PMC:4156421 / 16550-18366 JSONTXT

{"project":"2_test","denotations":[{"id":"25192356-24487276-90446774","span":{"begin":476,"end":478},"obj":"24487276"}],"text":"Analysis of variants in the vicinity of rs35705950 (MUC5B)\nThe availability of whole genome sequence allowed us to explore whether the MUC5B promoter variant contributes to increased risk for IPF, as opposed to alternatively serving only as a marker in linkage disequilibrium (LD) with other causative variant(s) in the same region (Figure 3a, Figure S2). For this analysis we used a recently described approach, Combined Annotation-Dependent Depletion scoring system (CADD) [21], which estimates the relative pathogenicity of variants based on a variety of predicted functional effects. We first used HapMap data for individuals of European ancestry to define LD in the vicinity (1 Mb in either direction) of rs35705950. The highest scoring SNV out of 2,284 in the region, a nonsense variant within MUC6 (C-score  = 42) failed manual validation, due to likely misalignment, and no other SNVs had C-scores above 23. The full table of variants and scores is provided as Table S2. We also investigated the region between the MUC5AC gene and the MUC5B start site for rare variants (AF\u003c2%) that overlap with regions that may possibly influence expression (Figure 3b). Only one SNP, rs35705950, overlapped with both DNAse hypersensitivity and transcription factor binding regions.\nFigure 3 Sequencing coverage and variant distribution within the MUC5B locus.\n(A) Sequence coverage of the MUC5B gene. (B) Rare variants neighboring the MUC5B promoter variant rs35705950. Variant track is colored by allele frequency (blue: AF\u003c2%, red: AF\u003c5%, black: AF\u003c10%). No other rare variants in this region overlap with putative transcription factor binding sites, consistent with the hypothesis that the rs35705950 is causative of MUC5B dysregulation. Plots were generated using the UCSC genome browser (http://www.genome.ucsc.edu)."}

{"project":"PubTator4TogoVar","denotations":[{"id":"27675","span":{"begin":1688,"end":1698},"obj":"SNP"},{"id":"27676","span":{"begin":1453,"end":1463},"obj":"SNP"},{"id":"27667","span":{"begin":1178,"end":1188},"obj":"SNP"},{"id":"27669","span":{"begin":710,"end":720},"obj":"SNP"}],"attributes":[{"id":"A27675","pred":"resolved_to","subj":"27675","obj":"tmVar:rs35705950;VariantGroup:27;RS#:35705950"},{"id":"A27676","pred":"resolved_to","subj":"27676","obj":"tmVar:rs35705950;VariantGroup:27;RS#:35705950"},{"id":"A27667","pred":"resolved_to","subj":"27667","obj":"tmVar:rs35705950;VariantGroup:27;RS#:35705950"},{"id":"A27669","pred":"resolved_to","subj":"27669","obj":"tmVar:rs35705950;VariantGroup:27;RS#:35705950"}],"text":"Analysis of variants in the vicinity of rs35705950 (MUC5B)\nThe availability of whole genome sequence allowed us to explore whether the MUC5B promoter variant contributes to increased risk for IPF, as opposed to alternatively serving only as a marker in linkage disequilibrium (LD) with other causative variant(s) in the same region (Figure 3a, Figure S2). For this analysis we used a recently described approach, Combined Annotation-Dependent Depletion scoring system (CADD) [21], which estimates the relative pathogenicity of variants based on a variety of predicted functional effects. We first used HapMap data for individuals of European ancestry to define LD in the vicinity (1 Mb in either direction) of rs35705950. The highest scoring SNV out of 2,284 in the region, a nonsense variant within MUC6 (C-score  = 42) failed manual validation, due to likely misalignment, and no other SNVs had C-scores above 23. The full table of variants and scores is provided as Table S2. We also investigated the region between the MUC5AC gene and the MUC5B start site for rare variants (AF\u003c2%) that overlap with regions that may possibly influence expression (Figure 3b). Only one SNP, rs35705950, overlapped with both DNAse hypersensitivity and transcription factor binding regions.\nFigure 3 Sequencing coverage and variant distribution within the MUC5B locus.\n(A) Sequence coverage of the MUC5B gene. (B) Rare variants neighboring the MUC5B promoter variant rs35705950. Variant track is colored by allele frequency (blue: AF\u003c2%, red: AF\u003c5%, black: AF\u003c10%). No other rare variants in this region overlap with putative transcription factor binding sites, consistent with the hypothesis that the rs35705950 is causative of MUC5B dysregulation. Plots were generated using the UCSC genome browser (http://www.genome.ucsc.edu)."}

{"project":"PubTatorOnTogoVar","denotations":[{"id":"27667","span":{"begin":1178,"end":1188},"obj":"SNP"},{"id":"27669","span":{"begin":710,"end":720},"obj":"SNP"},{"id":"27675","span":{"begin":1688,"end":1698},"obj":"SNP"},{"id":"27676","span":{"begin":1453,"end":1463},"obj":"SNP"},{"id":"T1","span":{"begin":1688,"end":1698},"obj":"SNP"},{"id":"T2","span":{"begin":1453,"end":1463},"obj":"SNP"},{"id":"T1","span":{"begin":1178,"end":1188},"obj":"SNP"},{"id":"T2","span":{"begin":710,"end":720},"obj":"SNP"}],"attributes":[{"id":"A27667","pred":"resolved_to","subj":"27667","obj":"tmVar:rs35705950;VariantGroup:27;RS#:35705950"},{"id":"A27669","pred":"resolved_to","subj":"27669","obj":"tmVar:rs35705950;VariantGroup:27;RS#:35705950"},{"id":"A27675","pred":"resolved_to","subj":"27675","obj":"tmVar:rs35705950;VariantGroup:27;RS#:35705950"},{"id":"A27676","pred":"resolved_to","subj":"27676","obj":"tmVar:rs35705950;VariantGroup:27;RS#:35705950"}],"text":"Analysis of variants in the vicinity of rs35705950 (MUC5B)\nThe availability of whole genome sequence allowed us to explore whether the MUC5B promoter variant contributes to increased risk for IPF, as opposed to alternatively serving only as a marker in linkage disequilibrium (LD) with other causative variant(s) in the same region (Figure 3a, Figure S2). For this analysis we used a recently described approach, Combined Annotation-Dependent Depletion scoring system (CADD) [21], which estimates the relative pathogenicity of variants based on a variety of predicted functional effects. We first used HapMap data for individuals of European ancestry to define LD in the vicinity (1 Mb in either direction) of rs35705950. The highest scoring SNV out of 2,284 in the region, a nonsense variant within MUC6 (C-score  = 42) failed manual validation, due to likely misalignment, and no other SNVs had C-scores above 23. The full table of variants and scores is provided as Table S2. We also investigated the region between the MUC5AC gene and the MUC5B start site for rare variants (AF\u003c2%) that overlap with regions that may possibly influence expression (Figure 3b). Only one SNP, rs35705950, overlapped with both DNAse hypersensitivity and transcription factor binding regions.\nFigure 3 Sequencing coverage and variant distribution within the MUC5B locus.\n(A) Sequence coverage of the MUC5B gene. (B) Rare variants neighboring the MUC5B promoter variant rs35705950. Variant track is colored by allele frequency (blue: AF\u003c2%, red: AF\u003c5%, black: AF\u003c10%). No other rare variants in this region overlap with putative transcription factor binding sites, consistent with the hypothesis that the rs35705950 is causative of MUC5B dysregulation. Plots were generated using the UCSC genome browser (http://www.genome.ucsc.edu)."}