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. 2017 Jul 17;109(13):1030-1038.
doi: 10.1002/bdr2.23605.

Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing

Jenna C Carlson  1 , Margaret A Taub  2 , Eleanor Feingold  1   3 , Terri H Beaty  4 , Jeffrey C Murray  5 , Mary L Marazita  3   6   7 , Elizabeth J Leslie  7
Affiliations

Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing

Jenna C Carlson et al. Birth Defects Res. .

Abstract

Background: Orofacial clefts (OFCs), including nonsyndromic cleft lip with or without cleft palate (NSCL/P), are common birth defects. NSCL/P is highly heterogeneous with multiple phenotypic presentations. Two common subtypes of NSCL/P are cleft lip (CL) and cleft lip with cleft palate (CLP) which have different population prevalence. Similarly, NSCL/P can be divided into bilateral and unilateral clefts, with unilateral being the most common. Individuals with unilateral NSCL/P are more likely to be affected on the left side of the upper lip, but right side affection also occurs. Moreover, NSCL/P is twice as common in males as in females. The goal of this study is to discover genetic variants that have different effects in case subgroups.

Methods: We conducted both common variant and rare variant analyses in 1034 individuals of Asian ancestry with NSCL/P, examining four sources of heterogeneity within CL/P: cleft type, sex, laterality, and side.

Results: We identified several regions associated with subtype differentiation: cleft type differences in 8q24 (p = 1.00 × 10-4 ), laterality differences in IRF6, a gene previously implicated with wound healing (p = 2.166 × 10-4 ), sex differences and side of unilateral CL differences in FGFR2 (p = 3.00 × 10-4 ; p = 6.00 × 10-4 ), and sex differences in VAX1 (p < 1.00 × 10-4 ) among others.

Conclusion: Many of the regions associated with phenotypic modification were either adjacent to or overlapping functional elements based on ENCODE chromatin marks and published craniofacial enhancers. We have identified multiple common and rare variants as potential phenotypic modifiers of NSCL/P, and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs. Birth Defects Research 109:1030-1038, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: complex trait; genetic epidemiology; orofacial cleft.

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Figures

Figure 1
Figure 1. CL vs. CLP cleft type modifiers
A) Cleft type (CL vs. CLP) association results from the common-variant meta-analysis of Filipino and Chinese populations. (B) – (E) Regional association plots for 9q22 (x2), 17q22, and 20q12 showing −log10(P-values) for SNPs with stronger association with CL (squares) and stronger association with CLP (circles) based on the direction of the odds ratio. Plots were generated using LocusZoom (Pruim et al., 2010). The recombination overlay (blue line, right y-axis) indicates the boundaries of the LD-block. Points are color coded according to pairwise linkage disequilibrium (r2) with the index SNP.
Figure 2
Figure 2. Unilateral vs. bilateral CL/P modifiers
(A) Laterality (unilateral vs. bilateral) association results from the common-variant meta-analysis of Filipino and Chinese populations. (B) – (C) Regional association plots for 1q32 and 17q22 showing −log10(P-values) for SNPs with stronger association with unilateral CL/P (squares) and stronger association with bilateral CL/P (circles) based on the direction of the odds ratio. Plots were generated using LocusZoom (Pruim et al., 2010). The recombination overlay (blue line, right y-axis) indicates the boundaries of the LD-block. Points are color coded according to pairwise linkage disequilibrium (r2) with the index SNP.
Figure 3
Figure 3. Sex-specific and side modifiers of CL/P
(A) Sex (male vs. female) association results from the common-variant meta-analysis of Filipino and Chinese populations. (B) Side (right unilateral vs. left unilateral) association results from the common-variant meta-analysis of Filipino and Chinese populations.
Figure 4
Figure 4. Significant rare variant windows with potential regulatory effects
(A) 8q24 for cleft type, (B) VAX1 for sex, and (C) FGFR2 for sex and side.
See this image and copyright information in PMC

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