GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels

A recent genome-wide association study (GWAS) identified a locus in chromosome 11 associated with the chronic cardiac form of Chagas disease. Here we aimed to elucidate the potential functional mechanism underlying this genetic association by analyzing the correlation among single nucleotide polymor...

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Autores principales:	Desiré Casares-Marfil, Martin Kerick, Eduardo Andrés-León, Pau Bosch-Nicolau, Israel Molina, Chagas Genetics CYTED Network, Javier Martin, Marialbert Acosta-Herrera
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/cf1f6ec80ef34ecc938e4827580116eb
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spelling	oai:doaj.org-article:cf1f6ec80ef34ecc938e4827580116eb2021-11-18T09:12:17ZGWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels1935-27271935-2735https://doaj.org/article/cf1f6ec80ef34ecc938e4827580116eb2021-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580254/?tool=EBIhttps://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735A recent genome-wide association study (GWAS) identified a locus in chromosome 11 associated with the chronic cardiac form of Chagas disease. Here we aimed to elucidate the potential functional mechanism underlying this genetic association by analyzing the correlation among single nucleotide polymorphisms (SNPs) and DNA methylation (DNAm) levels as cis methylation quantitative trait loci (cis-mQTL) within this region. A total of 2,611 SNPs were tested against 2,647 DNAm sites, in a subset of 37 chronic Chagas cardiomyopathy patients and 20 asymptomatic individuals from the GWAS. We identified 6,958 significant cis-mQTLs (False Discovery Rate [FDR]<0.05) at 1 Mb each side of the GWAS leading variant, where six of them potentially modulate the expression of the SAC3D1 gene, the reported gene in the previous GWAS. In addition, a total of 268 cis-mQTLs showed differential methylation between chronic Chagas cardiomyopathy patients and asymptomatic individuals. The most significant cis-mQTLs mapped in the gene bodies of POLA2 (FDR = 1.04x10-11), PLAAT3 (FDR = 7.22x10-03), and CCDC88B (FDR = 1.89x10-02) that have been associated with cardiovascular and hematological traits in previous studies. One of the most relevant interactions correlated with hypermethylation of CCDC88B. This gene is involved in the inflammatory response, and its methylation and expression levels have been previously reported in Chagas cardiomyopathy. Our findings support the functional relevance of the previously associated genomic region, highlighting the regulation of novel genes that could play a role in the chronic cardiac form of the disease. Author summary Genome-wide association studies (GWAS) have provided extensive information regarding the genetic component of complex traits, including parasitic diseases such as Chagas disease. However, these associations mapped in regulatory regions of the genome and assigning them a functional consequence have been cumbersome. In this study we aimed to evaluate the functional mechanism underlying the previously reported genomic association with chronic Chagas cardiomyopathy, by assessing the correlation between methylation changes and the underlying genetic variations within the region. These methylation quantitative trait loci (mQTLs) may be involved in gene expression regulation. We identified mQTLs in three genes that have been associated with cardiovascular diseases in previous studies. Interestingly, one of these genes was previously identified as differentially methylated and expressed in heart biopsies of chronic Chagas cardiomyopathy patients. Our results suggest novel genes that could play a role in the chronic Chagas cardiomyopathy, evidencing the functional relevance of the previously associated loci.Desiré Casares-MarfilMartin KerickEduardo Andrés-LeónPau Bosch-NicolauIsrael MolinaChagas Genetics CYTED NetworkJavier MartinMarialbert Acosta-HerreraPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 15, Iss 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
spellingShingle	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Desiré Casares-Marfil Martin Kerick Eduardo Andrés-León Pau Bosch-Nicolau Israel Molina Chagas Genetics CYTED Network Javier Martin Marialbert Acosta-Herrera GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels
description	A recent genome-wide association study (GWAS) identified a locus in chromosome 11 associated with the chronic cardiac form of Chagas disease. Here we aimed to elucidate the potential functional mechanism underlying this genetic association by analyzing the correlation among single nucleotide polymorphisms (SNPs) and DNA methylation (DNAm) levels as cis methylation quantitative trait loci (cis-mQTL) within this region. A total of 2,611 SNPs were tested against 2,647 DNAm sites, in a subset of 37 chronic Chagas cardiomyopathy patients and 20 asymptomatic individuals from the GWAS. We identified 6,958 significant cis-mQTLs (False Discovery Rate [FDR]<0.05) at 1 Mb each side of the GWAS leading variant, where six of them potentially modulate the expression of the SAC3D1 gene, the reported gene in the previous GWAS. In addition, a total of 268 cis-mQTLs showed differential methylation between chronic Chagas cardiomyopathy patients and asymptomatic individuals. The most significant cis-mQTLs mapped in the gene bodies of POLA2 (FDR = 1.04x10-11), PLAAT3 (FDR = 7.22x10-03), and CCDC88B (FDR = 1.89x10-02) that have been associated with cardiovascular and hematological traits in previous studies. One of the most relevant interactions correlated with hypermethylation of CCDC88B. This gene is involved in the inflammatory response, and its methylation and expression levels have been previously reported in Chagas cardiomyopathy. Our findings support the functional relevance of the previously associated genomic region, highlighting the regulation of novel genes that could play a role in the chronic cardiac form of the disease. Author summary Genome-wide association studies (GWAS) have provided extensive information regarding the genetic component of complex traits, including parasitic diseases such as Chagas disease. However, these associations mapped in regulatory regions of the genome and assigning them a functional consequence have been cumbersome. In this study we aimed to evaluate the functional mechanism underlying the previously reported genomic association with chronic Chagas cardiomyopathy, by assessing the correlation between methylation changes and the underlying genetic variations within the region. These methylation quantitative trait loci (mQTLs) may be involved in gene expression regulation. We identified mQTLs in three genes that have been associated with cardiovascular diseases in previous studies. Interestingly, one of these genes was previously identified as differentially methylated and expressed in heart biopsies of chronic Chagas cardiomyopathy patients. Our results suggest novel genes that could play a role in the chronic Chagas cardiomyopathy, evidencing the functional relevance of the previously associated loci.
format	article
author	Desiré Casares-Marfil Martin Kerick Eduardo Andrés-León Pau Bosch-Nicolau Israel Molina Chagas Genetics CYTED Network Javier Martin Marialbert Acosta-Herrera
author_facet	Desiré Casares-Marfil Martin Kerick Eduardo Andrés-León Pau Bosch-Nicolau Israel Molina Chagas Genetics CYTED Network Javier Martin Marialbert Acosta-Herrera
author_sort	Desiré Casares-Marfil
title	GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels
title_short	GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels
title_full	GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels
title_fullStr	GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels
title_full_unstemmed	GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels
title_sort	gwas loci associated with chagas cardiomyopathy influences dna methylation levels
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/cf1f6ec80ef34ecc938e4827580116eb
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GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels

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