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Genome-wide study of gene-by-sex interactions identifies risks for cleft palate
Medrxiv : the Preprint Server for Health Sciences
|May 15, 2024
Summary
Cleft palate (CP) exhibits sex-specific risks, with the gene LTBP1 identified as a key risk factor, particularly in females. These sex-specific genetic influences on CP are not apparent when analyzing both sexes together.
Area of Science:
- Genetics
- Developmental Biology
- Craniofacial Biology
Background:
- Structural birth defects impact 3-4% of live births, often displaying sex-biased prevalence.
- Orofacial clefts (OFCs), including cleft lip with or without cleft palate (CL/P) and cleft palate only (CP), are common craniofacial defects.
- While CL/P shows known sex-specific risks, CP's sex-specific genetic underpinnings remain largely unexplored.
Approach:
- Conducted sex-stratified genome-wide association studies (GWAS) on a trio-based cohort, analyzing proband sex.
- Performed genome-wide gene-by-sex (GxS) interaction testing to identify sex-specific genetic associations.
- Investigated the association of genetically regulated gene expression of significant GxS interaction genes with the CP phenotype.
Key Points:
- Identified 13 loci with significant GxS interactions for CP, with a top finding in the LTBP1 gene.
- LTBP1 plays a crucial role in regulating TGF-B bioavailability and its disruption causes craniofacial anomalies in model organisms.
- LTBP1 exhibits differential expression between sexes in mice and humans, and its genetically regulated expression is significantly associated with CP in female probands.
Conclusions:
- Demonstrated that cleft palate (CP) possesses sex-specific risks that are masked in combined-sex analyses.
- Identified LTBP1 as a candidate gene conferring risk for CP, with a notable impact in females.
- Highlights the importance of sex-specific genetic analyses in understanding the etiology of structural birth defects like CP.
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