A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals

Carlson, Jenna C.; Anand, Deepti; Butali, Azeez; Buxó, Carmen J.; Christensen, Kaare; Deleyiannis, Frederic W.‐B.; Hecht, Jacqueline; Moreno, Lina M.; Orioli, Iêda M.; Padilla, Carmencita D.; Shaffer, John R.; Vieira, Alexandre R.; Wehby, George L.; Weinberg, Seth M.; Murray, Jeffrey C.; Beaty, Terri H.; Saadi, Irfan; Lachke, Salil A.; Marazita, Mary L.; Feingold, Eleanor; Leslie, Elizabeth J.

doi:10.1002/gepi.22214

Cited by 37 publications

(75 citation statements)

References 52 publications

(76 reference statements)

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“…Additionally, 22 previously reported loci including 32 SNPs responsible for CL/P, CPO or CLP also showed marginal association ( P < 0.05) with CPO or CLO (S1 Table). Among these loci, two reported CPO SNPs rs61776460 in 1p36.11 ( GRHL3 , P = 9.31× 10 −3 ) and rs604328 in 5p13.2 ( UGT3A2 , P = 3.15× 10 −3 ) are weakly associated with CPO in this study [28]. For the four reported CPO SNPs by Butali A et al .…”

Section: Resultsmentioning

confidence: 55%

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Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

et al. 2019

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Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10−8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.

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Section: Resultsmentioning

confidence: 55%

“…1 , P = 8.83 × 10 −3 )[15, 16, 18] are also weakly associated with CPO in this study. Reported CLP SNPs rs560426 and rs66515264 in 1p22.1–21.3 ( ARHGAP29 , P = 1.79 × 10 −3 and P = 4.83 × 10 −3 respectively)[28], as well as rs1034832 in 8q21.3 ( DCAF4L2/CTB-118P15 . 2 , P = 2.60 × 10 −5 )[24] are weakly associated with CLO.…”

Section: Resultsmentioning

confidence: 99%

Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

et al. 2019

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“…Our results provide confirmatory evidence of some role (ARHGAP29, IRF6) in causing OFCs. Protein-altering DNMs were also identified in genes near recently reported GWAS loci (TFAP2A 26 , SHROOM3 25 ), adding evidence in support of their role in OFC etiology. Furthermore, this analysis also identified genes with DNMs not previously suggested as specific candidate genes within the suggestive or significant loci: ZFHX4 at 8q21, RBM15 at 1p13, UBN1 at 16p13.1 and HIRA at 22q11.2, thus providing additional evidence for novel OFC risk genes and loci.…”

Section: Resultsmentioning

confidence: 57%

“…Both genes had a pLI score of 1, were highly expressed in the hNCCs(top 20 th percentile), and were marker genes for the E0_E11 cell cluster (the olfactory epithelium) analyzed from the single-cell RNA sequencing data. Moreover, ZFHX4 is located at a suggestive GWAS locus (rs10808812; P=2.00 x 10 -6 ) 25 and is thus implicated in the etiology of OFCs through both LoF DNMs and evidence from common SNPs.…”

Section: Discussionmentioning

confidence: 99%

“…The clinically-relevant set of genes was constructed after a thorough literature search; known and suggested genes harboring mutations associated with OFC are summarized in Supplementary Table 4. The list of suggestive and significant loci use to identify DNMs in genes within 500kb was generated using data generated from Carlson et al (2019) 25 and Yu et al (2017) 26 .…”

Section: Statistical Analysis Of De Novo Variantsmentioning

confidence: 99%

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Codingde novomutations identified by WGS reveal novel orofacial cleft genes

Bishop

Perez

Sun

et al. 2020

Preprint

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While de novo mutations (DNMs) are known to increase risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 case-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.

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FAT4 identified as a potential modifier of orofacial cleft laterality

Curtis

Chang

Sun

et al. 2021

Genetic Epidemiology

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Orofacial clefts (OFCs) are common (1 in 700 births) congenital malformations that include a cleft lip (CL) and cleft lip and palate (CLP). These OFC subtypes are also heterogeneous themselves, with the CL occurring on the left, right, or both sides of the upper lip. Unilateral CL and CLP have a 2:1 bias towards left‐sided clefts, suggesting a nonrandom process. Here, we performed a study of left‐ and right‐sided clefts within the CL and CLP subtypes to better understand the genetic factors controlling cleft laterality. We conducted genome‐wide modifier analyses by comparing cases that had right unilateral CL (RCL; N = 130), left unilateral CL (LCL; N = 216), right unilateral CLP (RCLP; N = 416), or left unilateral CLP (LCLP; N = 638), and identified a candidate region on 4q28, 400 kb downstream from FAT4, that approached genome‐wide significance for LCL versus RCL (p = 8.4 × 10−8). Consistent with its potential involvement as a genetic modifier of CL, we found that Fat4 exhibits a specific domain of expression in the mesenchyme of the medial nasal processes that form the median upper lip. Overall, these results suggest that the epidemiological similarities in left‐ to right‐sided clefts in CL and CLP are not reflected in the genetic association results.

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A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals

Cited by 37 publications

References 52 publications

Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

Codingde novomutations identified by WGS reveal novel orofacial cleft genes

FAT4 identified as a potential modifier of orofacial cleft laterality

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