Computation and resource efficient genome-wide association analysis for large-scale imaging studies

Imaging genetics links genetic variations to brain structures and functions, but the computational challenges posed by high-dimensional imaging and genetic data are significant. In voxel-level genome-wide association studies, we introduce a Representation learning-based Voxel-level Genetic Analysis (RVGA) framework that reduces computational time and storage burden by over 200 times. RVGA enhances statistical power by denoising images and shares minimal datasets of summary statistics for associations across the whole genome of the entire image for secondary analyses. Additionally, it introduces a unified estimator for voxel heritability, genetic correlations between voxels, and cross-trait genetic correlations between voxels and non-imaging phenotypes. Applying RVGA to hippocampus shape and white matter microstructure in the UK Biobank (n = 53,454) reveals 39 and 275 novel loci, respectively. We identify heterogeneity in genetic architecture across images and subregions that share genetic bases with 14 brain-related phenotypes, such as the genetic correlation between the hippocampus and educational attainment, and between the anterior corona radiata and schizophrenia. RVGA replicates known genetic associations and uncovers new discoveries.