Dataset Information

Association of Common Genetic Variants in the CPSF7 and SDHAF2 Genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier.

ABSTRACT: Canine idiopathic pulmonary fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a genome-wide association study (GWAS) in the WHWT using whole genome sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide DNA library prep kit. After quality controls, 28 affected, 44 unaffected, and 1,843,695 informative single nucleotide polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both the cleavage and polyadenylation specific factor 7 (CPSF7) and succinate dehydrogenase complex assembly factor 2 (SDHAF2) genes (adjusted p = 0.016 and 0.024, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389; however, it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT. CPSF7 was recently associated with lung adenocarcinoma, further highlighting the potential relevance of our results because IPF and lung cancer share several pathological mechanisms.

SUBMITTER: Piras IS

PROVIDER: S-EPMC7349241 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Association of Common Genetic Variants in the <i>CPSF7</i> and <i>SDHAF2</i> Genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier.

Piras Ignazio S IS Bleul Christiane C Siniard Ashley A Wolfe Amanda J AJ De Both Matthew D MD Hernandez Alvaro G AG Huentelman Matthew J MJ

Genes 20200530 6

Canine idiopathic pulmonary fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a genome-wide association study (GWAS) in the WHWT using whole genome sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide DNA library prep kit. After quality contr ...[more]

PMID: 32486318

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Project description:Rationale: To identify functionally relevant common genetic risk variants associated with idiopathic pulmonary fibrosis (IPF), we performed expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) mapping, followed by co-localization of eQTL and mQTL with genetic association signals as well as mediation analysis. Methods: Illumina MEGA genotyping arrays, mRNA sequencing, and Illumina 850k methylation arrays were performed on lung tissue of participants with IPF (234 RNA and 345 DNA samples) and non-diseased control (188 RNA and 202 DNA samples). Transcriptome and methylome datasets were normalized for unknown batch effects using Probabilistic Estimation of Expression Residuals (PEER). eQTL, cell type-interaction eQTL, and mQTL analyses were performed in FastQTL and co-localization analysis in eCAVIAR separately for cases and controls. Benjamini-Hochberg false discovery rate was used for adjustment for multiple comparisons. Results: After appropriate adjustment, we identified 4,745 genes with significant eQTLs in controls and 6,047 in cases (FDR-adjusted p<0.05). Focusing on genetic variants within 10 primary IPF-associated genetic loci, we identified 27 eQTLs in controls and 24 eQTLs in cases (FDR-adjusted p<0.05). Among these signals, we identified association of rs35705950 with expression of MUC5B (Chr11 locus) and rs2076295 with expression of DSP (Chr6 locus) in both cases and controls. To address cell specificity, we performed cell type-interaction eQTL analysis and identified an association of rs2076295 with expression of DSP in smooth muscle cells. mQTL analysis identified CpGs in gene bodies of MUC5B (cg17589883) and DSP (cg08964675) associated with the lead variants in these two loci. eCAVIAR demonstrated strong co-localization of eQTL/mQTL and genetic signal in MUC5B (rs35705950) and DSP (rs2076295) in both cases and controls. Mediation analysis demonstrated partial mediation of the effect of common variants in MUC5B and DSP loci on disease risk though MUC5B and DSP gene expression. Functional validation of the mQTL in MUC5B demonstrates that the CpG is within a putative internal repressor element that interacts through a 3D loop with the enhancer containing the rs35705950 genetic variant. Conclusions: Using lung eQTL/mQTL, co-localization, and mediation analyses, we have established the functional validation of the common IPF genetic risk variants for MUC5B (rs35705950) and DSP (rs2076295). These results provide additional evidence that both MUC5B and DSP are involved in the etiology of IPF.

Dataset Information

Association of Common Genetic Variants in the CPSF7 and SDHAF2 Genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier.

Publications

Association of Common Genetic Variants in the <i>CPSF7</i> and <i>SDHAF2</i> Genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier.

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