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. 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

Jenna C Carlson  1   2 , Nichole L Nidey  3 , Azeez Butali  4 , Carmen J Buxo  5 , Kaare Christensen  6 , Frederic W-D Deleyiannis  7 , Jacqueline T Hecht  8 , L Leigh Field  9 , Lina M Moreno-Uribe  10 , Ieda M Orioli  11   12 , Fernando A Poletta  11   13 , Carmencita Padilla  14   15 , Alexandre R Vieira  16 , Seth M Weinberg  16 , George L Wehby  17 , Eleanor Feingold  1   2 , Jeffrey C Murray  18 , Mary L Marazita  1   16 , Elizabeth J Leslie  19
Affiliations

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

Jenna C Carlson et al. Genet Epidemiol. 2018 Oct.

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.

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Figures

Figure 1.
Figure 1.
Manhattan plot displaying the p-values from the gene-by-sex effect GWAS. Bolded points indicate a variant for which p-value for the two degree of freedom joint test of gene and gene-by-sex effect was less than 1.00 × 10−5.
Figure 2.
Figure 2.
Results for the 9q22.1 (A,D), 10q21.1 (B,E), and 13q13.3 (C,F) loci. Regional association plot show results for the gene-by-sex effect model. Points are color-coded based on linkage disequilbrium (r2) in Europeans. Plots were generated with LocusZoom (Pruim et al., 2010). Bar charts of the predicted probability of CL/P are shown, stratified by sex and adjusting for principal components of ancestry. Plots were generated with the ggplot2 package in R (R Core Team, 2017; Wickham, 2009).
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