which is approximately the number of conditionally independent variants tested once the MAF lower bound was extended from 1% to 0.1%. We calculated this threshold using three existing methods60–62. These methods make use of the eigenvalues of the matrix of LD (measured in R2) between SNPs, calculated with a spectral decomposition. We estimated the number of independent tests using the genotype data from a subset of the Haplotype Reference Consortium panel41. We first calculated LD blocks across the genome using the algorithm implemented in PLINK version 1.963 with default settings, and then we lowered the MAF threshold to 0.1% to accommodate all low frequency variants. Next, we calculated the effective number of independent tests within each LD block and between LD blocks using the aforementioned three methods, which we aggregated to get the total number of independent tests. The three techniques estimated the number of independent variants at 9.8–10.1 million independent tests, similar to other independent estimates64. A total of 278 sentinel variants (including the one genome-wide significant low-frequency variant) had p < 5×10−9, out of the original 406 with p < 5×10−8.
