Voxelwise Meta-Analysis of Brain Structural Associations with Genome-Wide Polygenic Risk for Alzheimer’s Disease

摘要

Polygenic risk scores (PRSs) may be used to investigate the effects of genetic risk for disease on complex human traits.Here we set out to determine how the overall genetic risk for Alzheimer’s disease (AD) shapes brain structure in non-ADpopulations. PRS scores were computed using results from the International Genomics of Alzheimer's Project (IGAP)study. PRSs were computed at 14 different significance thresholds in the IGAP results. The effect of PRS as a predictorof brain morphometry was mapped voxelwise on brain structure as determined by tensor-based morphometry (TBM) inthree cohorts: ADNI1, ADNI2, and HUNT. Our multi-cohort TBM framework first tests associations in each cohortindividually, then meta-analyzes findings in a common space. Higher PRS for AD was associated with greaterventricular and lower hippocampal volumes. Associations remained after removing the major AD risk gene, APOE, fromthe PRS. This cumulative influence of common genetic variants on brain-wide structural variation in nondementedindividuals may pinpoint genetic and neurological pathways that contribute to the preclinical assessment of disease risk.