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Genet Epidemiol. 2018 Oct;42(7):664-672. doi: 10.1002/gepi.22158. Epub 2018 Sep 11.

Genome-wide interaction studies identify sex-specific risk alleles for nonsyndromic orofacial clefts.

Author information

1
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
2
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
3
Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa.
4
Department of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, Iowa.
5
Dental and Craniofacial Genomics Core, School of Dental Medicine, University of Puerto Rico, San Juan, Puerto Rico.
6
Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
7
Department of Surgery, Plastic and Reconstructive Surgery Division, University of Colorado School of Medicine, Denver, Colorado.
8
Department of Pediatrics, McGovern Medical School and School of Dentistry, UT Health at Houston, Houston, Texas.
9
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
10
Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, Iowa.
11
ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.
12
Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
13
CEMIC-CONICET: Center for Medical Education and Clinical Research "Norberto Quirno", Buenos Aires, Argentina.
14
Department of Pediatrics, College of Medicine, University of the Philippines, Manila, Philippines.
15
The Philippine Genome Center, University of the Philippines System, Manilla, Philippines.
16
Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
17
Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, Iowa.
18
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
19
Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia.

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 × 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 × 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 × 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 × S effect in the 10q21 locus (rs72804706; p = 6.69 × 10 -9 ; OR = 2.62 CI [1.89, 3.62]) and 16 suggestive G × 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.

KEYWORDS:

cleft lip; cleft palate; genetic risk; oral facial cleft

PMID:
30277614
PMCID:
PMC6185762
[Available on 2019-10-01]
DOI:
10.1002/gepi.22158
[Indexed for MEDLINE]

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