A spectrum of recessiveness among Mendelian disease variants in UK Biobank

Abstract

Recent work has found increasing evidence of mitigated, incompletely penetrant phenotypes in heterozygous carriers of recessive Mendelian disease variants. We leveraged whole-exome imputation within the full UK Biobank cohort (n ∼ 500K) to extend such analyses to 3,475 rare variants curated from ClinVar and OMIM. Testing these variants for association with 58 quantitative traits yielded 102 significant associations involving variants previously implicated in 34 different diseases. Notable examples included a POR missense variant implicated in Antley-Bixler syndrome that associated with a 1.76 (SE 0.27) cm increase in height and an ABCA3 missense variant implicated in interstitial lung disease that associated with reduced FEV1/FVC ratio. Association analyses with 1,134 disease traits yielded five additional variant-disease associations. We also observed contrasting levels of recessiveness between two more-common, classical Mendelian diseases. Carriers of cystic fibrosis variants exhibited increased risk of several mitigated disease phenotypes, whereas carriers of spinal muscular atrophy alleles showed no evidence of altered phenotypes. Incomplete penetrance of cystic fibrosis carrier phenotypes did not appear to be mediated by common allelic variation on the functional haplotype. Our results show that many disease-associated recessive variants can produce mitigated phenotypes in heterozygous carriers and motivate further work exploring penetrance mechanisms.

Keywords: Mendelian disease; association study; penetrance; recessive disease.

Figure 1

Carriers of recessive Mendelian disease variants display quantitative phenotypes Mendelian diseases and their associated genes are listed to the left in each column, and effect size is plotted on the right for each associated quantitative trait in units of standard deviation (error bars, 95% CIs). Positive-effect variants are shown in red, negative-effect variants in blue, and variants not Bonferroni significant for one of the displayed traits in gray. Marker shapes correspond to effects on the gene and gene product as reported in ClinVar.

Figure 2

Cystic fibrosis carriers show mitigated phenotypes, but spinal muscular atrophy carriers do not (A) Carriers with the CFTR p.Phe508del inframe deletion exhibit increased risk of several mitigated disease phenotypes (data points, odds ratios; error bars, 95% CIs). (B) Genotyping for SMA carrier status using exome sequencing data from the UK Biobank. SMN1 and SMN2 copy numbers were estimated on the basis sequencing read depth, and SMA carriers (orange) were identified as those individuals estimated to have one functional copy of SMN1 (with a deletion allele on the homologous chromosome). (C) SMN1 deletion carriers did not display evidence of changes in any of three traits related to neuromuscular function (data points, mean values in units of standard deviations; error bars, 95% CIs).

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) 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.