Abstract Details

Title Impact of Genetic Susceptibility on Multiple Sclerosis Immune Methylome

Topic Multiple Sclerosis

Presentation(s) S17 - Multiple Sclerosis: Immunology/Basic Sciences (2:00 PM-2:12 PM)

Poster/Presentation
Number 006

Background Genetic factors explain approximately half of MS heritability, but the mechanisms through which they act are still largely unknown.

Objective To investigate if Multiple Sclerosis (MS) risk variants drive changes in DNA methylation and whether such changes colocalize implicating the variants that influence both MS risk and gene methylation.

Design/Methods Combining whole-genome DNA methylation from Illumina EPIC arrays and high-density genetic data, we performed genome-wide mapping of cis- (±1MB) and trans- (>1MB and inter-chromosomal) methylation Quantitative-Trait-Loci (meQTL), investigating ~780,000 CpGs and ~7.7 million Single Nucleotide Polymorphisms (SNPs) in whole blood from 426 MS patients from 9 European centers, adjusting for technical and sample-related factors and controlling for multiple testing using FDR.

Results We found that ~20% (151,855 CpGs) of the methylome in MS is influenced in cis by genetic variation. Trans-meQTL analysis detected 7 trans-chromosomal and 1 intra-chromosomal interaction. The vast majority (99%, 59,051/59,494) of testable overlapping meQTLs had previously been identified in a study based on ~32,000 healthy controls (GoDMC, 2021). Interestingly, 357 cis-meQTLs showed an opposite direction of effect in MS. Replication in peripheral blood mononuclear cells from 433 patients from the MultipleMS cohort and in an independent Italian and French cohort of 202 MS patients confirmed that 30% (109/357) meQTL effects are different between MS and controls. To investigate whether genetic variation drives both MS risk and DNA methylation, we utilized an extended Polygenic Risk Score comprising 585 SNPs, derived from the MultipleMS project. A Bayesian colocalization analysis identified ~30% (187/585) loci that affect both MS susceptibility and DNA methylation and are enriched in different immune processes.

Conclusions Identification of meQTLs, which differ in direction of effect between MS and controls, could reflect a relevant contribution from external factors. One-third of tested genetic risk for MS colocalizes with changes in DNA methylation forming solid basis for functional hypothesis.

Authors/Disclosures
Antonino Giordano (San Raffaele Scientific Institute) PRESENTER	Mr. Giordano has nothing to disclose.
Maria Needhamsen	No disclosure on file
Klementy Shchetynsky (Karolinska Institutet)	No disclosure on file
Pernilla Stridh (Karolinska Institutet)	No disclosure on file
Adil Harroud, MD (McGill University)	Dr. Harroud has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Dr. Harroud has received research support from National Multiple Sclerosis Society. The institution of Dr. Harroud has received research support from Multiple Sclerosis Society of Canada.
Christiane Gasperi	No disclosure on file
Iaroslav Zinevych	No disclosure on file
Kimmo Pääkkönen	No disclosure on file
Päivi Lahermo (University of Helsinki)	No disclosure on file
Sandra D'Alfonso	No disclosure on file
Nadia Barizzone (University of Eastern Piedmont)	No disclosure on file
Paola Cavalla	No disclosure on file
Antonio Gallo	Antonio Gallo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Antonio Gallo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Antonio Gallo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Antonio Gallo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis.
Elena Chinni (I.R.C.C.S Casa Sollievo della Sofferenza)	No disclosure on file
Bernhard Hemmer	No disclosure on file
Martina Flaskamp	No disclosure on file
Paula Uibel	No disclosure on file
Fredrik L. Piehl, MD, PhD (Neuroimmunology Unit, Dept Clinical Neuroscience, Karolinska Institutet)	Dr. Piehl has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Parexel/Chugai. The institution of Dr. Piehl has received research support from UCB. The institution of Dr. Piehl has received research support from Merck KGaA. Dr. Piehl has received personal compensation in the range of $10,000-$49,999 for serving as a member scientific advisory board with Swedish Medical products Agency.
Federica Esposito	Federica Esposito has received personal compensation in the range of $0-$499 for serving as a Consultant for Merck. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Federica Esposito has received personal compensation in the range of $0-$499 for serving as a Consultant for Novartis. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. The institution of Federica Esposito has received research support from Italian MS Society. The institution of Federica Esposito has received research support from Italian Ministry of Health. The institution of Federica Esposito has received research support from ERA Net. The institution of Federica Esposito has received research support from European Commission. Federica Esposito has received intellectual property interests from a discovery or technology relating to health care.
Elisabetta Mascia	No disclosure on file
Melissa Sorosina	No disclosure on file
Massimo Filippi, MD, FAAN (Ospedale San Raffaele, Neuroimaging Research Unit)	Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi;. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi- Genzyme, Takeda. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla.
Stefan Gustavsen (Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University)	No disclosure on file
Anna Olsson	No disclosure on file
Helle B. Sondergaard, PhD (Danish MS Center, University Hospital Rigshospitalet)	Dr. Sondergaard has nothing to disclose.
Annette Bang Oturai, MD	Dr. Oturai has nothing to disclose.
Benedicte Dubois (UZ Leuven)	No disclosure on file
Hanne H (Faculty of Medicine, University of Oslo)	No disclosure on file
Tone Berge	No disclosure on file
Steffan Bos	No disclosure on file
Pablo Villoslada, MD, PhD, FAAN (Hospital del Mar - Pompeu Fabra University)	Dr. Villoslada has received personal compensation for serving as an employee of Attune Neuroscience. Dr. Villoslada has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Accure Therapeutics. Dr. Villoslada has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Oculis. Dr. Villoslada has stock in Attune Neurosciences. Dr. Villoslada has stock in Bionure Investments. Dr. Villoslada has stock in Spiral Therapeutics. Dr. Villoslada has stock in Adhera Health. The institution of Dr. Villoslada has received research support from Start2Cure Foundation. The institution of Dr. Villoslada has received research support from NIH. The institution of Dr. Villoslada has received research support from Department of Defense. Dr. Villoslada has received intellectual property interests from a discovery or technology relating to health care.
Sara Llufriu	Sara Llufriu has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Sara Llufriu has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Sara Llufriu has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merci. Sara Llufriu has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbot. Sara Llufriu has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi.
Filippo Martinelli Boneschi	No disclosure on file
Roland Liblau	Roland Liblau has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Roland Liblau has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Roland Liblau has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Roland Liblau has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi-genzyme. Roland Liblau has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Servier. Roland Liblau has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Current Opinion in Immunology. The institution of Roland Liblau has received research support from Roche. The institution of Roland Liblau has received research support from ARSEP. The institution of Roland Liblau has received research support from Fondation pour la Recherche Médicale. The institution of Roland Liblau has received research support from Population Bio UK, Inc. The institution of Roland Liblau has received research support from ANR.
Beatrice Pignolet	Beatrice Pignolet has nothing to disclose.
Ingrid Kockum	No disclosure on file
Stephan Beck (UCL)	No disclosure on file
Janna Saarela (Institute for Molecular Medicine Finland, University of Helsinki)	No disclosure on file
Maja Jagodic (Karolinska Institutet)	No disclosure on file