Genome-wide Association Study of Tau PET in the Mayo Clinic Study of Aging
Vijay Ramanan1, Xuewei Wang2, Scott Przybelski1, Sheela Raghavan3, David Knopman1, Jonathan Graff-Radford1, Val Lowe1, Michelle Mielke1, Clifford Jack1, Ronald Petersen1, Owen Ross1, Prashanthi Vemuri1
1Mayo Clinic, 2Health Sciences Research, 3Radiology, Mayo Clinic
Objective:
To identify genetic factors associated with tau deposition in older adults.
Background:

Tau deposition is a key biological feature of Alzheimer’s disease, but the heritable influences on susceptibility and resistance to tau deposition are not well-understood.  The recent availability of tau-PET provides an opportunity to test the hypothesis that common genetic variants would be associated with entorhinal cortex (ERC) tau burden, a sensitive marker of early tau deposition.

Design/Methods:
Inclusion criteria included individuals over age 50 from the population-based Mayo Clinic Study of Aging with genome-wide genotype and regional tau-PET (AV-1451) data.  Following genotyping with the Illumina GSA array and standard quality control, 515,206 single nucleotide polymorphisms (SNPs) were available for analysis.  A genome-wide association study of ERC tau was performed using an additive genetic model and covarying for age and sex.  Post-hoc stratified analyses utilized amyloid positivity (global PiB>1.48) as a discriminator.
Results:

The study sample included 754 individuals (mean age 72.4 years, 54.6% men, 87.4% cognitively unimpaired).  A genome-wide significant association was identified for rs75546066, in an intergenic region on chromosome 9, with the minor (A, frequency=2.7%) allele associated with lower ERC tau (p=2.85x10-8, β=-0.49), and with a stronger effect in amyloid-negative (β=-0.51) versus amyloid-positive (β=-0.23) individuals.  No associations with ERC tau burden were identified for the SNPs defining APOE (apolipoprotein E) ɛ4 or for genotyped SNPs previously associated with AD in large case-control studies.  Three SNPs within MAPT (microtubule-associated protein tau) displayed nominal associations to ERC tau burden, including rs3785883 (p=0.04, β=0.07) which was previously associated with higher cerebrospinal fluid tau in an independent cohort.

Conclusions:

This study identified a novel genetic association with resistance to ERC tau deposition in older adults.  Our data also suggests that tau deposition may have a genetic architecture distinct from known AD risk genes, which may have implications for enhanced risk prediction and therapeutic targeting.