Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci

Ludwig, Kerstin U.; Mangold, Elisabeth; Herms, Stefan; Nowak, Stefanie; Reutter, Heiko; Paul, Anna; Becker, Jéssica; Herberz, Ruth; AlChawa, Taofik; Nasser, Entessar; Böhmer, Anne C.; Mattheisen, Manuel; Alblas, Margrieta; Barth, Sandra; Kluck, Nadine; Lauster, Carola; Braumann, Bert; Reich, Rudolf H.; Hemprich, Alexander; Pötzsch, Simone; Blaumeiser, Bettina; Daratsianos, Nikolaos; Kreusch, Thomas; Murray, Jeffrey C.; Marazita, Mary L.; Ruczinski, Ingo; Scott, Alan F.; Beaty, Terri H.; Kramer, Franz Josef; Wienker, Thomas F.; Steegers‐Theunissen, R.P.M.; Rubini, Michele; Mossey, Peter; Hoffmann, Per; Lange, Christoph; Cichon, Sven; Propping, Peter; Knapp, Michael; Nöthen, Markus M.

doi:10.1038/ng.2360

Cited by 311 publications

(457 citation statements)

References 16 publications

Supporting

Mentioning

416

Contrasting

Unclassified

Order By: Relevance

“…This same SNP was recently identified as a susceptibility locus for NSCL/P in a recent meta-analysis. 29 This marker maps to an intergenic region for which, so far, no functional information related to OFC is available. Although the meta-analysis of Ludwig et al 29 and the current study utilized many of the same individuals, this previous study did not test for PofO effects.…”

Section: Discussionmentioning

confidence: 99%

“…29 This marker maps to an intergenic region for which, so far, no functional information related to OFC is available. Although the meta-analysis of Ludwig et al 29 and the current study utilized many of the same individuals, this previous study did not test for PofO effects. Comparison of the TDT results for the NSCL/P group in the present and the trio-part of Ludwig et al 29 reveals they are in the same range (with the slight difference being attributed to different quality controls on samples).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

et al. 2013

Self Cite

View full text Add to dashboard Cite

Parent-of-origin (PofO) effects, such as imprinting are a phenomenon where the effect of variants depends on parental origin. Conventional association studies assume that phenotypic effects are independent of parental origin, and are thus severely underpowered to detect such non-Mendelian effects. Risk of orofacial clefts is influenced by genetic and environmental effects, the latter including maternal-specific factors such as perinatal smoking and folate intake. To identify variants showing PofO effects in orofacial clefts we have used a modification of the family-based transmission disequilibrium test to screen for biased transmission from mothers and fathers to affected offspring, biased ratios of maternal versus paternal transmission, and biased frequencies of reciprocal classes of heterozygotes among offspring. We applied these methods to analyze published genomewide single-nucleotide polymorphism (SNP) data from B2500 trios mainly of European and Asian ethnicity with non-syndromic orofacial clefts, followed by analysis of 64 candidate SNPs in a replication cohort of B1200 trios of European origin. In our combined analysis, we did not identify any SNPs achieving conventional genome-wide significance (Po5 Â 10 À8 ). However, we observed an overall excess of loci showing maternal versus paternal transmission bias (P ¼ 0.013), and identified two loci that showed nominally significant effects in the same direction in both the discovery and replication cohorts, raising the potential for PofO effects. These include a possible maternal-specific transmission bias associated with rs12543318 at 8q21.3, a locus identified in a recent meta-analysis of non-syndromic cleft (maternal-specific P ¼ 1.5 Â 10 À7 , paternal-specific P ¼ 0.17). Overall, we conclude from this analysis that there are subtle hints of PofO effects in orofacial clefting.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…Both genome-wide linkage and association studies have shown multiple genes influence risk to oral clefts (Mangold et al 2011;Marazita 2012) and recently at least a dozen different genes have been identified as genetic risk factors in genome-wide association studies (GWASs) (Ludwig et al 2012;Beaty et al 2013). Few of these genes, however, have causal variants identified.…”

mentioning

confidence: 99%

Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

et al. 2014

Self Cite

View full text Add to dashboard Cite

A dozen genes/regions have been confirmed as genetic risk factors for oral clefts in human association and linkage studies, and animal models argue even more genes may be involved. Genomic sequencing studies should identify specific causal variants and may reveal additional genes as influencing risk to oral clefts, which have a complex and heterogeneous etiology. We conducted a whole exome sequencing (WES) study to search for potentially causal variants using affected relatives drawn from multiplex cleft families. Two or three affected second, third, and higher degree relatives from 55 multiplex families were sequenced. We examined rare single nucleotide variants (SNVs) shared by affected relatives in 348 recognized candidate genes. Exact probabilities that affected relatives would share these rare variants were calculated, given pedigree structures, and corrected for the number of variants tested. Five novel and potentially damaging SNVs shared by affected distant relatives were found and confirmed by Sanger sequencing. One damaging SNV in CDH1, shared by three affected second cousins from a single family, attained statistical significance (P = 0.02 after correcting for multiple tests). Family-based designs such as the one used in this WES study offer important advantages for identifying genes likely to be causing complex and heterogeneous disorders.

show abstract

“…Uma meta--análise recente dos dois maiores GWAS realizados para FL/P NS BEATY et al, 2010a;BIRNBAUM et al, 2009b;BLANTON et al, 2005;BRITO et al, 2012a;GHASSIBÉ et al, 2005;HUANG et al, 2009;JAGOMÄGI et al 2010;LUDWIG et al, 2012;PAN et al, 2010;PARK et al, 2007;PEGELOW et al, 2008;RAHIMOV et al, 2008;SCAPOLI et al, 2005;. A maioria das variantes de IRF6 associadas à FL/P NS encontra--se em região não--codificante do gene, com um possível papel na regulação gênica ainda controverso.…”

Section: Fatores De Risco Genéticosunclassified

“…Apesar de diversos loci já terem sido identificados BIRNBAUN et al, 2009a;GRANT et al, 2009;LUDWIG et al, 2012;, estes não explicam totalmente a herdabilidade da FL/P NS. Os altos níveis de significância dos sinais de associação ainda precisam ser traduzidos em um entendimento completo dos genes ou elementos genéticos dos loci que estão mediando a susceptibilidade à doença.…”

Section: Expressão Gênica Nas Doenças Complexasunclassified

Investigação do papel de SNVs (single nucleotide variants) na etiologia da fissura lábio-palatina não sindrômica

Silva¹

View full text Add to dashboard Cite

DedicatóriaÀ minha família, em especial à minha mãe. AgradecimentosPrimeiramente gostaria de agradecer à Rita, minha orientadora, que desde o primeiro contato me recebeu de braços abertos no laboratório. Por sempre me incentivar e apoiar no que quero fazer.À minha mãe, melhor amiga, terapeuta, que sempre me faz ver o lado bom de tudo.Pelo amor, confiança, carinho, incentivo e suporte infinitos. Aos meus irmãos, meus amores, que me completam. Ao Maurício, meu pai, por sempre estar ao meu lado.Ao Léo, que em mais uma etapa concluída está ao meu lado, me incentivando, consolando e apoiando meus devaneios.Ao meu pai João, pela confiança e oportunidades.Minhas avós, e em especial ao meu avô, meu exemplo.Às minhas tias e tios, pelo eterno apoio. Em especial Ana e Gerson, pelo teto, comida e roupa lavada e todo carinho de pais que sempre tiveram comigo. E o mais importante: o vinhozinho.Aos meus amigos, por sempre me lembrar do que é realmente importante na vida.À todos do lab200, por tornarem o ambiente de trabalho tão agradável. Em especial à Ka e Lu (minha vida seria muito mais difícil sem os sábios conselhos e as inúmeras caronas), Jozinha, Gelsu, Dani Bueno, May, Andressa, Simone, Luquinhas, Brunão… À Ciba, minha co--orientadora, por todo carinho, amizade e conhecimento dispensados. Por sempre me apoiar de todas as formas possíveis e imagináveis.

show abstract

Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci

Cited by 311 publications

References 16 publications

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

Investigação do papel de SNVs (single nucleotide variants) na etiologia da fissura lábio-palatina não sindrômica

Contact Info

Product

Resources

About