Mandaviya, Pooja R.Joehanes, RobyAïssi, DylanKühnel, BrigitteMarioni, Riccardo E.Truong, VinhStolk, LisetteBeekman, MarianBonder, Marc JanFranke, LudeGieger, ChristianHuan, TianxiaoIkram, M. ArfanKunze, SonjaLiang, LimingLindemans, JanLiu, ChunyuMcRae, Allan F.Mendelson, Michael M.Müller-Nurasyid, MartinaPeters, AnnetteSlagboom, P. ElineStarr, John M.Trégouët, David-AlexandreUitterlinden, André G.van Greevenbroek, Marleen M. J.van Heemst, Dianavan Iterson, MaartenWells, Philip S.Yao, ChenDeary, Ian J.Gagnon, FranceHeijmans, Bastiaan T.Levy, DanielMorange, Pierre-EmmanuelWaldenberger, MelanieHeil, Sandra G.van Meurs, Joyce B. J.2017-12-062017Mandaviya, P. R., R. Joehanes, D. Aïssi, B. Kühnel, R. E. Marioni, V. Truong, L. Stolk, et al. 2017. “Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes.” PLoS ONE 12 (10): e0182472. doi:10.1371/journal.pone.0182472. http://dx.doi.org/10.1371/journal.pone.0182472.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34493087Background: DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. Methods: Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. Results: Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. Conclusions: Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.en-USBiology and life sciencesCell biologyChromosome biologyChromatinChromatin modificationDNA methylationGeneticsEpigeneticsGene expressionDNADNA modificationBiochemistryNucleic acidsPhysical SciencesChemistryChemical ReactionsMethylationMathematical and Statistical TechniquesStatistical MethodsMeta-AnalysisMathematicsStatistics (Mathematics)Biology and Life SciencesMolecular GeneticsMolecular BiologyGenetic LociCell BiologyCellular TypesAnimal CellsBlood CellsWhite Blood CellsImmune CellsImmunologyMedicine and Health SciencesChromosome BiologyChromosomesAutosomesChromosome PairsSocial SciencesSociologyConsortiaJournal Article2017-12-0610.1371/journal.pone.0182472