTN for p-tau and t-tau, and the 7p22 locus (top hit: rs60871478, an intronic variant for DNAAF5, also known as HEATR2) for p-tau. The 7p22 locus is novel and co-localized with the brain DNAAF5 expression. While no heterogeneity from underlying disease status was observed for the above GWAS signals, some disease risk loci suggested disease specific associations with these biomarkers. ConclusionsOur study identified a novel association at the intronic region of DNAAF5 associated with increased levels of p-tau across all diseases. We also observed some disease specific genetic associations with these biomarkers.