DOI: 10.20350/digitalcsic/13845
title: Datasets related to a study aimed to identify genetic markers of CDA by subphenotypes associated with cardiotoxicity

description: [Global description: context, project description, and purpose of research, methodology used] Here we present a series of supplemental datasets that complement our study entitled "A Systems Medicine approach to identify genetic markers of cardiotoxicity due to anthracyclines in cancer patients." The datasets presented here were used to generate the main and supplementary figures and tables of the indicated study. The study consists of the identification of genetic markers of cardiotoxicity due to anthracyclines (CDA). CDA is a complex genesis disease or complex trait, and because of this, there is a component of missing heritability. Therefore, it is not possible to identify genetic markers associated with CDA risk. Here, we propose that molecular subphenotypes associated with the CDA may be a strategy for identifying some of this missing heritability and risk markers associated with it. A similar strategy could be applied to identify markers of other diseases of complex genesis. This study is done using a genetically heterogeneous cohort of mice that developed breast cancer and was treated with doxorubicin or a combined treatment of doxorubicin and docetaxel. The mouse cohort was generated by backcross, so each mouse is genetically unique. Post-chemotherapy heart damage was assessed by quantifying fibrosis's cardiac area and the thickness of myocardial fibers. The genetic regions associated with CDA were assessed by massive genotyping and genetic linkage analysis. Several molecular subphenotypes were quantified in the myocardium, and their association with the CDA was evaluated. Posteriormente, se identificaron cuáles de ellos se asociaron a CDA de forma más fuerte estadísticamente en modelos multivariantes. Y qué regiones genéticas de rasgo complejo (QTLs) asociados a los subfenotipos moleculares mejor explicaron la CDA. Esta estrategia sirvió para identificar en la cohorte de ratones genes cuyas formas alélicas podrían ser candidatos a expliar el riesgo de CDA. Variantes alélicas de esos genes se evaluaron en 4 cohortes de pacientes con cáncer tratados con antraciclinas, y cuya CDA se evaluó por ecocarciografía o Resonancia Magnética cardiaca (CMR).Subsequently, we identified which of them were most statistically associated with CDA in multivariate models. Moreover, which complex trait genetic regions (QTLs) associated with molecular subphenotypes best explained CDA. This strategy served to identify in the cohort of mice genes whose allelic forms could be candidates for the risk of CDA. Allelic variants of these genes were evaluated in four cohorts of cancer patients treated with anthracyclines and whose CDA was evaluated by echocardiography or cardiac magnetic resonance imaging (CMR).
description: [Specific raised questions and responses] Who produced the data? The data has been produced by the article of the work indicated above. Names and affiliations are listed below. Is the title specific enough? Initially, we have proposed above this title: "Datasets related to a study aimed to identify genetic markers of CDA by subphenotypes associated with cardiotoxicity." Why has the data been created? As noted above, these datasets are supplementary material with which the main and supplementary figures and tables of our indicated work have been generated. What limitations do the data have (for example, sensitive data has been deleted)? All confidential patient information is not present. We haven't even had access to it, following current legal regulations. How should the data be interpreted? These data sets cannot be separated from the main article in which they are used. To better understand their context, researchers have to see them in the global scenario of our work. Are there gaps in the data, or do they give a complete picture of the topic studied? As indicated above, data should be viewed and interpreted in the global context of our study What processes have generated the data? The processes that generated the data are indicated in the overview of the data above and individually for each of them. Thus, each dataset is accompanied by a legend within the document. They are also listed below in the individual descriptions for each dataset. What does the data measure in the columns of the files? As indicated, each dataset individually indicates the information contained in each dataset. What software is required to be able to read the data? The data is in Excel format. How should the data be quoted? The data should be cited in the context of the work to which they belongs, once it is published and free of the embargo. Can the data be reused? What use licenses are assigned to you? In principle, yes. If additional clinical information is required, it is available from the principal investigators of the references listed in our work, and of which they are also co-authors, upon reasonable request. Are there more versions of the data? where? In principle, I do not think so beyond our files and copies. Have the technical terms and acronyms referenced by the data been defined? A legend with the appropriate descriptions accompanies each dataset. Have the geographic and chronological parameters of the data been qualified? The data has been generated by the authors of the work. Elsewhere we indicate the authors of the work, their contributions, and affiliations. Are keywords sufficiently data-specific? Are they based on any thesaurus? Keywords are based on our study. We include the following: CDA, missing heritability, subphenotype, pathophenotype, complex trait. What is the name of the research project in which the data are framed? The main research project in which the data is framed is as follows. Títle: "Chemotherapy cardiotoxicity in the elderly: a translational and personnel approach." Ref.: PIE14/00066 Who has financed data production and management? Each of the authors of the study has its funding. Below are the grants that are included in the acknowledgments section of our manuscript and showed below.
description: Supplemental Dataset 1: CDA pathophenotypes after doxorubicin treatment. We treated 71 mice carrying breast cancer with doxorubicin. Each mouse was generated by backcrossing; thus, each one is genetically unique. Cardiotoxicity due to anthracyclines (CDA) was evaluated by automatically quantifying the heart fibrosis area and the average area of myocardial fibers as pathophenotypes of cardiotoxicity using the Ariol slide scanner. The histopathological damage was evaluated in the subendocardium and subepicardium from five randomly chosen regions of each sample (averages in μm2 are shown). The data set is related to Figure 2 and Table S1 and associated with Figure 3 and Table S2.-- Supplemental Dataset 2: CDA pathophenotypes after the combined therapy. We treated 61 mice carrying breast cancer with the combined therapy with doxorubicin and docetaxel. Each mouse was generated by backcrossing; thus, each one is genetically unique. Cardiotoxicity due to anthracyclines (CDA) was evaluated by automatically quantifying the heart fibrosis area and the average area of myocardial fibers as pathophenotypes of cardiotoxicity using the Ariol slide scanner. The histopathological damage was evaluated in the subendocardium and subepicardium from five randomly chosen regions of each sample (averages in μm2 are shown). The data set is related to Figure 2 and Table S1 and associated with Figure 3 and Table S2.-- Supplemental Dataset 3: CDA subphenotypes after doxorubicin therapy. Myocardium molecular subphenotypes after doxorubicin therapy. Proteins were quantified by a multiplex bead array (Luminex). TGFβ units are shown in pg/mL. The rest of the protein levels are shown in molecular fluorescence intensity (MFI) Units. The telomeric length was quantified by QPCR (RQ units). miRNAs were quantified by QPCR (RQ units). QPCR analyses were assessed by the ΔΔCT method; we show the averages of triplicates. It is related to Tables S3-S6 and indirectly associated with Figure 4a, b.-- Supplemental Dataset 4: CDA subphenotypes after the combined therapy. Myocardium molecular subphenotypes after the combined therapy with doxorubicin and docetaxel. Proteins were quantified by a multiplex bead array (Luminex). TGFβ units are shown in pg/mL. The rest of the protein levels are shown in molecular fluorescence intensity (MFI) Units. The telomeric length was quantified by QPCR (RQ units). miRNAs were quantified by QPCR (RQ units). QPCR analyses were assessed by the ΔΔCT method; we show the averages of triplicates. It is related to Tables S3-S6 and indirectly associated with Figure 4a, b.-- Supplemental Dataset 5: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after doxorubicin therapy in all mice. Correlation of Spearman. It is related to Figure 4a, b.-- Supplemental Dataset 6: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after doxorubicin therapy in young mice. Correlation of Spearman. It is related to Figure 4a, b.-- Supplemental Dataset 7: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after doxorubicin therapy in old mice. Correlation of Spearman. It is related to Figure 4a, b.-- Supplemental Dataset 8: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after the combined therapy in all mice. Correlation of Spearman. It is related to Figure 4a, b.-- Supplemental Dataset 9: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after the combined therapy in young mice. Correlation of Spearman. It is related to Figure 4a, b.-- Supplemental Dataset 10: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after the combined therapy in old mice. Correlation of Spearman. It is related to Figure 4a, b.-- Supplemental Dataset 11: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after doxorubicin therapy in all mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 5a.-- Supplemental Dataset 12: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after doxorubicin therapy in young mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 5a. -- Supplemental Dataset 13: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after doxorubicin therapy in old mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 5a.-- Supplemental Dataset 14: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after the combined therapy in all mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 5b.-- Supplemental Dataset 15: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after the combined therapy in young mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 5b.-- Supplemental Dataset 16: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after the combined therapy in old mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 5b.-- Supplemental Dataset 17: Massive genotyping of mouse cohort treated with doxorubicin. The genome-wide scan was carried out at the Spanish National Centre of Genotyping (CeGEN) at the Spanish National Cancer Research Centre (CNIO, Madrid, Spain). The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. It is related to Figures 5a and 6a.-- Supplemental Dataset 18: Massive genotyping of mouse cohort treated with the combined therapy. The genome-wide scan was carried out at the Spanish National Centre of Genotyping (CeGEN) at the Spanish National Cancer Research Centre (CNIO, Madrid, Spain). The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. It is related to Figures 5b and 6b.-- Supplemental Dataset 19: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after doxorubicin therapy in all mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 6a.-- Supplemental Dataset 20: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after doxorubicin therapy in young mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 6a.-- Supplemental Dataset 21: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after doxorubicin therapy in old mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 6a.-- Supplemental Dataset 22: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after the combined therapy in all mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 6b.-- Supplemental Dataset 23: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after the combined therapy in young mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 6b.-- Supplemental Dataset 24: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after the combined therapy in old mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript). It is related to Figure 6b.-- Supplemental Dataset 25: Human breast cancer cohort-1 genotyping. The association of genetic variants with CDA was evaluated in four patient cohorts previously published by some of us. Here, 53 anthracycline-treated breast cancer patients (Breast Cancer cohort-1) [Ref-12 of our manusript], the cardiac function was assessed by echocardiography to evaluate the left ventricular ejection fraction (LVEF). SNVs were detected on the Infinium™ Global Screening Array-24 v2.0 BeadChip. Data were imputed using the Michigan Imputation Server with Minimac4 [Ref. 24 of our manuscirip]; after retrieving the data, all markers with R2 &lt; 0.7 were removed from the analysis before proceeding further. SNVs related to candidate genes identified in the mouse cohort were evaluated. It is related to Table 1.-- Supplemental Dataset 26: Genes and genetic markers that were chosen to be evaluated in the breast cancer cohort-1 for the case and control assessment and also for CDA as a continuous variable. The chosen human genetic markers belong to allelic forms of candidate genes identified in the backcross mouse cohort associated with CDA risk variation. It is related to Table1.-- Supplemental Dataset 27: Human breast cancer cohort-1 and CDA evaluation through the Left Ventricular Ejection Fraction (LVEF) determined by echocardiography. LVEF values are shown before chemotherapy (LVEF-1), at first follow-up after treatment was completed (LVEF-2), and the increment of LVEF (difference between LVEF- 1 and LVEF-2). These values were used to evaluate CDA risk as a continuous variable. It is related to Table 1.-- Supplemental Dataset 28: Human breast cancer cohort-2 genotyping. The association of genetic variants with CDA was evaluated in four patient cohorts previously published by some of us. Here, 420 anthracycline-treated breast cancer patients (Breast Cancer cohort-1) [Ref-13 of our manusript], the cardiac function was assessed by echocardiography to evaluate the left ventricular ejection fraction (LVEF). SNVs were detected on the Infinium™ Global Screening Array-24 v2.0 BeadChip. Data were imputed using the Michigan Imputation Server with Minimac4 [ref. 24 of our manuscript]; after retrieving the data, all markers with R2 &lt; 0.7 were removed from the analysis before proceeding further. SNVs related to candidate genes identified in the mouse cohort were evaluated. It is related to Table 1.-- Supplemental Dataset 29: Genes and genetic markers that were chosen to be evaluated in the breast cancer cohort-2 for the case and control assessment and also for CDA as a continuous variable. The chosen human genetic markers belong to allelic forms of candidate genes identified in the backcross mouse cohort associated with CDA risk variation. It is related to Table1.-- Supplemental Dataset 30: Human breast cancer cohort-2 and CDA evaluation through the Left Ventricular Ejection Fraction (LVEF) determined by echocardiography. LVEF values are shown before chemotherapy (LVEF-1), at first follow-up after treatment was completed (LVEF-2), and the increment of LVEF (difference between LVEF- 1 and LVEF-2). These values were used to evaluate CDA risk as a continuous variable. It is related to Table 1.-- Supplemental Dataset 31: Pediatric cancer cohort genotyping. The association of genetic variants with CDA was evaluated in four patient cohorts previously published by some of us. Here, 71 anthracycline-treated pediatric cancer patients (Pediatric cohort) [Ref-11 of our manusript], the cardiac function was assessed by echocardiography to evaluate the left ventricular fractional shortening (LVFS). SNVs were detected on the Infinium™ Global Screening Array-24 v2.0 BeadChip. Data were imputed using the Michigan Imputation Server with Minimac4 [ref. 24 of our manuscript]; after retrieving the data, all markers with R2 &lt; 0.7 were removed from the analysis before proceeding further. SNVs related to candidate genes identified in the mouse cohort were evaluated. It is related to Table 1.-- Supplemental Dataset 32: Genes and genetic markers that were chosen to be evaluated in the pediatric cohort for the case and control assessment and also for CDA as a continuous variable. The chosen human genetic markers belong to allelic forms of candidate genes identified in the backcross mouse cohort associated with CDA risk variation. It is related to Table1.-- Supplemental Dataset 33: Pediatric cohort and CDA evaluation through the Left Ventricular Fractional Shortening (LVFS) determined by echocardiography. LVEF values are shown before chemotherapy (LVEF-1), at first follow-up after treatment was completed (LVEF-2), and the increment of LVEF (difference between LVEF- 1 and LVEF-2). These values were used to evaluate CDA risk as a continuous variable. It is related to Table 1.-- Supplemental Dataset 34: Human cancer Cardiac Magnetic Resonance (CMR) cohort genotyping. The association of genetic variants with CDA was evaluated in four patient cohorts previously published by some of us. Cardiac Magnetic Resonance (CMR) was carried out in 24 cancer patients (CMR cohort) [Ref-14 of our manuscript]. CMR was carried out at baseline and after every two cycles of a regular course of anthracycline therapy. It is related to Table 1. -- Supplemental Dataset 35: Genes and genetic markers that were chosen to be evaluated in the CMR cancer cohort for the case and control assessment and also for CDA as a continuous variable. The chosen human genetic markers belong to allelic forms of candidate genes identified in the backcross mouse cohort associated with CDA risk variation. It is related to Table 1.