This study aims to systematically investigate mental health risks and multi-omics mechanisms in adults with congenital craniofacial anomalies (CFA), with a specific focus on cleft lip and/or palate (CL/P), using the UK Biobank.
Due to shared embryonic developmental origins (e.g., neural crest differentiation) and similar psychosocial burdens (facial disfigurement), we hypothesize that CL/P and related CFA subtypes share overlapping genetic risks and mental health outcomes.
1. Phenotype Analysis:We will construct a broad CFA cohort, identifying cases via ICD codes (specifically Q35-Q37 for CL/P, Q75 for craniofacial dysostosis, etc.) and surgical records. We will compare the prevalence of depression, anxiety, and quality of life against controls, specifically analyzing if the CL/P subgroup exhibits distinct risk patterns compared to other CFAs.
2. Genetic Risk Assessment:Construct polygenic risk scores (PRS) for CFA and psychiatric disorders. We will quantify the genetic correlation between structural facial anomalies and mental phenotypes to test for pleiotropy.
3. Genomic Discovery:Perform GWAS on the expanded CFA cohort to identify susceptibility loci. By aggregating CL/P with biologically related phenotypes, we aim to increase statistical power to identify novel pathways.
4. Proteomic Biomarkers:Analyze plasma proteomic data to identify inflammatory or developmental protein markers associated with psychiatric comorbidity.
5. Multi-Omics Integration:Construct a “Gene-Protein-Psychology” network to propose molecular hypotheses for the comorbidity of CFA and mental illness.
Scientific Basis:
a) Shared Biology: CL/P and other CFAs share genetic etiology in neural crest development (e.g., IRF6, 8q24).
b) Data Advantages:UKB enables the unique linkage of rare structural defects with adult mental health, proteomics, and genomics.