Genome-wide study of gene-by-sex interactions identifies risks for cleft palate

Kelsey Robinson¹, Randy Parrish^{1

2}, Wasiu Lanre Adeyemo³, Terri H Beaty⁴, Azeez Butali⁵, Carmen J Buxó⁶, Lord J J Gowans⁷, Jacqueline T Hecht⁸, Lina Moreno Uribe⁹, Jeffrey C Murray¹⁰, Gary M Shaw¹¹, Seth M Weinberg^{12

13}, Harrison Brand¹⁴, Mary L Marazita^{12

13}, David J Cutler¹, Michael P Epstein¹, Jingjing Yang¹, Elizabeth J Leslie¹⁵

Affiliations

¹ Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.
² Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Emory University, Atlanta, GA, 30322, USA.
³ Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos, 101017, Nigeria.
⁴ Department of Epidemiology, Johns Hopkins University, Baltimore, MD, 21218, USA.
⁵ Department of Oral Biology, Radiology, and Medicine, University of Iowa, Iowa City, IA, 52242, USA.
⁶ School of Dental Medicine, University of Puerto Rico, San Juan, PR, 00925, USA.
⁷ Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
⁸ Department of Pediatrics, McGovern Medical School, University of Texas Health at Houston, Houston, TX, 77030, USA.
⁹ Department of Orthodontics and The Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA, 52242, USA.
¹⁰ Department of Pediatrics, University of Iowa, Iowa City, IA, 52242, USA.
¹¹ Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA.
¹² Department of Oral and Craniofacial Sciences, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
¹³ Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
¹⁴ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
¹⁵ Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA. ejlesli@emory.edu.

PMID: 39361040
PMCID: PMC12087800
DOI: 10.1007/s00439-024-02704-y

Genome-wide study of gene-by-sex interactions identifies risks for cleft palate

Kelsey Robinson et al. Hum Genet. 2024 Nov.

. 2024 Nov;143(11):1341-1352.

doi: 10.1007/s00439-024-02704-y. Epub 2024 Oct 3.

Authors

Affiliations

¹ Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.
² Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Emory University, Atlanta, GA, 30322, USA.
³ Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos, 101017, Nigeria.
⁴ Department of Epidemiology, Johns Hopkins University, Baltimore, MD, 21218, USA.
⁵ Department of Oral Biology, Radiology, and Medicine, University of Iowa, Iowa City, IA, 52242, USA.
⁶ School of Dental Medicine, University of Puerto Rico, San Juan, PR, 00925, USA.
⁷ Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
⁸ Department of Pediatrics, McGovern Medical School, University of Texas Health at Houston, Houston, TX, 77030, USA.
⁹ Department of Orthodontics and The Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA, 52242, USA.
¹⁰ Department of Pediatrics, University of Iowa, Iowa City, IA, 52242, USA.
¹¹ Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA.
¹² Department of Oral and Craniofacial Sciences, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
¹³ Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
¹⁴ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
¹⁵ Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA. ejlesli@emory.edu.

PMID: 39361040
PMCID: PMC12087800
DOI: 10.1007/s00439-024-02704-y

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 (G × S) interaction testing. There were 13 loci significant for G × S 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 G × S 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.

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Conflict of interest statement

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Figures

**Fig 1**
Miami plot highlighting differences in suggestive SNPs in females (top) and males (bottom). The dotted line represents suggestive significance at p=1×10⁻⁵, and the solid line represents p=5×10⁻⁸

**Fig 2**
Relative risks for males and females demonstrating GxS effect SNPs at (A) 2p22.3 and (B) 5q33.1, and (C) gene-driven SNP (*i.e.*, similar effect regardless of sex) at 12q21.1 with 95% confidence intervals. The dotted line at 1 represents null risk. Light blue and dark blue represent heterozygous and homozygous males, respectively while light and dark pink represent heterozygous and homozygous females, respectively

**Fig 3**
Comparing relative risks with 95% confidence intervals across the top 10 SNPs for GxS effects (top) and two gene-driven SNPs (bottom) to relative risk from TDTs in the full cohort and stratified by sex. Risks are shown for GxS (black), female only TDT (pink), male only TDT (blue), and full cohort TDT (green). An asterisk next to the locus name denotes relative risk by heterozygosity shown in Fig 2

See this image and copyright information in PMC

Update of

Genome-wide study of gene-by-sex interactions identifies risks for cleft palate.
Robinson K, Parrish R, Adeyemo WL, Beaty TH, Butali A, Buxó CJ, Gowans LJ, Hecht JT, Moreno L, Murray JC, Shaw GM, Weinberg SM, Brand H, Marazita ML, Cutler DJ, Epstein MP, Yang J, Leslie EJ. Robinson K, et al. medRxiv [Preprint]. 2024 May 3:2024.05.01.24306701. doi: 10.1101/2024.05.01.24306701. medRxiv. 2024. Update in: Hum Genet. 2024 Nov;143(11):1341-1352. doi: 10.1007/s00439-024-02704-y. PMID: 38746184 Free PMC article. Updated. Preprint.

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Genome-wide study of gene-by-sex interactions identifies risks for cleft palate

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Genome-wide study of gene-by-sex interactions identifies risks for cleft palate

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