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Background  Epigenetic inactivation of  O  6 -methylguanine DNA-methyltransferase ( MGMT ) is associated with increased sensitivity to alkylating chemotherapeutic agents in glioblastoma patients. The genetic background underlying  MGMT  gene methylation may explain individual differences in treatment response and provide a clue to a personalized treatment strategy. Making use of the longitudinal twin design, we aimed, for the first time, to estimate the genetic contributions to  MGMT  methylation in a Danish twin cohort.    Methods  DNA-methylation from whole blood (18 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs) repeated 10 years apart from the Longitudinal Study of Aging Danish Twins (LSADT) were used to search for genetic and environmental contributions to DNA-methylation at 170 CpG sites of across the  MGMT  gene. Both univariate and bivariate twin models were applied. The intraclass correlations, performed on cross-sectional data (246 MZ twin pairs) from an independent study population, the Middle-Aged Danish Twins (MADT), were used to assess the genetic influence at each CpG site of  MGMT  for replication.    Results  Univariate twin model revealed twelve CpG sites showing significantly high heritability at intake (wave 1,  h  2  > 0.43), and seven CpG sites with significant heritability estimates at end of follow-up (wave 2,  h  2  > 0.5). There were six significant CpG sites, located at the gene body region, that overlapped among the two waves ( h  2  > 0.5), of which five remained significant in the bivariate twin model, which was applied to both waves. Within MZ pair correlation in these six CpGs from MADT demarks top level of genetic influence. There were 11 CpGs constantly have substantial common environmental component over the 10 years.    Conclusions  We have identified 6 CpG sites linked to the  MGMT  gene with strong and persistent genetic control based on their DNA methylation levels. The genetic basis of  MGMT  gene methylation could help to explain individual differences in glioblastoma treatment response and most importantly, provide references for mapping the methylation Quantitative Trait Loci (meQTL) underlying the genetic regulation.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13148-021-01009-5.

Genetic and environmental determinants of O6-methylguanine DNA-methyltransferase (MGMT) gene methylation: a 10-year longitudinal study of Danish twins