Correction to: Genomic analyses in African populations identify novel risk loci for cleft palate.
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PROVIDER: S-EPMC10505450 | biostudies-literature | 2023 Jun
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Correction to: Genomic analyses in African populations identify novel risk loci for cleft palate.
Human molecular genetics 20230601 12
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Project description:Orofacial clefts are common developmental disorders that pose significant clinical, economical and psychological problems. We conducted genome-wide association analyses for cleft palate only (CPO) and cleft lip with or without palate (CL/P) with ~17 million markers in sub-Saharan Africans. After replication and combined analyses, we identified novel loci for CPO at or near genome-wide significance on chromosomes 2 (near CTNNA2) and 19 (near SULT2A1). In situ hybridization of Sult2a1 in mice showed expression of SULT2A1 in mesenchymal cells in palate, palatal rugae and palatal epithelium in the fused palate. The previously reported 8q24 was the most significant locus for CL/P in our study, and we replicated several previously reported loci including PAX7 and VAX1.
| S-EPMC6400042 | biostudies-literature
Project description:Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation.
| S-EPMC5333091 | biostudies-literature
Project description:We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; P(NSCLP) = 6.51 × 10(-11); homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84-3.16).
| S-EPMC3598617 | biostudies-literature
Project description:The 3 major subphenotypes observed in patients with nonsyndromic orofacial clefts (NSOFCs) are nonsyndromic cleft lip only (NSCLO), nonsyndromic cleft lip with palate (NSCLP), and nonsyndromic cleft palate only (NSCPO). However, the genetic architecture underlying NSCPO is largely unknown. Here we performed a 2-stage genome-wide association study (GWAS) on NSCPO and replication analyses of selected variants in other NSOFCs from the Chinese Han population. We identified a novel locus (15q24.3) and a known locus (1q32.2) where variants in or near the gene reached genome-wide significance (2.80 × 10-13 < P < 1.72 × 10-08) in a test for association with NSCPO in a case-control design. Although a variant from 15q24.3 was found to be significantly associated with both NSCPO and NSCLP, the direction of estimated effects on risk were opposite. Our functional annotation of the risk alleles within 15q24.3 coupled with previously established roles of the candidate genes within identified risk loci in periderm development, embryonic patterning, and/or regulation of cellular processes supports their involvement in palate development and the pathogenesis of cleft palate. Our study advances the understanding of the genetic basis of NSOFCs and provides novel insights into the pathogenesis of NSCPO.
| S-EPMC8256250 | biostudies-literature
Project description:Although several genome-wide association studies (GWAS) of non-syndromic cleft lip with or without cleft palate (NSCL/P) have been reported, more novel association signals are remained to be exploited. Here, we performed an in-depth analysis of our previously published Chinese GWAS cohort study with replication in an extra dbGaP case-parent trios and another in-house Nanjing cohort, and finally identified five novel significant association signals (rs11119445: 3' of SERTAD4, P = 6.44 × 10-14 ; rs227227 and rs12561877: intron of SYT14, P = 5.02 × 10-13 and 2.80 × 10-11 , respectively; rs643118: intron of TRAF3IP3, P = 4.45 × 10-6 ; rs2095293: intron of NR6A1, P = 2.98 × 10-5 ). The mean (standard deviation) of the weighted genetic risk score (wGRS) from these SNPs was 1.83 (0.65) for NSCL/P cases and 1.58 (0.68) for controls, respectively (P = 2.67 × 10-16 ). Rs643118 was identified as a shared susceptible factor of NSCL/P among Asians and Europeans, while rs227227 may contribute to the risk of NSCL/P as well as NSCPO. In addition, sertad4 knockdown zebrafish models resulted in down-regulation of sox2 and caused oedema around the heart and mandibular deficiency, compared with control embryos. Taken together, this study has improved our understanding of the genetic susceptibility to NSCL/P and provided further clues to its aetiology in the Chinese population.
| S-EPMC7754035 | biostudies-literature
Project description:Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
| S-EPMC5446189 | biostudies-literature
Project description:OBJECTIVE:Cleft lip and/or cleft palate (CL/P) are congenital anomalies of the face and have multifactorial etiology, with both environmental and genetic risk factors playing crucial roles. Though at least 40 loci have attained genomewide significant association with nonsyndromic CL/P, these loci largely reside in noncoding regions of the human genome, and subsequent resequencing studies of neighboring candidate genes have revealed only a limited number of etiologic coding variants. The present study was conducted to identify etiologic coding variants in GREM1, a locus that has been shown to be largely associated with cleft of both lip and soft palate. PATIENTS AND METHOD:We resequenced DNA from 397 sub-Saharan Africans with CL/P and 192 controls using Sanger sequencing. Following analyses of the sequence data, we observed 2 novel coding variants in GREM1. These variants were not found in the 192 African controls and have never been previously reported in any public genetic variant database that includes more than 5000 combined African and African American controls or from the CL/P literature. RESULTS:The novel variants include p.Pro164Ser in an individual with soft palate cleft only and p.Gly61Asp in an individual with bilateral cleft lip and palate. The proband with the p.Gly61Asp GREM1 variant is a van der Woude (VWS) case who also has an etiologic variant in IRF6 gene. CONCLUSION:Our study demonstrated that there is low number of etiologic coding variants in GREM1, confirming earlier suggestions that variants in regulatory elements may largely account for the association between this locus and CL/P.
| S-EPMC6081638 | biostudies-literature
Project description:Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signals within this high-density dataset are enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinement approach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation.
| S-EPMC5409059 | biostudies-literature
Project description: Not available
| S-EPMC11548905 | biostudies-literature
Project description:ObjectiveThe etiology of cleft palate (CP) is poorly understood compared with that of cleft lip with or without palate (CL ± P). Recently, variants in Grainyhead like transcription factor 3 (GRHL3) were reported to be associated with a risk for CP in European and some African populations including Nigeria, Ghana, and Ethiopia. In order to identify genetic variants that may further explain the etiology of CP, we sequenced GRHL3 in a South African population to determine if rare variants in GRHL3 are associated with the presence of syndromic or nonsyndromic CP.DesignWe sequenced the exons of GRHL3 in 100 cases and where possible, we sequenced the parents of the individuals to determine the segregation pattern and presence of de novo variants.SettingThe cleft clinics from 2 public, tertiary hospitals in Durban, South Africa (SA), namely Inkosi Albert Luthuli Central Hospital and KwaZulu-Natal Children's Hospital.Patients, participantsOne hundred patients with CL ± P and their parents.InterventionsSaliva samples were collected.Main outcome measuresTo ascertain the genetic variants in the GRHL3 gene in patients with CL ± P in SA.ResultsFive variants in GRHL3 were observed; 3 were novel and 2 were known variants. The novel variants were intronic variants (c.1062 + 77A>G and c.627 + 1G>A) and missense variant (p.Asp169Gly).ConclusionsThis study provides further evidence that variants in GRHL3 contribute to the risk of nonsyndromic CP in African populations, specifically, in the South African population.
| S-EPMC9790085 | biostudies-literature