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 Tegner; Mark Slee; Helmut Butzkueven; Ingrid Kockum; Lara Kular; Vilija G. Jokubaitis; Vilija G. Jokubaitis; Lars Alfredsson; Lars Alfredsson; Anne-Louise Ponsonby; Bruce V. Taylor; Rodney J. Scott; Rodney J. Scott; Jeannette Lechner-Scott; Ausimmune/AusLong Investigators Group

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 Tegner, Mark Slee, Helmut Butzkueven, Ingrid Kockum, Lara Kular, Vilija G. Jokubaitis, Vilija G. Jokubaitis, Lars Alfredsson, Lars Alfredsson, Anne-Louise Ponsonby, Bruce V. Taylor, Rodney J. Scott, Rodney J. Scott, Jeannette Lechner-Scott, Ausimmune/AusLong Investigators Group

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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 (US)
Pages (from-to)	12576
Journal	International journal of molecular sciences
Volume	24
Issue number	16
DOIs	https://doi.org/10.3390/ijms241612576
State	Published - Aug 8 2023

Bibliographical note

KAUST Repository Item: Exported on 2023-09-06
Acknowledgements: This study was supported by the following funding bodies: NHMRC (AusLong) grant APP1127819, NMSS (AusImmune) grant RG-1803-30499, and MSRA (severity study) grant 18-0424. The authors acknowledge support from the National Genomics Infrastructure in Stockholm funded by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation and the Swedish Research Council, and SNIC/Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. The Ausimmune/AusLong investigators group: Robyn Lucas (National Centre for Epidemiology and Population Health, Canberra), Keith Dear (Duke Kunshan University, Kunshan, China), Ingrid van der Mei, Leigh Blizzard, Steve Simpson-Yap, Simon Broadley (Griffith University, Gold Coast, Australia), David Williams, Cameron Shaw and Caron Chapman (Barwon Health, Geelong, Australia), Alan Coulthard (University of Queensland, Brisbane, Australia), and Patricia Valery (QIMR Berghofer Medical Research Institute, Brisbane, Australia), as well as Terry Doyer and Michael Pender. The authors would also like to acknowledge Peri Noori and David Gomez-Cabrero for their contribution to the work on isolated B cells. Finally, the authors would like to thank all the pwMS and control subjects who participated in this research.

ASJC Scopus subject areas

Organic Chemistry
Spectroscopy
Molecular Biology
Catalysis
Physical and Theoretical Chemistry
Inorganic Chemistry
Computer Science Applications

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https://repository.kaust.edu.sa/bitstream/10754/690158/6/ijms-24-12576.pdf

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Xavier, A., Maltby, V. E., Ewing, E., Campagna, M. P., Burnard, S. M., Tegner, J., Slee, M., Butzkueven, H., Kockum, I., Kular, L., Jokubaitis, V. G., Jokubaitis, V. G., Alfredsson, L., Alfredsson, L., Ponsonby, A.-L., Taylor, B. V., Scott, R. J., Scott, R. J., Lechner-Scott, J., & Group, AA. I. (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), 12576. https://doi.org/10.3390/ijms241612576

@article{a6c3cc5bf2504475bd3e8927329223a1,

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.",

author = "Alexandre Xavier and Maltby, {Vicki E.} and Ewoud Ewing and Campagna, {Maria Pia} and Burnard, {Sean M.} and Jesper Tegner and Mark Slee and Helmut Butzkueven and Ingrid Kockum and Lara Kular and Jokubaitis, {Vilija G.} and Jokubaitis, {Vilija G.} and Lars Alfredsson and Lars Alfredsson and Anne-Louise Ponsonby and Taylor, {Bruce V.} and Scott, {Rodney J.} and Scott, {Rodney J.} and Jeannette Lechner-Scott and Group, {Ausimmune/AusLong Investigators}",

note = "KAUST Repository Item: Exported on 2023-09-06 Acknowledgements: This study was supported by the following funding bodies: NHMRC (AusLong) grant APP1127819, NMSS (AusImmune) grant RG-1803-30499, and MSRA (severity study) grant 18-0424. The authors acknowledge support from the National Genomics Infrastructure in Stockholm funded by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation and the Swedish Research Council, and SNIC/Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. The Ausimmune/AusLong investigators group: Robyn Lucas (National Centre for Epidemiology and Population Health, Canberra), Keith Dear (Duke Kunshan University, Kunshan, China), Ingrid van der Mei, Leigh Blizzard, Steve Simpson-Yap, Simon Broadley (Griffith University, Gold Coast, Australia), David Williams, Cameron Shaw and Caron Chapman (Barwon Health, Geelong, Australia), Alan Coulthard (University of Queensland, Brisbane, Australia), and Patricia Valery (QIMR Berghofer Medical Research Institute, Brisbane, Australia), as well as Terry Doyer and Michael Pender. The authors would also like to acknowledge Peri Noori and David Gomez-Cabrero for their contribution to the work on isolated B cells. Finally, the authors would like to thank all the pwMS and control subjects who participated in this research.",

year = "2023",

month = aug,

day = "8",

doi = "10.3390/ijms241612576",

language = "English (US)",

volume = "24",

pages = "12576",

journal = "International journal of molecular sciences",

issn = "1422-0067",

publisher = "MDPI",

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Xavier, A, Maltby, VE, Ewing, E, Campagna, MP, Burnard, SM, Tegner, J, Slee, M, Butzkueven, H, Kockum, I, Kular, L, Jokubaitis, VG, Jokubaitis, VG, Alfredsson, L, Alfredsson, L, Ponsonby, A-L, Taylor, BV, Scott, RJ, Scott, RJ, Lechner-Scott, J & Group, AAI 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, pp. 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

AU - Slee, Mark

AU - Butzkueven, Helmut

AU - Kockum, Ingrid

AU - Kular, Lara

AU - Jokubaitis, Vilija G.

AU - Alfredsson, Lars

AU - Ponsonby, Anne-Louise

AU - Taylor, Bruce V.

AU - Scott, Rodney J.

AU - Lechner-Scott, Jeannette

AU - Group, Ausimmune/AusLong Investigators

N1 - KAUST Repository Item: Exported on 2023-09-06 Acknowledgements: This study was supported by the following funding bodies: NHMRC (AusLong) grant APP1127819, NMSS (AusImmune) grant RG-1803-30499, and MSRA (severity study) grant 18-0424. The authors acknowledge support from the National Genomics Infrastructure in Stockholm funded by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation and the Swedish Research Council, and SNIC/Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. The Ausimmune/AusLong investigators group: Robyn Lucas (National Centre for Epidemiology and Population Health, Canberra), Keith Dear (Duke Kunshan University, Kunshan, China), Ingrid van der Mei, Leigh Blizzard, Steve Simpson-Yap, Simon Broadley (Griffith University, Gold Coast, Australia), David Williams, Cameron Shaw and Caron Chapman (Barwon Health, Geelong, Australia), Alan Coulthard (University of Queensland, Brisbane, Australia), and Patricia Valery (QIMR Berghofer Medical Research Institute, Brisbane, Australia), as well as Terry Doyer and Michael Pender. The authors would also like to acknowledge Peri Noori and David Gomez-Cabrero for their contribution to the work on isolated B cells. Finally, the authors would like to thank all the pwMS and control subjects who participated in this research.

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.

UR - http://hdl.handle.net/10754/690158

UR - https://www.mdpi.com/1422-0067/24/16/12576

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

U2 - 10.3390/ijms241612576

DO - 10.3390/ijms241612576

M3 - Article

C2 - 37628757

SN - 1422-0067

VL - 24

SP - 12576

JO - International journal of molecular sciences

JF - International journal of molecular sciences

IS - 16

ER -

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

Abstract

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