Dataset Information

Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts.

ABSTRACT: Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the "missing" heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP-Seq studies in craniofacial tissues or cell lines contained multiple low-frequency (0.01-1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low-frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p-value?=?.0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p-value?=?.001). These findings suggest that low-frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.

SUBMITTER: Shaffer JR

PROVIDER: S-EPMC6374160 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts.

Shaffer John R JR LeClair Jessica J Carlson Jenna C JC Feingold Eleanor E Buxó Carmen J CJ Christensen Kaare K Deleyiannis Frederic W B FWB Field L Leigh LL Hecht Jacqueline T JT Moreno Lina L Orioli Ieda M IM Padilla Carmencita C Vieira Alexandre R AR Wehby George L GL Murray Jeffrey C JC Weinberg Seth M SM Marazita Mary L ML Leslie Elizabeth J EJ

American journal of medical genetics. Part A 20181224 3

Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the "missing" heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic ...[more]

PMID: 30582786

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Project description:Orofacial clefts (OFCs) are congenital dysmorphologies of the human face and oral cavity, with a global incidence of 1 per 700 live births. These anomalies exhibit a multifactorial pattern of inheritance, with genetic and environmental factors both playing crucial roles. Many loci have been implicated in the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries, through genome-wide association studies and candidate gene studies. However, few populations of African descent have been studied to date. Here, the authors show evidence of an association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia, and Nigeria). The authors genotyped 48 single-nucleotide polymorphisms that were selected from previous genome-wide association studies and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1,070 unaffected relatives, and 1,078 unrelated controls. The authors also directly sequenced 7 genes in 184 nonsyndromic OFC (NSOFC) cases and 96 controls from Ghana. Population-specific associations were observed in the case-control analyses of the subpopulations, with West African subpopulations (Ghana and Nigeria) showing a similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, P = 5.10 × 10(-3)), 8q24 (rs987525, P = 1.22 × 10(-3)), and VAX1 (rs7078160, P = 0.04) were nominally associated with NSCL/P, and MSX1 (rs115200552, P = 0.01), TULP4 (rs651333, P = 0.04), CRISPLD2 (rs4783099, P = 0.02), and NOG1 (rs17760296, P = 0.04) were nominally associated with NSCPO. Moreover, 7 loci exhibited evidence of threshold overtransmission in NSOFC cases through the transmission disequilibrium test and through analyses of the family-based association for disease traits. Through DNA sequencing, the authors also identified 2 novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29 In conclusion, the authors have shown evidence for the association of many loci with NSCL/P and NSCPO. To the best of this knowledge, this study is the first to demonstrate any of these association signals in any African population.

Project description:Risk loci identified through genome-wide association studies have explained about 25% of the phenotypic variations in nonsyndromic orofacial clefts (nsOFCs) on the liability scale. Despite the notable sex differences in the incidences of the different cleft types, investigation of loci for sex-specific effects has been understudied. To explore the sex-specific effects in genetic etiology of nsOFCs, we conducted a genome-wide gene × sex (GxSex) interaction study in a sub-Saharan African orofacial cleft cohort. The sample included 1,019 nonsyndromic orofacial cleft cases (814 cleft lip with or without cleft palate and 205 cleft palate only) and 2,159 controls recruited from 3 sites (Ethiopia, Ghana, and Nigeria). An additive logistic model was used to examine the joint effects of the genotype and GxSex interaction. Furthermore, we examined loci with suggestive significance (P < 1E-5) in the additive model for the effect of the GxSex interaction only. We identified a novel risk locus on chromosome 8p22 with genome-wide significant joint and GxSex interaction effects (rs2720555, p2df = 1.16E-08, pGxSex = 1.49E-09, odds ratio [OR] = 0.44, 95% CI = 0.34 to 0.57). For males, the risk of cleft lip with or without cleft palate at this locus decreases with additional copies of the minor allele (p < 0.0001, OR = 0.60, 95% CI = 0.48 to 0.74), but the effect is reversed for females (p = 0.0004, OR = 1.36, 95% CI = 1.15 to 1.60). We replicated the female-specific effect of this locus in an independent cohort (p = 0.037, OR = 1.30, 95% CI = 1.02 to 1.65), but no significant effect was found for the males (p = 0.29, OR = 0.86, 95% CI = 0.65 to 1.14). This locus is in topologically associating domain with craniofacially expressed and enriched genes during embryonic development. Rare coding mutations of some of these genes were identified in nsOFC cohorts through whole exome sequencing analysis. Our study is additional proof that genome-wide GxSex interaction analysis provides an opportunity for novel findings of loci and genes that contribute to the risk of nsOFCs.

Dataset Information

Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts.

Publications

Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts.

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