Robust Inference With Ghostknockoffs in Genome‐Wide Association Studies With Sample Relatedness

Abstract

Genome‐wide association studies (GWASs) have been extensively adopted to depict the underlying genetic architecture of complex traits. Recent studies show that knockoff‐based methods can identify variants with unique, potentially causal effects on phenotypes. However, their statistical validity and effectiveness in studies with related individuals, such as the UK Biobank, remain unexplored. In this paper, we extensively evaluate a simple and effective analytical strategy that integrates GhostKnockoffs and state‐of‐the‐art marginal association tests. We show that this approach is robust to arbitrary relatedness structure as long as the input Z‐scores are derived from valid generalized linear mixed models. This robustness also extends GhostKnockoffs to other GWASs settings, including meta‐analysis of studies with sample overlap when the input score test Z‐scores are properly calibrated, and association test statistics beyond score tests in independent sample settings. We demonstrate the method's validity and practical utility using simulation studies and a meta‐analysis of nine European ancestral genome‐wide association studies and whole exome/genome sequencing studies for the Alzheimer's disease.