Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.
Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Emory University, Atlanta, GA, 30322, USA.
Hum Genet. 2024 Nov;143(11):1341-1352. doi: 10.1007/s00439-024-02704-y. Epub 2024 Oct 3.
Structural birth defects affect 3-4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified genome-wide association studies (GWAS) based on proband sex followed by a genome-wide gene-by-sex (G × S) interaction testing. There were 13 loci significant for G × S interactions, with the top finding in LTBP1 (RR = 3.37 [2.04-5.56], p = 1.93 × 10). LTBP1 plays a role in regulating TGF-β bioavailability, and knockdown in both mice and zebrafish lead to craniofacial anomalies. Further, there is evidence for differential expression of LTBP1 between males and females in both mice and humans. Therefore, we tested the association between the imputed genetically regulated gene expression of genes with significant G × S interactions and the CP phenotype. We found significant association for LTBP1 in cell cultured fibroblasts in female probands (p = 0.0013) but not in males. Taken altogether, we show there are sex-specific risks for CP that are otherwise undetectable in a combined sex cohort, and LTBP1 is a candidate risk gene, particularly in females.
结构出生缺陷影响所有活产儿的 3-4%，并且根据类型，往往表现出性别偏倚的方式。口腔面裂（OFC）是最常见的颅面结构出生缺陷，通常分为唇裂伴或不伴腭裂（CL/P）和单纯腭裂（CP）。以前的研究发现 CL/P 存在性别特异性风险，但这些风险尚未在 CP 中进行评估。CL/P 在男性中更为常见，CP 在女性中更为常见，因此我们假设 CP 也会存在性别特异性差异。使用基于三重的队列，我们根据先证者的性别进行了性别分层的全基因组关联研究（GWAS），然后进行了全基因组基因与性别（G×S）相互作用测试。有 13 个位点与 G×S 相互作用显著，其中 LTBP1 的发现最为显著（RR=3.37[2.04-5.56]，p=1.93×10）。LTBP1 在调节 TGF-β 的生物利用度方面发挥作用，在小鼠和斑马鱼中的敲低都会导致颅面异常。此外，在小鼠和人类中都有证据表明 LTBP1 在雄性和雌性之间存在差异表达。因此，我们测试了具有显著 G×S 相互作用的基因的遗传调控基因表达与 CP 表型之间的关联。我们发现，在女性先证者的细胞培养成纤维细胞中，LTBP1 存在显著关联（p=0.0013），而在男性中则没有。总的来说，我们表明 CP 存在性别特异性风险，在男女混合队列中无法检测到，LTBP1 是一个候选风险基因，尤其是在女性中。
