Replication of novel susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24 in Estonian and Lithuanian patients

Nikopensius, Tiit; Ambrozaitytė, Laima; Ludwig, Kerstin U.; Birnbaum, Stefanie; Jagomägi, Triin; Saag, Mare; Matulevičienė, Aušra; Linkevičienė, Laura; Herms, Stefan; Knapp, Michael; Hoffmann, Per; Nöthen, Markus M.; Kučinskas, Vaidutis; Metspalu, Andres; Mangold, Elisabeth

doi:10.1002/ajmg.a.33024

Cited by 38 publications

(33 citation statements)

References 8 publications

(9 reference statements)

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“…The first genome‐wide association study in Germany reported a major susceptibility locus on chromosome 8q24.21 (Birnbaum et al, 2009a). This association has subsequently been confirmed in independent samples of European descent, with rs987525 being the most significant marker across all studies (Grant et al, 2009; Nikopensius et al, 2009; Beaty et al, 2010; Blanton et al, 2010). Two additional CL/P susceptibility loci with genome‐wide significance were identified on 17q22 and 10q25.3 in a follow‐up study that included an enlarged German genome‐wide association study sample and a replication sample of mixed European origin (Mangold et al, 2010).…”

Section: Introductionmentioning

confidence: 72%

Variation in FGF1, FOXE1, and TIMP2genes is associated with nonsyndromic cleft lip with or without cleft palate

Nikopensius

Kempa

Ambrozaitytė

et al. 2011

Birth Defects Research Part A: Clinical and Molecular Teratolog

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Our results provide for the first time evidence implicating FGF1 in the occurrence of CL/P, and support TIMP2 and WNT9B as novel loci predisposing to CL/P. We have also replicated recently reported significant associations between variants in or near FOXE1 and CL/P. It is likely that variation in FOXE1, TIMP2, and the FGF and Wnt signaling pathway genes confers susceptibility to nonsyndromic CL/P in Northeastern European populations.

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Section: Introductionmentioning

confidence: 72%

Variation in FGF1, FOXE1, and TIMP2genes is associated with nonsyndromic cleft lip with or without cleft palate

Nikopensius

Kempa

Ambrozaitytė

et al. 2011

Birth Defects Research Part A: Clinical and Molecular Teratolog

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“…Similar results for rs987525 were obtained in a study on the Central European sample which showed a 1.7-fold increase in the risk of nsCL/P under the dominant inheritance model 19 . Although the association between rs987525 and the risk of nsCL/P has been replicated in numerous studies on various ethnicities [28][29][30][31] , the underlying functional mechanism remains unknown as rs987525 resides in a region of the genome containing no known genes 12 . It is possible that rs987525 or a linked causal SNP affects tissue-specific enhancers, altering the expression of one or more unspecified genes.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

Salagovic¹,

Klimčáková²,

Zabavnikova³

et al. 2017

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is the most common orofacial birth defect with an aetiology involving both genetic and environmental factors. Genome-wide association studies (GWAS) have identified several genomic susceptibility regions for nsCL/P. In the present study, the three well established single nucleotide polymorphisms (SNPs) identified by GWAS (rs987525 at 8q24, rs7078160 at 10q25, and rs227731 at 17q22 loci) and one SNP identified by candidate gene study (rs642961 in IRF6 gene at 1q32 locus) were analysed for an association with nsCL/P in Slovak population. Methods. Nucleotide variants were genotyped in 165 nsCL/P patients and 326 unaffected controls. All variants of interest were genotyped using high-resolution melting analysis after real-time PCR. Results. We found significant differences between patient and control groups with respect to the allele and genotype frequencies for the SNPs at the 1q32, 8q24, and 17q22 loci. SNP at the 10q25 locus showed a trend toward association with nsCL/P risk. Conclusions.The results suggest that SNPs at the 1q32, 8q24 and 17q22 loci may contribute to the nsCL/P risk in Slovak population.

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“…A prototypical example is the gene desert at human chromosome 8q24. A 640kb region in this interval is devoid of protein-coding genes, but is a major susceptibility locus for cleft palate with a calculated population attributable risk of 41% (35, 52, 53) and is significantly linked to normal variation in several facial morphology traits (16). We identified four craniofacial enhancer candidate sequences in this risk interval, two of which drive reproducible craniofacial reporter activity at e11.5 in transgenic mice (fig.…”

Section: Craniofacial Enhancers Within Disease-associated Intervalsmentioning

confidence: 99%

Fine Tuning of Craniofacial Morphology by Distant-Acting Enhancers

Attanasio

Nord

Zhu

et al. 2013

Science

227

279

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The shape of the human face and skull is largely genetically determined, but the genetic drivers of craniofacial morphology remain poorly understood. Here we used a combination of epigenomic profiling, in vivo characterization of candidate enhancer sequences in transgenic mice, and targeted deletion experiments to examine the role of distant-acting enhancers in craniofacial development. We identified complex regulatory landscapes, consisting of enhancers that drive a remarkable spatial complexity of developmental expression patterns. Deletion of individual craniofacial enhancers from the mouse genome resulted in significant alterations of craniofacial shape, demonstrating their functional importance in defining face and skull morphology. These results demonstrate that enhancers play a pervasive role in mammalian craniofacial development and suggest that enhancer sequence variation contributes to human facial morphology.

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Replication of novel susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24 in Estonian and Lithuanian patients

Cited by 38 publications

References 8 publications

Variation in FGF1, FOXE1, and TIMP2genes is associated with nonsyndromic cleft lip with or without cleft palate

Variation in FGF1, FOXE1, and TIMP2genes is associated with nonsyndromic cleft lip with or without cleft palate

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

Fine Tuning of Craniofacial Morphology by Distant-Acting Enhancers

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