Faculty, Staff and Student Publications

Language

English

Publication Date

11-1-2024

Journal

Human Genetics

DOI

10.1007/s00439-024-02704-y

PMID

39361040

PMCID

PMC12087800

PubMedCentral® Posted Date

11-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Structural birth defects affect 3–4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified genome-wide association studies (GWAS) based on proband sex followed by a genome-wide gene-by-sex (GxS) interaction testing. There were 13 loci significant for GxS interactions, with the top finding in LTBP1 (RR=3.37 [2.04 – 5.56], p=1.93×10−6). LTBP1 plays a role in regulating TGF-β bioavailability, and knockdown in both mice and zebrafish lead to craniofacial anomalies. Further, there is evidence for differential expression of LTBP1 between males and females in both mice and humans. Therefore, we tested the association between the imputed genetically regulated gene expression of genes with significant GxS interactions and the CP phenotype. We found significant association for LTBP1 in cell cultured fibroblasts in female probands (p=0.0013) but not in males. Taken altogether, we show there are sex-specific risks for CP that are otherwise undetectable in a combined sex cohort, and LTBP1 is a candidate risk gene, particularly in females.

Keywords

Cleft Palate, Humans, Genome-Wide Association Study, Male, Female, Animals, Mice, Latent TGF-beta Binding Proteins, Zebrafish, Cleft Lip, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Sex Factors, Risk Factors

Published Open-Access

yes

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