Goovaerts Seppe, Naqvi Sahin, Hoskens Hanne, Herrick Noah, Yuan Meng, Shriver Mark D, Shaffer John R, Walsh Susan, Weinberg Seth M, Wysocka Joanna, Claes Peter
Department of Human Genetics, KU Leuven, Leuven, Belgium.
Medical Imaging Research Center, University Hospitals Leuven, Leuven, Belgium.
Commun Biol. 2025 Mar 15;8(1):439. doi: 10.1038/s42003-025-07875-6.
Large-scale GWAS studies have uncovered hundreds of genomic loci linked to facial and brain shape variation, but only tens associated with cranial vault shape, a largely overlooked aspect of the craniofacial complex. Surrounding the neocortex, the cranial vault plays a central role during craniofacial development and understanding its genetics are pivotal for understanding craniofacial conditions. Experimental biology and prior genetic studies have generated a wealth of knowledge that presents opportunities to aid further genetic discovery efforts. Here, we use the conditional FDR method to leverage GWAS data of facial shape, brain shape, and bone mineral density to enhance SNP discovery for cranial vault shape. This approach identified 120 independent genomic loci at 1% FDR, nearly tripling the number discovered through unconditioned analysis and implicating crucial craniofacial transcription factors and signaling pathways. These results significantly advance our genetic understanding of cranial vault shape and craniofacial development more broadly.
大规模全基因组关联研究（GWAS）已经发现了数百个与面部和脑形状变异相关的基因组位点，但与颅顶形状相关的只有数十个，而颅顶形状是颅面复合体中一个很大程度上被忽视的方面。颅顶围绕着新皮质，在颅面发育过程中起着核心作用，了解其遗传学对于理解颅面疾病至关重要。实验生物学和先前的遗传学研究已经产生了大量知识，为进一步的基因发现工作提供了机会。在这里，我们使用条件错误发现率（FDR）方法，利用面部形状、脑形状和骨矿物质密度的GWAS数据，以加强对颅顶形状的单核苷酸多态性（SNP）发现。这种方法在1%的错误发现率下确定了120个独立的基因组位点，几乎是通过无条件分析发现的数量的三倍，并涉及关键的颅面转录因子和信号通路。这些结果显著推进了我们对颅顶形状以及更广泛的颅面发育的遗传学理解。
