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

• Published in: Genetic epidemiology Vol. 42; no. 7; pp. 664 - 672
• Main Authors: Carlson, Jenna C., Nidey, Nichole L., Butali, Azeez, Buxo, Carmen J., Christensen, Kaare, Deleyiannis, Frederic W.‐D., Hecht, Jacqueline T., Field, L. Leigh, Moreno‐Uribe, Lina M., Orioli, Ieda M., Poletta, Fernando A., Padilla, Carmencita, Vieira, Alexandre R., Weinberg, Seth M., Wehby, George L., Feingold, Eleanor, Murray, Jeffrey C., Marazita, Mary L., Leslie, Elizabeth J.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-10-2018
• Subjects: Alleles; Birth; Brain - abnormalities; Case-Control Studies; Chromosome 10; cleft lip; Cleft Lip - genetics; Cleft lip/palate; cleft palate; Cleft Palate - genetics; Congenital defects; Epistasis, Genetic; Female; Females; Gene Frequency - genetics; Genetic diversity; Genetic Loci; Genetic Predisposition to Disease; genetic risk; Genome-Wide Association Study; Genomes; Humans; Male; Males; Models, Genetic; oral facial cleft; Orofacial clefts; Polymorphism, Single Nucleotide; Risk Factors; Sex Characteristics; Sex differences; Sexual dimorphism; cleft lip; cleft palate; oral facial cleft; genetic risk
• ISSN: 0741-0395; 1098-2272; 1098-2272
• DOI: 10.1002/gepi.22158

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.