Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.越来越多的证据表明，非综合征性唇腭裂（non-syndromic cleft lip/palate, nsCL/P）的遗传风险变异，同样与面部形态的正常范围变异存在关联。然而，既往相关分析大多局限于候选单核苷酸多态性（single nucleotide polymorphism, SNPs），且研究结果始终无法得到一致重复。本研究采用多基因风险评分（polygenic risk scores, PRS），检验nsCL/P与7种生物学相关面部表型之间的遗传重叠情况。在发现遗传重叠证据的分析中，我们通过双向孟德尔随机化（Mendelian randomization, MR）验证了以下假说：nsCL/P的遗传易感性与所关联的面部表型存在因果关系。针对两项研究中5804名欧洲血统个体的分析显示，我们通过PRS方法获得了nsCL/P与人中宽度之间存在显著遗传重叠的强有力证据：nsCL/P的PRS每增加1个标准差，其人中宽度便会减少0.10毫米（95%置信区间C.I.：0.054~0.146；P=2×10^-5）。后续MR分析进一步支持了二者的因果关系：nsCL/P的遗传变异可统一导致人中宽度降低。除上述核心分析外，我们在针对6136名个体开展的全基因组关联研究（Genome-wide Association Study, GWAS）中，还鉴定出了5q22.2和7p15.2两个位点处的全新人中宽度相关风险基因座。本研究结果支持nsCL/P的易患阈值遗传模型，该模型与人中发育异常存在关联。