Our linear mixed model (LMM) analyses, performed in a subset of 15 individual studies comprising 59,380 individuals, provided strong evidence that the inflated statistics were driven predominantly by the highly polygenic nature of the trait. This approach utilizes a genomic relationship matrix (GRM) calculated through genome-wide SNP data to correct for distant relatedness between all pairs of individuals within a study. This resulted in a single λGC of 1.20. This value was entirely consistent with the single λGC of 1.20 obtained from the standard GWAS analysis of the same individuals and a single λGC of 1.94 obtained from the full 253,288 individuals (Supplementary Table 4). Because this approach may be overly conservative for a strongly genetic and highly polygenic trait, each study additionally repeated the analyses for each chromosome using a GRM generated from the remaining 21 chromosomes, or in the case of the largest study (WGHS) repeating the analysis for all odd numbered chromosomes using a GRM generated from the even numbered chromosomes and vice versa. The single λGC inflation factor for this analysis, 1.23, was also entirely consistent with the standard GWAS results (Online Methods, Supplementary Note, and Supplementary Table 4).
