Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10−8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.

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Functional magnetic resonance imaging (fMRI) has been used to investigate sex‐related differences in brain abnormalities in patients with irritable bowel syndrome (IBS). Like IBS, women with functional constipation (FC) are 2.1 times as many as men. No study has been performed yet to examine sex‐related differences in brain activity and connectivity in patients with FC. Here, we employed resting‐state fMRI with amplitude of low‐frequency fluctuation (ALFF) to investigate brain functional differences in 51 patients with FC (34 females) and 52 healthy controls (34 females). Results showed abdominal pain and abdominal distension correlated with trait (TAI) and state (SAI) anxiety ratings in the female FC group, and abdominal distension correlated with sensation of incomplete evacuation in the male FC group. Two‐way ANOVA revealed sex effects on ALFF in precentral gyrus, thalamus, insula (INS), and orbital frontal cortex (OFC, PFWE < 0.05). Post hoc test showed that the female FC group had lower ALFF than males in these brain regions (P < 0.01), and ALFF in INS and OFC was correlated with abdominal pain and difficulty of defecation, respectively. Seed voxel correlation analysis showed that the female FC group had weaker connectivity than males between INS and lateral OFC (lOFC). INS‐lOFC connectivity was negatively correlated with the anxiety score in the female FC group and was negatively correlated with abdominal distension in the male FC group. These findings provide the first insight into sex‐related differences in patients with FC and highlight that INS and OFC play an important role in modulating the intrinsic functional connectivity of the resting brain network showing that this role is influenced by sex.

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