Effects of Methyl-Group Metabolism and Lifestyle Factors on Genome-Wide DNA Methylation

The aim of this thesis is to study the association of methyl-group metabolism, nutritional and lifestyle factors with genome-wide DNA methylation. The first section of this thesis includes two literature reviews. Chapter 2 is a literature review of Hcy and its role in DNA methylation. Chapter 3 is a systematic literature review of the relation between micro- and macro- nutrients and DNA methylation in humans across the life course.
The second section of this thesis focuses on a key metabolite of the methyl-group metabolism, Hcy. Chapter 4 is a meta-analysis of EWASs to investigate the association between plasma Hcy and DNA methylation in leukocytes of 2,035 individuals from six cohorts. In Chapter 5, we used genetically defined elevated Hcy as an instrument, i.e. the MTHFR 677C>T variant and the combined weighted genetic risk score of 18 previously studied Hcy-associated variants, to test whether genetically defined elevated Hcy levels are associated with DNA methylation changes in leukocytes of 9,894 individuals from 12 cohorts. In Chapter 6, we conducted an interaction study to investigate the effect of elevated Hcy in individuals by MTHFR 677C>T genotype on genome-wide DNA methylation in leukocytes of 1280 individuals from 2 cohorts.
The third section of this thesis focuses on nutrition and lifestyle factors. Chapter 7 is a meta-analysis of EWASs to investigate the association of folate intake and vitamin B12 intake with DNA methylation in leukocytes of 5,841 participants from 10 cohorts. Chapter 8 focuses on association between cigarette smoking as a lifestyle factor and DNA methylation in leukocyte assessed in 15,907 individuals (2,433 current, 6,518 former, and 6,956 never smokers) from 16 cohorts.