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.

最近的工作发现越来越多的证据表明，隐性孟德尔病变异杂合携带者的表型有所减轻，不完全渗透。我们利用完整英国生物银行队列（n ~ 500K）中的全外显子组插补，将此类分析扩展到从 ClinVar 和 OMIM 策划的 3,475 个罕见变异。测试这些变异与 58 个数量性状的关联，得出了 102 个显着关联，涉及先前与 34 种不同疾病有关的变异。值得注意的例子包括与 Antley-Bixler 综合征相关的POR错义变异，该变异与身高增加 1.76 (SE 0.27) cm 相关，以及与间质性肺疾病相关的ABCA3错义变异，与 FEV1/FVC 比值降低相关。对 1,134 种疾病特征的关联分析产生了另外 5 种变异疾病关联。我们还观察到两种更常见的经典孟德尔疾病之间的隐性程度存在差异。囊性纤维化变异的携带者表现出几种减轻的疾病表型的风险增加，而脊髓性肌萎缩等位基因的携带者没有表现出表型改变的证据。囊性纤维化携带者表型的不完全外显似乎不是由功能单倍型上的常见等位基因变异介导的。我们的结果表明，许多与疾病相关的隐性变异可以在杂合携带者中产生减轻的表型，并激发进一步探索外显机制的工作。