Indencleef Karlijne, Hoskens Hanne, Lee Myoung Keun, White Julie D, Liu Chenxing, Eller Ryan J, Naqvi Sahin, Wehby George L, Moreno Uribe Lina M, Hecht Jacqueline T, Long Ross E, Christensen Kaare, Deleyiannis Frederic W, Walsh Susan, Shriver Mark D, Richmond Stephen, Wysocka Joanna, Peeters Hilde, Shaffer John R, Marazita Mary L, Hens Greet, Weinberg Seth M, Claes Peter
Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, Belgium.
Medical Imaging Research Center, UZ Leuven, Leuven, Belgium.
Front Genet. 2021 Feb 22;12:626403. doi: 10.3389/fgene.2021.626403. eCollection 2021.
Unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features. The presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population. To explore this hypothesis, we first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P versus 3,171 controls. We observed distinct facial features between parents and controls across 59 global-to-local facial segments at nominal significance ( ≤ 0.05) and 52 segments at Bonferroni corrected significance ( < 1.2 × 10), respectively. Next, we quantified these distinct facial features as univariate traits in another dataset of 8,246 unaffected European individuals and performed a genome-wide association study. We identified 29 independent genetic loci that were associated ( < 5 × 10) with at least one of the tested endophenotypic traits, and nine genetic loci also passed the study-wide threshold ( < 8.47 × 10). Of the 29 loci, 22 were in proximity of loci previously associated with normal facial variation, 18 were near genes that show strong evidence in orofacial clefting (OFC), and another 10 showed some evidence in OFC. Additionally, polygenic risk scores for NSCL/P showed associations with the endophenotypic traits. This study thus supports the hypothesis of a shared genetic architecture of normal facial development and OFC.
非综合征性唇裂伴或不伴腭裂（NSCL/P）患者的未患病亲属表现出独特的面部特征。在未经过选择的更大人群中，这种面部内表型的存在可能是对NSCL/P潜在遗传易感性的一种表达。为了探究这一假设，我们首先将面部划分为63个部分重叠的区域，这些区域代表了从整体到局部的面部形态，然后通过对比264名NSCL/P患者的未患病父母与3171名对照者的三维面部图像来定义内表型特征。我们分别在名义显著性水平（≤0.05）下观察到父母与对照者在59个从整体到局部的面部节段存在明显的面部特征差异，在经Bonferroni校正的显著性水平（<1.2×10）下观察到52个节段存在差异。接下来，我们在另一个包含8246名未患病欧洲人的数据集中，将这些明显的面部特征量化为单变量性状，并进行了全基因组关联研究。我们鉴定出29个独立的基因位点与至少一种测试的内表型性状相关（<5×10），其中9个基因位点也超过了全研究范围的阈值（<8.47×10）。在这29个基因位点中，22个与先前与正常面部变异相关的基因位点相邻，18个靠近在口腔颌面部裂隙（OFC）中有充分证据的基因，另外10个在OFC中也有一些证据。此外，NSCL/P的多基因风险评分与内表型性状相关。因此，本研究支持正常面部发育和OFC具有共同遗传结构的假设。
