Dissertation
Investigating the missing heritability for nonsyndromic orofacial clefts in an African population
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2023
DOI: 10.25820/etd.007117
Abstract
Nonsyndromic orofacial clefts (NSOFCs) are the most common birth defects affecting the head and neck. These defects have significant medical, psychological, and financial implications. Genetic alterations are important factors contributing to the development of these defects. Previous genetic studies on NSOFCs were largely among individuals of European descent and have led to the identification of over 60 genetic risk loci, explaining 20-30 % of the estimated heritability for NSOFCs. Therefore, to identify the missing heritability, we investigated the genetic causes of NSOFCs in an African population - the most genetically diverse population.
Our study replicated and meta-analyzed suggestive genome-wide significant signals from the first African genome-wide association study on NSOFCs. Through this approach, we identified additional novel genome-wide significant loci (10q24 and 2q22) and replicated some of the previously reported ones (MTHFD1, PTCH1, and 8q24) contributing to the risk of NSOFCs. Pathway-based analysis revealed that cell adhesion and neurogenesis were highly associated with NSOFCs.
In addition, we evaluated the contributions of rare genetic variations by analyzing rare coding variants. We identified 18 genes, including both novel and known genes, harboring rare variants associated with NSOFCs. Subsequently, we prioritized 11 genes with robust expression in relevant craniofacial structures during human face development of which five (PRDM16, MASP2, ALKBH8, CENPF, and PDZD8 genes) have been previously implicated in vertebrate craniofacial development and diseases.
Furthermore, we checked for genetic overlap between the two major NSOFC phenotypes (NSCL/P and NSCPO) and identified three genetic variations that influence the risk for both phenotypes in opposite directions. Using mouse transcriptomics data, we identified consistently expressed and enriched genes in relevant craniofacial structures within the same TAD (1MB) as the variants. Subsequently, we prioritized MDN1, MAP3k7, KMT2A, ARCN1, and VDAC2 genes as top candidates for their potential roles in NSOFCs pathogenesis.
Overall, our studies demonstrated the uniqueness of the African population in uncovering novel loci associated with NSOFCs. We replicated some of the previously reported loci and discovered novel loci. Insights from mouse and human transcriptomics data provided valuable evidence underpinning these associations and the plausible mechanisms. Thus, our findings can lay the foundation for novel therapeutic interventions and prevention strategies for NSOFCs.
Details
- Title: Subtitle
- Investigating the missing heritability for nonsyndromic orofacial clefts in an African population
- Creators
- Azeez A. Alade
- Contributors
- Paul Romitti (Advisor)Azeez Butali (Advisor)Michael O'Rorke (Committee Member)Eric Van Otterloo (Committee Member)Erliang Zeng (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Epidemiology
- Date degree season
- Summer 2023
- DOI
- 10.25820/etd.007117
- Publisher
- University of Iowa
- Number of pages
- 189 pages
- Copyright
- Copyright 2023 Azeez A. Alade
- Language
- English
- Date submitted
- 05/22/2023
- Public Abstract (ETD)
Nonsyndromic orofacial clefts (NSOFCs) are common birth defects characterized by gaps in the upper lip or roof of the mouth. These defects have significant medical, psychological, and financial impacts on affected individuals and their families. Genetic changes are important factors contributing to the development of these defects. However, many of these disease-causing genetic changes remain unknown. Previous genetic studies mainly focused on people of European descent. Therefore, we investigated the genetic causes of NSOFCs in an African population, which is known for its genetic diversity.
First, we analyzed the DNA of African individuals with and without NSOFCs to identify common genetic changes contributing to NSOFCs. We identified specific areas in the DNA that were associated with an increased risk of these birth defects. Some of these areas were already known, but our study also uncovered new areas that had not been linked to NSOFCs before.
Additionally, we analyzed rare genetic changes within a gene to identify genes that are associated with NSOFCs. We identified 18 genes, including both new and known ones, harboring rare changes associated with NSOFCs. Eleven genes were further prioritized based on their potential roles during the development of the face, with five of them having evidence linking them to craniofacial development and diseases.
Furthermore, we investigated the genetic overlap between two types of NSOFCs (cleft lip and palate vs cleft palate only) and found genetic changes that influence the risk for each type in opposite ways. Then, we used data from mice and humans to identify specific genes that are likely influenced by the genetic changes and involved in the development of these birth defects. Overall, our findings provide new insights into the genetic causes of NSOFCs. By understanding these genetic factors, we can develop better strategies for the prevention and treatment of these birth defects.
- Academic Unit
- Epidemiology; Craniofacial Anomalies Research Center
- Record Identifier
- 9984454436302771
Metrics
15 Record Views