Multi-trait genome-wide analyses of the brain imaging phenotypes in UK Biobank

Abstract

Many genetic variants identified in genome-wide association studies (GWAS) are associated with multiple, sometimes seemingly unrelated, traits. This motivates multi-trait association analyses, which have successfully identified novel associated loci for many complex diseases. While appealing, most existing methods focus on analyzing a relatively small number of traits, and may yield inflated Type 1 error rates when a large number of traits need to be analyzed jointly. As deep phenotyping data are becoming rapidly available, we develop a novel method, referred to as aMAT (adaptive multi-trait association test), for multi-trait analysis of any number of traits. We applied aMAT to GWAS summary statistics for a set of 58 volumetric imaging derived phenotypes from the UK Biobank. aMAT had a genomic inflation factor of 1.04, indicating the Type 1 error rate was well controlled. More important, aMAT identified 24 distinct risk loci, 13 of which were ignored by standard GWAS. In comparison, the competing methods either had a suspicious genomic inflation factor or identified much fewer risk loci. Finally, four additional sets of traits have been analyzed and provided similar conclusions.