Genetic Investigations of Cleft Lip with or without Cleft Palate: A Literature Review and Genome-wide Association Study

Cleft lip with or without cleft palate (CL/P) is one of the most common congenital anomalies worldwide, with a complex etiology involving both genetic and environmental fac- tors. This thesis provides a comprehensive literature review of the epidemiology, psychology, healthcare costs, and genetics of CL/P, followed by an original genome-wide association study (GWAS) and downstream analyses in a Filipino population. The literature review traces the historical understanding of CL/P, discussing its epidemiology across different populations, the psychological impact on affected individuals, and the substantial healthcare costs as- sociated with treatment. The review then discusses the genetic aspects of CL/P, covering heritability estimates, segregation analyses, linkage studies, genome-wide association stud- ies (GWAS), gene-environment interactions, sequencing studies, animal models, and phe- notypic heterogeneity. The original research presented is a GWAS of CL/P in a Filipino cohort of 1,399 unrelated individuals (882 cases, 517 controls). The study identified a novel locus, KCNQ5, and replicated associations at three known loci: ARHGAP29, IRF6, and SHROOM3. A gene-based test using mBAT-combo highlighted potential masking effects in several genes, including IRF6. A transcriptome-wide association study (TWAS) further sup- ported the involvement of known clefting loci. Fine-mapping analyses and conditional and joint multiple-SNP analysis (COJO) provided insights into putative causal variants, partic- ularly the missense variant rs2235371 in IRF6, which showed strong functional evidence and high linkage disequilibrium with the top signal. This thesis underscores the importance of conducting genetic studies in diverse populations to better understand the genetic architec- ture of complex traits like CL/P and to address disparities in genetic research. The public health relevance of this work lies in its potential to improve our understanding of CL/P eti- ology, which could lead to better prevention strategies, earlier diagnosis, and more targeted treatments, ultimately reducing the burden of this condition on affected individuals, families, and healthcare systems. The findings contribute to the growing body of knowledge on the genetic basis of CL/P and provide a foundation for future research aimed at elucidating the etiology of this condition and improving strategies for prevention, diagnosis, and treatment.