Exogenous factors have been associated with altering DNAm levels, both at specific loci and globally (averaged across all repeat elements), including changes in diet7, and exposure to cigarette smoking8 and arsenic9. Extensive research implicates environmental variables in the development of schizophrenia, especially during fetal and perinatal life, including maternal stress and infections, obstetric complications, and maternal nutrition during pregnancy6. For example, the Dutch famine of 1944–1945 led to a spike in the number of cases of schizophrenia two decades later10. Many of these factors have previously been associated with altering DNA methylation levels11,12. Lastly, several recent papers have explored the role of sequence variation on site- and region-specific DNA methylation13,14. The DNA sequence itself plays a large role in the maintenance of DNAm15, providing one potential mechanism, namely changes in DNAm, for the clinical associations of single nucleotide polymorphism (SNPs) from large genome-wide association studies (GWAS).
