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

• Type of Material: Article
• Authors: Jenna C. Carlson, University of Pittsburgh; Nichole L. Nidey, University of Iowa; Azeez Butali, University of Iowa; Carmen J. Buxo, University of Puerto Rico; Kaare Christensen, University of Southern Denmark; Frederic W-D Deleyiannis, University of Colorado; Jacqueline T. Hecht, University of Texas Houston; L. Leigh Field, University of British Columbia; Lina M. Moreno-Uribe, University of Iowa; Ieda M. Orioli, National Institute of Population Medical Genetics; Fernando A. Poletta, National Institute of Population Medical Genetics; Carmencita Padilla, University of the Philippines; Alexandre R. Vieira, University of Pittsburgh; Seth M. Weinberg, University of Pittsburgh; George L. Wehby, University of Iowa; Eleanor Feingold, University of Pittsburgh; Jeffrey C. Murray, University of Iowa; Mary L. Marazita, University of Pittsburgh; Elizabeth Leslie, Emory University
• Language: English
• Date: 2018-10-01
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/gepi.22158
• Title of Journal or Parent Work: GENETIC EPIDEMIOLOGY
• Volume: 42
• Issue: 7
• Start Page: 664
• End Page: 672
• Grant/Funding Information: Additional support was provided by the Philippine Band of Mercy, the Hope Foundation Inc., Operation Smile, and the Noordhoff Craniofacial Foundation Philippines Inc. Genotyping and data cleaning were provided via an NIH contract to the Johns Hopkins Center for Inherited Disease Research: HHSN268201200008I.; This work was supported by grants from the National Institutes of Health (NIH): R00-DE025060 [EJL], X01-HG007485 [MLM, EF], R01-DE016148 [MLM, SMW], U01-DE024425 [MLM], R37-DE008559 [JCM, MLM], R01-DE009886 [MLM], R21-DE016930 [MLM], R01-DE014667 [LM], R01-DE012472 [MLM], R01-DE011931 [JTH], R01-DE011948 [KC], U01-DD000295 [GLW], K99-DE024571 [CJB]; and PICT-2016–3869 [FAP].], S21-MD001830 [CJB], U54-MD007587 [CJB]).
• Keywords: GENE-ENVIRONMENT INTERACTION; FREQUENT CAUSE; TBX22 MUTATIONS; SUSCEPTIBILITY LOCUS; MATERNAL SMOKING; INOSITOL POLYPHOSPHATE MULTIKINASE; Life Sciences & Biomedicine; ORAL CLEFTS; PALATE; Genetics & Heredity; Mathematical & Computational Biology; oral facial cleft; LIP; cleft palate; ASSOCIATION; cleft lip; Science & Technology; genetic risk
• Research Categories: Biology, Genetics; Health Sciences, Medicine and Surgery

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.