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New basal cell carcinoma susceptibility loci.

Stacey SN, Helgason H, Gudjonsson SA, Thorleifsson G, Zink F, Sigurdsson A, Kehr B, Gudmundsson J, Sulem P, Sigurgeirsson B, Benediktsdottir KR, Thorisdottir K, Ragnarsson R, Fuentelsaz V, Corredera C, Gilaberte Y, Grasa M, Planelles D, Sanmartin O, Rudnai P, Gurzau E, Koppova K, Nexø BA, Tjønneland A, Overvad K, Jonasson JG, Tryggvadottir L, Johannsdottir H, Kristinsdottir AM, Stefansson H, Masson G, Magnusson OT, Halldorsson BV, Kong A, Rafnar T, Thorsteinsdottir U, Vogel U, Kumar R, Nagore E, Mayordomo JI, Gudbjartsson DF, Olafsson JH, Stefansson K - Nat Commun (2015)

Bottom Line: Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)).Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor.In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.

View Article: PubMed Central - PubMed

Affiliation: deCODE Genetics/AMGEN, Sturlugata 8, Reykjavik 101, Iceland.

ABSTRACT
In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.

No MeSH data available.


Related in: MedlinePlus

New BCC association signals. Loci are (a) 2p24 MYCN, (b) 2q33 CASP8-ALS2CR12, (c) 8q21 ZFHX4 and (d) 10p14 GATA3 loci in the Icelandic sample. Data are based on association signals (expressed as −log10(P) derived by logistic regression) for variants identified by whole-genome sequencing and imputation. The index SNP at each locus is labelled. Other variants are plotted in colours according to their r2 values relative to the index SNP as indicated in the legend (a). Recombination rates, in cM/Mb and based on Icelandic data, are plotted as red lines. The lower panel sections shows the locations of RefSeq genes and the chromosomal position (hg18 Build 36). The regions shown are ±500 kb from the index SNP except for 10p14 GATA3, where the region is extended to −1 Mb to show the location of the GATA3 gene.
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f1: New BCC association signals. Loci are (a) 2p24 MYCN, (b) 2q33 CASP8-ALS2CR12, (c) 8q21 ZFHX4 and (d) 10p14 GATA3 loci in the Icelandic sample. Data are based on association signals (expressed as −log10(P) derived by logistic regression) for variants identified by whole-genome sequencing and imputation. The index SNP at each locus is labelled. Other variants are plotted in colours according to their r2 values relative to the index SNP as indicated in the legend (a). Recombination rates, in cM/Mb and based on Icelandic data, are plotted as red lines. The lower panel sections shows the locations of RefSeq genes and the chromosomal position (hg18 Build 36). The regions shown are ±500 kb from the index SNP except for 10p14 GATA3, where the region is extended to −1 Mb to show the location of the GATA3 gene.

Mentions: We observed BCC association signals at 2p24 from a group of variants with minor allele frequencies around 10.2%. The strongest signal came from rs57244888[C], with odds ratio (OR)=0.77, P=1.4 × 10−8 (Fig. 1a, Table 1). The peak is in the intergenic region between MYCN and FAM49A and is separated from both genes by regions of moderate recombination rates (Fig. 1a). We generated a single-track Centaurus assay for rs57244888 and genotyped it in replication samples from Spain, Denmark and eastern Europe. The association replicated significantly in the non-Icelandic samples (OR=0.74, P=6.9 × 10−5) and there was no evidence of heterogeneity between the sample sets (Table 1). Combining the Icelandic and non-Icelandic data provided strong overall evidence of an association (OR=0.76, P=4.7 × 10−12).


New basal cell carcinoma susceptibility loci.

Stacey SN, Helgason H, Gudjonsson SA, Thorleifsson G, Zink F, Sigurdsson A, Kehr B, Gudmundsson J, Sulem P, Sigurgeirsson B, Benediktsdottir KR, Thorisdottir K, Ragnarsson R, Fuentelsaz V, Corredera C, Gilaberte Y, Grasa M, Planelles D, Sanmartin O, Rudnai P, Gurzau E, Koppova K, Nexø BA, Tjønneland A, Overvad K, Jonasson JG, Tryggvadottir L, Johannsdottir H, Kristinsdottir AM, Stefansson H, Masson G, Magnusson OT, Halldorsson BV, Kong A, Rafnar T, Thorsteinsdottir U, Vogel U, Kumar R, Nagore E, Mayordomo JI, Gudbjartsson DF, Olafsson JH, Stefansson K - Nat Commun (2015)

New BCC association signals. Loci are (a) 2p24 MYCN, (b) 2q33 CASP8-ALS2CR12, (c) 8q21 ZFHX4 and (d) 10p14 GATA3 loci in the Icelandic sample. Data are based on association signals (expressed as −log10(P) derived by logistic regression) for variants identified by whole-genome sequencing and imputation. The index SNP at each locus is labelled. Other variants are plotted in colours according to their r2 values relative to the index SNP as indicated in the legend (a). Recombination rates, in cM/Mb and based on Icelandic data, are plotted as red lines. The lower panel sections shows the locations of RefSeq genes and the chromosomal position (hg18 Build 36). The regions shown are ±500 kb from the index SNP except for 10p14 GATA3, where the region is extended to −1 Mb to show the location of the GATA3 gene.
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Related In: Results  -  Collection

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f1: New BCC association signals. Loci are (a) 2p24 MYCN, (b) 2q33 CASP8-ALS2CR12, (c) 8q21 ZFHX4 and (d) 10p14 GATA3 loci in the Icelandic sample. Data are based on association signals (expressed as −log10(P) derived by logistic regression) for variants identified by whole-genome sequencing and imputation. The index SNP at each locus is labelled. Other variants are plotted in colours according to their r2 values relative to the index SNP as indicated in the legend (a). Recombination rates, in cM/Mb and based on Icelandic data, are plotted as red lines. The lower panel sections shows the locations of RefSeq genes and the chromosomal position (hg18 Build 36). The regions shown are ±500 kb from the index SNP except for 10p14 GATA3, where the region is extended to −1 Mb to show the location of the GATA3 gene.
Mentions: We observed BCC association signals at 2p24 from a group of variants with minor allele frequencies around 10.2%. The strongest signal came from rs57244888[C], with odds ratio (OR)=0.77, P=1.4 × 10−8 (Fig. 1a, Table 1). The peak is in the intergenic region between MYCN and FAM49A and is separated from both genes by regions of moderate recombination rates (Fig. 1a). We generated a single-track Centaurus assay for rs57244888 and genotyped it in replication samples from Spain, Denmark and eastern Europe. The association replicated significantly in the non-Icelandic samples (OR=0.74, P=6.9 × 10−5) and there was no evidence of heterogeneity between the sample sets (Table 1). Combining the Icelandic and non-Icelandic data provided strong overall evidence of an association (OR=0.76, P=4.7 × 10−12).

Bottom Line: Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)).Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor.In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.

View Article: PubMed Central - PubMed

Affiliation: deCODE Genetics/AMGEN, Sturlugata 8, Reykjavik 101, Iceland.

ABSTRACT
In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.

No MeSH data available.


Related in: MedlinePlus