Figure 4.
Age at diagnosis modeling reveals novel recessive effects driven by damaging bi-allelic variants
(A) Flow diagram of our approach. To investigate whether homozygous and/or CH effects are associated with a difference in lifetime risk of disease development, we performed Cox proportional hazards modeling for gene-trait combinations in which ≥5 samples are 2-hit carriers (CH or homozygotes) and ≥100 samples that are heterozygotes. Among Bonferroni (Bonf.) significant associations (p < 1.89 × 10−7), we filter to gene-trait pairs for which at least 5 samples carry multiple variants disrupting the same haplotype and test for an association between CH or homozygous carrier status and lifetime disease risk (corresponding to HRs ≥1).
(B) HRs when comparing CH and homozygous status versus heterozygous carrier status. Throughout, we display hazard ratios and corresponding p values after taking the polygenic contribution into account by conditioning on off-chromosome PRSs for heritable traits that pass our quality control cutoffs. p values following inclusion of polygenic contribution to disease status are provided where PRSs are predictive. HRs for gene-traits with ≥2 individuals with multiple cis variants on the same haplotype are displayed in pink. Only associations that pass the stringent Bonferroni significance threshold (p < 1.89 × 10−7) cutoff are illustrated.
(C) HRs when comparing wild-type, heterozygous, CH, and homozygous carrier status against individuals that harbor ≥2 putatively damaging variants on the same haplotype. 95% CIs are shown in the figure.