Fig. 3: Associations between F12 variant carrier status and adverse events.

a Cox proportional hazards regression modeling followed by trans-cohort meta-analysis was performed to examine the associations between F12 variant carrier status (FIS = 1.0) and the occurrence of VTE, bleeding, and sepsis (blue) in the UKB and AoU datasets (N = 703,745). Using the same approach, separate effect size estimates (±95% CI) for each phenotype were generated using only synonymous variants in F12 (orange). Models were adjusted for sex and ancestry as well as the additional covariates listed in Tables S7 and S8. b, c In assessments restricted to UKB dataset (N = 414,670), we used Kaplan–Meier analysis to compare overall mortality between F12 variant carriers and non-carriers, followed by two-sample comparisons of markers of fertility. Two-sided t-test P values are shown; whiskers show 5th–95th percentile range, and individual values falling above the 95th percentile are not shown. (Live births: WT N = 244,079, variant N = 989, 424 outliers not shown; still births: WT N = 77,899, variant N = 449, 855 outliers not shown; children fathered: WT N = 204,370, variant N = 767, 796 outliers not shown). d Using serial Firth’s logistic regression analyses adjusting for age, sex, and ancestry, we evaluated the associations between 138 discrete infection phenotypes and F12 variant carrier status. The “any infection” category denotes positive status for any of the 138 phenotypes. Upward triangles represent directionally positive associations, whereas downward triangles represent directionally negative associations. The dashed line represents the Bonferroni-corrected statistical significance threshold, P < 3.6 × 10⁻⁴.