Antonino Giordano1, Maria Needhamsen1, Klementy Shchetynsky1, Pernilla Stridh1, Adil Harroud2, Christiane Gasperi3, Iaroslav Zinevych3, Kimmo Paakkonen 4, Paivi Lahermo4, Sandra D'Alfonso5, Nadia Barizzone5, Paola Cavalla6, Antonio Gallo7, Elena Chinni8, Bernhard Hemmer3, Martina Clara Flaskamp3, Paula Uibel3, Fredrik Piehl1, Federica Esposito9, Elisabetta Mascia9, Melissa Sorosina9, Massimo Filippi9, Stefan Gustavsen10, Anna Olsson10, Helle Bach Søndergaard10, Annette Oturai10, Benedicte Dubois11, Hanne Catherine Flinstad Harbo12, Tone Berge13, Steffan Daniel Bos12, Pablo Villoslada14, Sara Llufriu15, Filippo Martinelli Boneschi16, Roland Liblau17, Beatrice Pignolet17, Ingrid Kockum1, Stephan Beck18, Janna Saarela4, Maja Jagodic1
1Department of Clinical Neuroscience, Karolinska Institutet, 2McGill University, 3Department of Neurology, School of Medicine, Technical University of Munich, 4Institute for Molecular Medicine Finland, Helsinki Institute for Life Sciences, University of Helsinki, 5Department of Health Sciences, Amedeo Avogadro University of Eastern Piedmont, 6Department of Neuroscience and Mental Health, City of Health and Science University Hospital of Torino, 7Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania Luigi Vanvitelli, 8Fondazione IRCCS Casa Sollievo Della Sofferenza, 9Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 10Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, 11Leuven Brain Institute, 12Department of Neurology, 13Department of Research, Innovation and Education, Oslo University Hospital, 14Hospital del Mar - Pompeu Fabra University, 15Institut d’Investigacions Biomedicas August Pi Sunyer and Department of Neurology, Hospital Clínic de Barcelona, 16University of Milan, 17Université Toulouse III, Infinity - Institut Toulousain des Maladies Infectieuses et Inflammatoires, 18Medical Genomics, University College London Cancer Institute
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.
Background:
Genetic factors explain approximately half of MS heritability, but the mechanisms through which they act are still largely unknown.
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.