DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes

Alexandre Xavier; Vicki E. Maltby; Ewoud Ewing; Maria Pia Campagna; Sean M. Burnard; Jesper N. Tegner; Mark Slee; Helmut Butzkueven; Ingrid Kockum; Lara Kular; Ausimmune/AusLong Investigators Group; Vilija G. Jokubaitis; Trevor Kilpatrick; Lars Alfredsson; Maja Jagodic; Anne Louise Ponsonby; Bruce V. Taylor; Rodney J. Scott; Rodney A. Lea; Jeannette Lechner-Scott

doi:10.3390/ijms241612576

DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes

Alexandre Xavier, Vicki E. Maltby, Ewoud Ewing, Maria Pia Campagna, Sean M. Burnard, Jesper N. Tegner, Mark Slee, Helmut Butzkueven, Ingrid Kockum, Lara Kular, Ausimmune/AusLong Investigators Group, Vilija G. Jokubaitis, Trevor Kilpatrick, Lars Alfredsson, Maja Jagodic, Anne Louise Ponsonby, Bruce V. Taylor, Rodney J. Scott, Rodney A. Lea, Jeannette Lechner-Scott

College of Medicine and Public Health

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Abstract

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10⁻²⁹) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10⁻¹⁷). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.

Original language	English
Article number	12576
Number of pages	20
Journal	International Journal of Molecular Sciences
Volume	24
Issue number	16
DOIs	https://doi.org/10.3390/ijms241612576
Publication status	Published - 8 Aug 2023

Keywords

cell deconvolution
epigenetics
epigenome-wide association studies
genetic risk
methylation
multiple sclerosis

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Final published versionFinal published version, 3.51 MBLicence: CC BY

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Xavier, A., Maltby, V. E., Ewing, E., Campagna, M. P., Burnard, S. M., Tegner, J. N., Slee, M., Butzkueven, H., Kockum, I., Kular, L., Ausimmune/AusLong Investigators Group, Jokubaitis, V. G., Kilpatrick, T., Alfredsson, L., Jagodic, M., Ponsonby, A. L., Taylor, B. V., Scott, R. J., Lea, R. A., & Lechner-Scott, J. (2023). DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes. International Journal of Molecular Sciences, 24(16), Article 12576. https://doi.org/10.3390/ijms241612576

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title = "DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes",

abstract = "Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10−29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10−17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.",

keywords = "cell deconvolution, epigenetics, epigenome-wide association studies, genetic risk, methylation, multiple sclerosis",

author = "Alexandre Xavier and Maltby, {Vicki E.} and Ewoud Ewing and Campagna, {Maria Pia} and Burnard, {Sean M.} and Tegner, {Jesper N.} and Mark Slee and Helmut Butzkueven and Ingrid Kockum and Lara Kular and {Ausimmune/AusLong Investigators Group} and Jokubaitis, {Vilija G.} and Trevor Kilpatrick and Lars Alfredsson and Maja Jagodic and Ponsonby, {Anne Louise} and Taylor, {Bruce V.} and Scott, {Rodney J.} and Lea, {Rodney A.} and Jeannette Lechner-Scott and Robyn Lucas and Keith Dear and {van der Mei}, Ingrid and Leigh Blizzard and Steve Simpson-Yap and Simon Broadley and David Williams and Cameron Shaw and Caron Chapman and Alan Coulthard and Valery, {Patricia C.}",

year = "2023",

month = aug,

day = "8",

doi = "10.3390/ijms241612576",

language = "English",

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journal = "International Journal of Molecular Sciences",

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Xavier, A, Maltby, VE, Ewing, E, Campagna, MP, Burnard, SM, Tegner, JN, Slee, M, Butzkueven, H, Kockum, I, Kular, L, Ausimmune/AusLong Investigators Group, Jokubaitis, VG, Kilpatrick, T, Alfredsson, L, Jagodic, M, Ponsonby, AL, Taylor, BV, Scott, RJ, Lea, RA & Lechner-Scott, J 2023, 'DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes', International Journal of Molecular Sciences, vol. 24, no. 16, 12576. https://doi.org/10.3390/ijms241612576

TY - JOUR

T1 - DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes

AU - Xavier, Alexandre

AU - Maltby, Vicki E.

AU - Ewing, Ewoud

AU - Campagna, Maria Pia

AU - Burnard, Sean M.

AU - Tegner, Jesper N.

AU - Slee, Mark

AU - Butzkueven, Helmut

AU - Kockum, Ingrid

AU - Kular, Lara

AU - Ausimmune/AusLong Investigators Group

AU - Jokubaitis, Vilija G.

AU - Kilpatrick, Trevor

AU - Alfredsson, Lars

AU - Jagodic, Maja

AU - Ponsonby, Anne Louise

AU - Taylor, Bruce V.

AU - Scott, Rodney J.

AU - Lea, Rodney A.

AU - Lechner-Scott, Jeannette

AU - Lucas, Robyn

AU - Dear, Keith

AU - van der Mei, Ingrid

AU - Blizzard, Leigh

AU - Simpson-Yap, Steve

AU - Broadley, Simon

AU - Williams, David

AU - Shaw, Cameron

AU - Chapman, Caron

AU - Coulthard, Alan

AU - Valery, Patricia C.

PY - 2023/8/8

Y1 - 2023/8/8

N2 - Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10−29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10−17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.

AB - Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10−29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10−17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.

KW - cell deconvolution

KW - epigenetics

KW - epigenome-wide association studies

KW - genetic risk

KW - methylation

KW - multiple sclerosis

UR - http://www.scopus.com/inward/record.url?scp=85168747799&partnerID=8YFLogxK

UR - http://purl.org/au-research/grants/NHMRC/1127819

U2 - 10.3390/ijms241612576

DO - 10.3390/ijms241612576

M3 - Article

C2 - 37628757

AN - SCOPUS:85168747799

SN - 1661-6596

VL - 24

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 16

M1 - 12576

ER -

DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes

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