Figure 3.

Common variants on haplotypes opposite recessive alleles in carriers of two Mendelian diseases do not appear to modify penetrance of carrier phenotypes

(A) The “modified penetrance” model of Castel et al. (2018)²³ posits that cis-eQTLs can increase or decrease severity of a deleterious variant by modulating the quantity of functional protein produced by the opposite haplotype.

(B) To test this hypothesis, we examined opposite haplotypes (blue chromosomes) in heterozygous carriers of recessive disease variants (orange stars on yellow chromosomes). We tested variants carried on these opposite haplotypes for association with mitigated phenotypes observed in carriers.

(C and D) Manhattan plots showing association test results for variants on the opposite haplotype of deleterious variants in FLG and CFTR with asthma (the phenotype most strongly associated with carrier status in each case). No association reached Bonferroni significance (red line).

(E and F) Power analyses for the tests conducted in (C) and (D) indicate that these tests were well-powered to detect common variant effects with odds ratios > 1.2.