Exome sequencing enables association tests between phenotypes and protein-coding variants across the allele frequency spectrum. We performed a variant-level exome-wide association study (ExWAS) to test for associations between all 18,780 phenotypes and 2,108,983 variants observed in at least six participants of European ancestry (that is, MAF > 0.001%). We used three genetic models (Methods), equating to 118.8 billion tests. We used a two-sided Fisher’s exact test for binary traits and linear regression for quantitative traits. Using a P value threshold of P ≤ 2 × 10−9 (Methods) and excluding the MHC region (chromosome 6: 25–35 Mb), we identified 5,193 significant genotype–phenotype associations for binary traits and 41,754 associations for quantitative traits (Supplementary Table 2, 3).
