Developing a novel tau-based polygenic score (TPGS)

The objective of this study is to develop a novel tau polygenic score (TPGS). We hypothesize that variation in genes associated with tauopathies—which are genes related to tau-metabolism or differentially expressed in comparative studies of iPSC-derived neurons, astrocytes, and microglia generated from carriers of MAPT pathogenic variants vs. isogenic controls—is associated with greater risk of sporadic primary and secondary tauopathy.

Study Design: We will utilize summary statistics from large genome-wide association studies of tauopathies, selecting relevant variants that are flanking genes implicated by functional studies. Data requested from NG00169 will be analyzed in parallel with other publicly-available GWAS summary statistics as well as internal data generated at UCSF. To our knowledge, we do not anticipate that combining these datasets will increase risk of participant re-identification due to these datasets deriving from non-overlapping cohorts.

Analysis Plan: We will assess multiple methods for generating the TPGS, and test whether they are associated with primary (FTLD-tau, PSP) and secondary (AD) tauopathy risk and endophenotypes of tauopathy (e.g., tau pathological burden, measures of tau in CSF). First, we will classify genetic variants using machine learning methods. We hypothesize that machine learning can be used to improve biologically driven predictions for diagnoses, pathology, and biomarkers. We will also leverage summary statistics from NG00169 to generate polygenic scores from a preselected, MAPT-related marker list. We will apply to our internal whole genome sequencing discovery dataset. The TPGS will be further validated in a separate internal cohort.

Collaboration: Data obtained through this application will not be shared with researchers at other institutions.

Tauopathies are a class of neurodegenerative diseases characterized by the abnormal accumulation of the tau protein. Tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), are influenced by the combination of genetic variants that are present within an individual. Polygenic scores (PGS) can be used to estimate an individual’s genetic susceptibility for developing a trait. In this study, we will be generating a new tau polygenic score (TPGS) to predict the likelihood that a person will develop traits associated with tauopathies, such as increased tau in blood plasma. We will use summary statistics generated from genome-wide association studies in order to calculate the risk that each genetic variant carriers. Then, we will calculate individual risk scores in a cohort of UCSF research participants in order to validate the scoring algorithm.