Figure 1 |. Rare variant associations for HbA1C are comparatively strong.
a, The number of exome-wide significant predicted high or moderate impact variant associations across 24 quantitative phenotypes. Single variant associations were determined using the efficient mixed-model association expedited (EMMAX) method50, and gene-level associations were determined using burden testing. Yellow: P ≤ 1.8 × 10−8 (as derived from a previously determined threshold49 of P ≤ 4.3 × 10−7 and Bonferroni correction for 24 phenotypes) and exome-wide significant gene-level associations. Blue: P ≤ 1.0 × 10−7 (as derived from the traditional exome-wide significance threshold of P ≤ 2.5 × 10−6 and Bonferroni correction for 24 phenotypes). b, Manhattan plot of all gene-level HbA1C associations determined via burden testing. Those reaching exome-wide significance (P ≤ 1.0 × 10−7; red line) are labeled. c,d, Effect sizes (mmol/mol) for rare variant gene-level associations for G6PD (c) (n = 1,382 for AA; n = 1,930 for EA; n = 41,689 for EU; n = 1,861 for SA; n = 892 for HS) and PIEZO1 (d) (n = 905 for AA; n = 1,340 for EA; n = 42,061 for EU; n = 789 for SA; n = 484 for HS). Previously reported7 nearby common variant associations (n = 7,564 for AA; n = 20,838 for EA; n = 123,665 for EU; n = 8,874 for SA) are shown for comparison. Gene-level effects are displayed from the strongest associated variant mask. AA, African-American; EA, East Asian; EU, European; HS, Hispanic; SA, South Asian; M-A, meta-analysis. Error bars indicate 95% confidence intervals.