Summary-data based Mendelian randomization identifies gene expression regulatory polymorphisms associated with bovine paratuberculosis by modulation of the nuclear factor Kappa β (NF-κß)-mediated inflammatory response

Figures

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  Fig. 1. Study design. Summary data from GWAS and cis-eQTL mapping were used to perform the SMR analysis. The approach starts with the individual normalized RNA-counts, then identifies genetic variants controlling differences in gene expression, and finally checks whether the identified cis-eQTLs are indeed associated with disease outcomes using summary GWAS data from a bigger population classified according to the presence or absence of PTB-associated lesions. Two eQTL datasets from peripheral blood (PB) and ileocecal valve (ICV) were applied together with three GWAS datasets from the comparisons: focal, multifocal or diffuse lesions versus (vs) controls. Using these two different omics data, the SMR method discover biological mechanisms behind PTB outcomes

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  Fig. 2. Manhattan plots of cis-eQTL mapping results. a cis-eQTLs identified in PB samples within 1 Mb upstream of a TSS. b cis-eQTLs identified in ICV samples within 1 Mb upstream of a TSS. The plot shows in the Y axis the –log10 (Pβ-values) of each SNP and in the X axis the chromosome where each cis-eQTL is located. Each dot represents a SNP along the Bos taurus genome. The dotted lines represent the Pβ-values that correspond to a FDR equal to 0.05. c, d The chart shows the genomic distributions of the PB (c) and ICV (d) cis-eQTLs identified within 1 Mb upstream of a TSS according to the Ensembl Variant Effector Predictor (VEP)

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  Fig. 3. Locus plots showing the significant genes EGR4 and MGC134040, their locations within chromosomes 11 and 3, respectively. Y axis represents the negative log of the significant P-values and X axis represents the negative log of the P-values. Dots in the top plots represent the P-values for SNPs from the GWAS analysis. Rhombuses represent the P-values from the SMR analyses, highlighted in red if significant. In the middle plots, crosses represent the Pβ-values of the cis-eQTLs located in the plotted region. In the bottom plots are represented all genes in each plotted region. a. SMR results using cis-eQTLs identified in PB samples and GWAs results of a case–control study where cases were animals with multifocal lesions and controls were animals without lesions. The dotted red line represents FDR ≤ 0.05 corresponding to P [SMR] = 10–5. b. SMR results using ci-eQTLs identified in ICV samples and GWAs results of a case–control study where cases were animals with diffuse lesions and controls were animals without lesions. The dotted red line represents FDR ≤ 0.05 corresponding to P [SMR] = 10–4