Hypomethylation mediates genetic association with the major histocompatibility complex genes in Sjögren’s syndrome

Differential methylation of immune genes has been a consistent theme observed in Sjögren’s syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and labial salivary glands (LSGs). Multiple studies have found associations supporting genetic control of DNA methylation in SS, which in the absence...

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Published inPloS one Vol. 16; no. 4; p. e0248429
Main Authors Chi, Calvin, Taylor, Kimberly E., Quach, Hong, Quach, Diana, Criswell, Lindsey A., Barcellos, Lisa F.
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 22.04.2021
Public Library of Science (PLoS)
Subjects
Adult
Biology and life sciences
Care and treatment
Computer applications
CpG islands
Data processing
Development and progression
Disease
DNA Methylation
DNA probes
Engineering schools
Epidemiology
Epigenesis, Genetic
Epigenetics
Female
Gene expression
Gene loci
Genetic aspects
Genomes
Genomics
Health aspects
Health risk assessment
Health risks
Humans
Laboratories
Major Histocompatibility Complex
Medicine and Health Sciences
Methylation
Middle Aged
Morbidity
Outdoor air quality
Principal components analysis
Probes
Public health
Quality control
Quantitative Trait Loci
Questioning
Research facilities
Rheumatology
Sjogren's syndrome
Sjogren's Syndrome - genetics
United States
United States > US
San Francisco California
California
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Abstract Differential methylation of immune genes has been a consistent theme observed in Sjögren’s syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and labial salivary glands (LSGs). Multiple studies have found associations supporting genetic control of DNA methylation in SS, which in the absence of reverse causation, has positive implications for the potential of epigenetic therapy. However, a formal study of the causal relationship between genetic variation, DNA methylation, and disease status is lacking. We performed a causal mediation analysis of DNA methylation as a mediator of nearby genetic association with SS using LSGs and genotype data collected from 131 female members of the Sjögren’s International Collaborative Clinical Alliance registry, comprising of 64 SS cases and 67 non-cases. Bumphunter was used to first identify differentially-methylated regions (DMRs), then the causal inference test (CIT) was applied to identify DMRs mediating the association of nearby methylation quantitative trait loci (MeQTL) with SS. Bumphunter discovered 215 DMRs, with the majority located in the major histocompatibility complex (MHC) on chromosome 6p21.3. Consistent with previous findings, regions hypomethylated in SS cases were enriched for gene sets associated with immune processes. Using the CIT, we observed a total of 19 DMR-MeQTL pairs that exhibited strong evidence for a causal mediation relationship. Close to half of these DMRs reside in the MHC and their corresponding meQTLs are in the region spanning the HLA-DQA1 , HLA-DQB1 , and HLA-DQA2 loci. The risk of SS conferred by these corresponding MeQTLs in the MHC was further substantiated by previous genome-wide association study results, with modest evidence for independent effects. By validating the presence of causal mediation, our findings suggest both genetic and epigenetic factors contribute to disease susceptibility, and inform the development of targeted epigenetic modification as a therapeutic approach for SS.
AbstractList Differential methylation of immune genes has been a consistent theme observed in Sjögren's syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and labial salivary glands (LSGs). Multiple studies have found associations supporting genetic control of DNA methylation in SS, which in the absence of reverse causation, has positive implications for the potential of epigenetic therapy. However, a formal study of the causal relationship between genetic variation, DNA methylation, and disease status is lacking. We performed a causal mediation analysis of DNA methylation as a mediator of nearby genetic association with SS using LSGs and genotype data collected from 131 female members of the Sjögren's International Collaborative Clinical Alliance registry, comprising of 64 SS cases and 67 non-cases. Bumphunter was used to first identify differentially-methylated regions (DMRs), then the causal inference test (CIT) was applied to identify DMRs mediating the association of nearby methylation quantitative trait loci (MeQTL) with SS. Bumphunter discovered 215 DMRs, with the majority located in the major histocompatibility complex (MHC) on chromosome 6p21.3. Consistent with previous findings, regions hypomethylated in SS cases were enriched for gene sets associated with immune processes. Using the CIT, we observed a total of 19 DMR-MeQTL pairs that exhibited strong evidence for a causal mediation relationship. Close to half of these DMRs reside in the MHC and their corresponding meQTLs are in the region spanning the HLA-DQA1, HLA-DQB1, and HLA-DQA2 loci. The risk of SS conferred by these corresponding MeQTLs in the MHC was further substantiated by previous genome-wide association study results, with modest evidence for independent effects. By validating the presence of causal mediation, our findings suggest both genetic and epigenetic factors contribute to disease susceptibility, and inform the development of targeted epigenetic modification as a therapeutic approach for SS.
About the Authors: Calvin Chi Roles Formal analysis, Methodology, Visualization, Writing – original draft Affiliations Center for Computational Biology, College of Engineering, University of California, Berkeley, Berkeley, California, United States of America, Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America ORCID logo https://orcid.org/0000-0002-4757-0559 Kimberly E. Taylor Roles Data curation, Resources, Writing – review & editing Affiliation: Department of Medicine, Russell/Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, California, United States of America Hong Quach Roles Data curation, Project administration Affiliation: Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America Diana Quach Roles Data curation, Project administration Affiliation: Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America Lindsey A. Criswell Contributed equally to this work with: [...]we performed the causal inference test (CIT) developed by Millstein et al. to find DMR-meQTL pairs where the DMR shows strong evidence of mediating the risk of surrounding meQTLs on SS [24]. [...]probes identified with probe-binding specificity and polymorphic targets problems, or cross-reactive probes, were removed [36, 37]. The final processed dataset consisted of 336,040 CpG sites. Since no subject had more than 5% of probes with detection p-value > 0.01, all 131 subjects were retained.
Differential methylation of immune genes has been a consistent theme observed in Sjögren’s syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and labial salivary glands (LSGs). Multiple studies have found associations supporting genetic control of DNA methylation in SS, which in the absence of reverse causation, has positive implications for the potential of epigenetic therapy. However, a formal study of the causal relationship between genetic variation, DNA methylation, and disease status is lacking. We performed a causal mediation analysis of DNA methylation as a mediator of nearby genetic association with SS using LSGs and genotype data collected from 131 female members of the Sjögren’s International Collaborative Clinical Alliance registry, comprising of 64 SS cases and 67 non-cases. Bumphunter was used to first identify differentially-methylated regions (DMRs), then the causal inference test (CIT) was applied to identify DMRs mediating the association of nearby methylation quantitative trait loci (MeQTL) with SS. Bumphunter discovered 215 DMRs, with the majority located in the major histocompatibility complex (MHC) on chromosome 6p21.3. Consistent with previous findings, regions hypomethylated in SS cases were enriched for gene sets associated with immune processes. Using the CIT, we observed a total of 19 DMR-MeQTL pairs that exhibited strong evidence for a causal mediation relationship. Close to half of these DMRs reside in the MHC and their corresponding meQTLs are in the region spanning the HLA-DQA1 , HLA-DQB1 , and HLA-DQA2 loci. The risk of SS conferred by these corresponding MeQTLs in the MHC was further substantiated by previous genome-wide association study results, with modest evidence for independent effects. By validating the presence of causal mediation, our findings suggest both genetic and epigenetic factors contribute to disease susceptibility, and inform the development of targeted epigenetic modification as a therapeutic approach for SS.
Differential methylation of immune genes has been a consistent theme observed in Sjögren's syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and labial salivary glands (LSGs). Multiple studies have found associations supporting genetic control of DNA methylation in SS, which in the absence of reverse causation, has positive implications for the potential of epigenetic therapy. However, a formal study of the causal relationship between genetic variation, DNA methylation, and disease status is lacking. We performed a causal mediation analysis of DNA methylation as a mediator of nearby genetic association with SS using LSGs and genotype data collected from 131 female members of the Sjögren's International Collaborative Clinical Alliance registry, comprising of 64 SS cases and 67 non-cases. Bumphunter was used to first identify differentially-methylated regions (DMRs), then the causal inference test (CIT) was applied to identify DMRs mediating the association of nearby methylation quantitative trait loci (MeQTL) with SS. Bumphunter discovered 215 DMRs, with the majority located in the major histocompatibility complex (MHC) on chromosome 6p21.3. Consistent with previous findings, regions hypomethylated in SS cases were enriched for gene sets associated with immune processes. Using the CIT, we observed a total of 19 DMR-MeQTL pairs that exhibited strong evidence for a causal mediation relationship. Close to half of these DMRs reside in the MHC and their corresponding meQTLs are in the region spanning the HLA-DQA1, HLA-DQB1, and HLA-DQA2 loci. The risk of SS conferred by these corresponding MeQTLs in the MHC was further substantiated by previous genome-wide association study results, with modest evidence for independent effects. By validating the presence of causal mediation, our findings suggest both genetic and epigenetic factors contribute to disease susceptibility, and inform the development of targeted epigenetic modification as a therapeutic approach for SS.Differential methylation of immune genes has been a consistent theme observed in Sjögren's syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and labial salivary glands (LSGs). Multiple studies have found associations supporting genetic control of DNA methylation in SS, which in the absence of reverse causation, has positive implications for the potential of epigenetic therapy. However, a formal study of the causal relationship between genetic variation, DNA methylation, and disease status is lacking. We performed a causal mediation analysis of DNA methylation as a mediator of nearby genetic association with SS using LSGs and genotype data collected from 131 female members of the Sjögren's International Collaborative Clinical Alliance registry, comprising of 64 SS cases and 67 non-cases. Bumphunter was used to first identify differentially-methylated regions (DMRs), then the causal inference test (CIT) was applied to identify DMRs mediating the association of nearby methylation quantitative trait loci (MeQTL) with SS. Bumphunter discovered 215 DMRs, with the majority located in the major histocompatibility complex (MHC) on chromosome 6p21.3. Consistent with previous findings, regions hypomethylated in SS cases were enriched for gene sets associated with immune processes. Using the CIT, we observed a total of 19 DMR-MeQTL pairs that exhibited strong evidence for a causal mediation relationship. Close to half of these DMRs reside in the MHC and their corresponding meQTLs are in the region spanning the HLA-DQA1, HLA-DQB1, and HLA-DQA2 loci. The risk of SS conferred by these corresponding MeQTLs in the MHC was further substantiated by previous genome-wide association study results, with modest evidence for independent effects. By validating the presence of causal mediation, our findings suggest both genetic and epigenetic factors contribute to disease susceptibility, and inform the development of targeted epigenetic modification as a therapeutic approach for SS.
About the Authors: Calvin Chi Roles Formal analysis, Methodology, Visualization, Writing – original draft Affiliations Center for Computational Biology, College of Engineering, University of California, Berkeley, Berkeley, California, United States of America, Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America ORCID logo https://orcid.org/0000-0002-4757-0559 Kimberly E. Taylor Roles Data curation, Resources, Writing – review & editing Affiliation: Department of Medicine, Russell/Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, California, United States of America Hong Quach Roles Data curation, Project administration Affiliation: Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America Diana Quach Roles Data curation, Project administration Affiliation: Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America Lindsey A. Criswell Contributed equally to this work with: [...]we performed the causal inference test (CIT) developed by Millstein et al. to find DMR-meQTL pairs where the DMR shows strong evidence of mediating the risk of surrounding meQTLs on SS [24]. [...]probes identified with probe-binding specificity and polymorphic targets problems, or cross-reactive probes, were removed [36, 37]. The final processed dataset consisted of 336,040 CpG sites. Since no subject had more than 5% of probes with detection p-value > 0.01, all 131 subjects were retained.
Audience Academic
Author Barcellos, Lisa F.
Quach, Hong
Criswell, Lindsey A.
Taylor, Kimberly E.
Quach, Diana
Chi, Calvin
AuthorAffiliation 1 Center for Computational Biology, College of Engineering, University of California, Berkeley, Berkeley, California, United States of America
3 Department of Medicine, Russell/Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, California, United States of America
Beth Israel Deaconess Medical Center-Harvard Medical School, UNITED STATES
2 Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America
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Snippet Differential methylation of immune genes has been a consistent theme observed in Sjögren’s syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and...
Differential methylation of immune genes has been a consistent theme observed in Sjögren's syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and...
About the Authors: Calvin Chi Roles Formal analysis, Methodology, Visualization, Writing – original draft Affiliations Center for Computational Biology,...
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SubjectTerms Adult
Biology and life sciences
Care and treatment
Computer applications
CpG islands
Data processing
Development and progression
Disease
DNA Methylation
DNA probes
Engineering schools
Epidemiology
Epigenesis, Genetic
Epigenetics
Female
Gene expression
Gene loci
Genetic aspects
Genomes
Genomics
Health aspects
Health risk assessment
Health risks
Humans
Laboratories
Major Histocompatibility Complex
Medicine and Health Sciences
Methylation
Middle Aged
Morbidity
Outdoor air quality
Principal components analysis
Probes
Public health
Quality control
Quantitative Trait Loci
Questioning
Research facilities
Rheumatology
Sjogren's syndrome
Sjogren's Syndrome - genetics
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Title Hypomethylation mediates genetic association with the major histocompatibility complex genes in Sjögren’s syndrome
URI https://www.ncbi.nlm.nih.gov/pubmed/33886574
https://www.proquest.com/docview/2516826538
https://www.proquest.com/docview/2518224543
https://pubmed.ncbi.nlm.nih.gov/PMC8062105
https://doaj.org/article/c11b66334bc24771b69701ce39d609d6
http://dx.doi.org/10.1371/journal.pone.0248429
Volume 16
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