Genome Wide Interaction Studies Identify Sex-Specific Risk Alleles for Nonsyndromic Orofacial Clefts
Genome Wide Interaction Studies Identify Sex-Specific Risk Alleles for Nonsyndromic Orofacial Clefts
Abstract Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G x S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G x S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test (p < 1.00 × 10?5) by examining the G x S effects from the same model. Out of the 133 loci with suggestive results (p < 1.00 × 10?5) for the joint test, we observed one genome-wide significant G x S effect in the 10q21 locus (rs72804706; p = 6.69 × 10?9; OR = 2.62 [1.89, 3.62]) and 16 suggestive G x S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.
Orioli Ieda M.、Vieira Alexandre R.、Weinberg Seth M.、Wehby George L.、Feingold Eleanor、Murray Jeffrey C.、Leslie Elizabeth J.、Christensen Kaare、Deleyiannis Frederic W-D、Marazita Mary L.、Nidey Nichole L.、Padilla Carmencita、Buxo Carmen J.、Moreno-Uribe Lina M.、Butali Azeez、Carlson Jenna C.、Hecht Jacqueline T.、Field L. Leigh、Poletta Fernando A.
ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics)||Department of Genetics, Institute of Biology, Federal University of Rio de JaneiroCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of PittsburghCenter for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of PittsburghDepartment of Health Management and Policy, College of Public Health, University of IowaDepartment of Human Genetics, Graduate School of Public Health, University of Pittsburgh||Department of Biostatistics, Graduate School of Public Health, University of PittsburghDepartment of Pediatrics, Carver College of Medicine, University of IowaDepartment of Human Genetics, Emory University School of Medicine, Emory UniversityDepartment of Epidemiology, Institute of Public Health, University of Southern DenmarkDepartment of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of MedicineDepartment of Human Genetics, Graduate School of Public Health, University of Pittsburgh||Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of PittsburghDepartment of Epidemiology, College of Public Health, University of IowaDepartment of Pediatrics, College of Medicine, University of the Philippines Manila, 1000 and the Philippine Genome Center, University of the Philippines System 1101Dental and Craniofacial Genomics Core, School of Dental Medicine, University of Puerto RicoDepartment of Orthodontics, College of Dentistry, University of IowaDepartment of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry, University of IowaDepartment of Human Genetics, Graduate School of Public Health, University of Pittsburgh||Department of Biostatistics, Graduate School of Public Health, University of PittsburghDepartment of Pediatrics, McGovern Medical School and School of Dentistry UT Health at HoustonDepartment of Medical Genetics, University of British ColumbiaECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics)||CEMIC-CONICET: Center for Medical Education and Clinical Research ?°Norberto Quirno?±
基础医学遗传学口腔科学
Oral Facial Cleftcleft lipcleft palategenetic risk
Orioli Ieda M.,Vieira Alexandre R.,Weinberg Seth M.,Wehby George L.,Feingold Eleanor,Murray Jeffrey C.,Leslie Elizabeth J.,Christensen Kaare,Deleyiannis Frederic W-D,Marazita Mary L.,Nidey Nichole L.,Padilla Carmencita,Buxo Carmen J.,Moreno-Uribe Lina M.,Butali Azeez,Carlson Jenna C.,Hecht Jacqueline T.,Field L. Leigh,Poletta Fernando A..Genome Wide Interaction Studies Identify Sex-Specific Risk Alleles for Nonsyndromic Orofacial Clefts[EB/OL].(2025-03-28)[2025-05-31].https://www.biorxiv.org/content/10.1101/329599.点此复制
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