Robust inference with GhostKnockoffs in genome-wide association studies

Abstract

Genome-wide association studies (GWASs) have been extensively adopted to depict the underlying genetic architecture of complex diseases. Motivated by GWASs' limitations in identifying small effect loci to understand complex traits' polygenicity and fine-mapping putative causal variants from proxy ones, we propose a knockoff-based method which only requires summary statistics from GWASs and demonstrate its validity in the presence of relatedness. We show that GhostKnockoffs inference is robust to its input Z-scores as long as they are from valid marginal association tests and their correlations are consistent with the correlations among the corresponding genetic variants. The property generalizes GhostKnockoffs to other GWASs settings, such as the meta-analysis of multiple overlapping studies and studies based on association test statistics deviated from score tests. We demonstrate GhostKnockoffs' performance using empirical simulation and a meta-analysis of nine European ancestral genome-wide association studies and whole exome/genome sequencing studies. Both results demonstrate that GhostKnockoffs identify more putative causal variants with weak genotype-phenotype associations that are missed by conventional GWASs