SynthesisPLoS genetics2016
Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene.
Synthesis in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 3 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
48 citing papers in PubMed, 3 syntheses or guidelines pooled it, 85 citations in OpenAlex.
- Genome-wide meta-analyses identify five new risk loci for nonsyndromic orofacial clefts in the Chinese Han population.Molecular genetics & genomic medicine · 2023Pooled it
- Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate.Human genetics · 2017Pooled it
- Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip ± cleft palate and cleft palate only.Human molecular genetics · 2017Pooled it
- Trial
- Genome-wide assessment of rare protein-coding variants identifies associations with non-syndromic cleft lip/palate.European journal of human genetics : EJHG · 2026Article
- Expanding the Genetic Spectrum of Non-Syndromic Cleft Lip and Palate Through Whole-Exome Sequencing.International journal of molecular sciences · 2025Article
- Compound inheritance of EHHADH and MASP1 mutations contributes to nonsyndromic cleft lip: familial analysis and zebrafish models.Biology open · 2025Article
- Haploinsufficiency of GRHL2 is associated with orofacial clefting in humans.Human molecular genetics · 2025Article
- Functional Annotation of De Novo Variants Found Near GWAS Loci Associated With Cleft Lip With or Without Cleft Palate.Birth defects research · 2025Article
- Functional variant at 19q13.3 confers nonsyndromic cleft palate susceptibility by regulatingiScience · 2025Article
- Gene expression patterns of the developing human face at single cell resolution reveal cell type contributions to normal facial variation and disease risk.bioRxiv : the preprint server for biology · 2025Article
- Functional Validation of Noncoding Variants Associated With Nonsyndromic Orofacial Cleft.Human mutation · 2025Review
- Ezh2-dependent methylation in oral epithelia promotes secondary palatogenesis.Birth defects research · 2023Article
- Association betweenGenes · 2023Article
- Rare variant modifier analysis identifies variants in SEC24D associated with orofacial cleft subtypes.Human genetics · 2023Article
- Rare genetic variants inmedRxiv : the preprint server for health sciences · 2023Article
- Article
- Prioritization of non-coding elements involved in non-syndromic cleft lip with/without cleft palate through genome-wide analysis ofHGG advances · 2023Article
- Identification of novel susceptibility genes for non-syndromic cleft lip with or without cleft palate using NGS-based multigene panel testing.Molecular genetics and genomics : MGG · 2022Article
- Decoding the Human Face: Progress and Challenges in Understanding the Genetics of Craniofacial Morphology.Annual review of genomics and human genetics · 2022Review
Corrections and comments
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Authors and funding
20 authors at 11 institutions in 9 countries.
Funding
Abstract
Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13 × 10(-14) for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32-1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94-1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47-9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.