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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

Carriers of the rs700635[C] BCC risk allele show preferential retention of CASP8 intron 8.RNA-seq data was obtained from blood from genotyped donors. These were n=24 rs700635[C/C] homozygotes (shown in red), n=117 rs700635[C/A] heterozygotes (shown in green) and n=114 rs700635[A/A] homozygotes (shown in blue). The x axis is the genomic position in Mb (hg18/Build36). The y axis is, for each genotypic group, the median count of normalized reads (normalized for each individual to the total number of aligned reads). The structure of the RefSeq transcript variants is shown beneath the graphs. (a) The genomic region covering the coding exons of CASP8. (b) Zoom showing the exon 8, exon 8L region extending through intron 8 to the minor exon targeted by the NM_033358 probe. (c) Zoom showing the splice junction between exon 8L and intron 8.
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f4: Carriers of the rs700635[C] BCC risk allele show preferential retention of CASP8 intron 8.RNA-seq data was obtained from blood from genotyped donors. These were n=24 rs700635[C/C] homozygotes (shown in red), n=117 rs700635[C/A] heterozygotes (shown in green) and n=114 rs700635[A/A] homozygotes (shown in blue). The x axis is the genomic position in Mb (hg18/Build36). The y axis is, for each genotypic group, the median count of normalized reads (normalized for each individual to the total number of aligned reads). The structure of the RefSeq transcript variants is shown beneath the graphs. (a) The genomic region covering the coding exons of CASP8. (b) Zoom showing the exon 8, exon 8L region extending through intron 8 to the minor exon targeted by the NM_033358 probe. (c) Zoom showing the splice junction between exon 8L and intron 8.

Mentions: Given the biological importance of CASP8, we initiated a more detailed investigation of its expression. We generated blood RNA-seq data from an independent set of 261 genotyped individuals. For rs700635[C], we confirmed that RNA abundance in the NM_033358 probe region is increased in risk allele carriers. However, RNA-seq revealed that the entire intron 8 sequence between exon 8L and the probe region is preferentially retained in carriers (Fig. 4a,b). This coincides with the reduced expression of the major exons of the CASP8 gene in association with rs700635[C] (β=−0.65 P=1.7 × 10−12, Supplementary Table 2). Reverse transcription–PCR (RT–PCR) of 76 blood RNA samples (using probes as shown in Fig. 2d) reconfirmed these findings (Supplementary Fig. 5).


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)

Carriers of the rs700635[C] BCC risk allele show preferential retention of CASP8 intron 8.RNA-seq data was obtained from blood from genotyped donors. These were n=24 rs700635[C/C] homozygotes (shown in red), n=117 rs700635[C/A] heterozygotes (shown in green) and n=114 rs700635[A/A] homozygotes (shown in blue). The x axis is the genomic position in Mb (hg18/Build36). The y axis is, for each genotypic group, the median count of normalized reads (normalized for each individual to the total number of aligned reads). The structure of the RefSeq transcript variants is shown beneath the graphs. (a) The genomic region covering the coding exons of CASP8. (b) Zoom showing the exon 8, exon 8L region extending through intron 8 to the minor exon targeted by the NM_033358 probe. (c) Zoom showing the splice junction between exon 8L and intron 8.
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f4: Carriers of the rs700635[C] BCC risk allele show preferential retention of CASP8 intron 8.RNA-seq data was obtained from blood from genotyped donors. These were n=24 rs700635[C/C] homozygotes (shown in red), n=117 rs700635[C/A] heterozygotes (shown in green) and n=114 rs700635[A/A] homozygotes (shown in blue). The x axis is the genomic position in Mb (hg18/Build36). The y axis is, for each genotypic group, the median count of normalized reads (normalized for each individual to the total number of aligned reads). The structure of the RefSeq transcript variants is shown beneath the graphs. (a) The genomic region covering the coding exons of CASP8. (b) Zoom showing the exon 8, exon 8L region extending through intron 8 to the minor exon targeted by the NM_033358 probe. (c) Zoom showing the splice junction between exon 8L and intron 8.
Mentions: Given the biological importance of CASP8, we initiated a more detailed investigation of its expression. We generated blood RNA-seq data from an independent set of 261 genotyped individuals. For rs700635[C], we confirmed that RNA abundance in the NM_033358 probe region is increased in risk allele carriers. However, RNA-seq revealed that the entire intron 8 sequence between exon 8L and the probe region is preferentially retained in carriers (Fig. 4a,b). This coincides with the reduced expression of the major exons of the CASP8 gene in association with rs700635[C] (β=−0.65 P=1.7 × 10−12, Supplementary Table 2). Reverse transcription–PCR (RT–PCR) of 76 blood RNA samples (using probes as shown in Fig. 2d) reconfirmed these findings (Supplementary Fig. 5).

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