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Background   O  6 -methylguanine-DNA methyltransferase (MGMT) is a pivotal enzyme for repairing DNA alkylation damage. Epigenetic modification of  MGMT  has been well known as a promising prognostic biomarker for glioma. However, the significance of genetic variations of  MGMT  in glioma carcinogenesis has not been fully elucidated.    Methods  The associations between expression quantitative trait loci (eQTLs) of  MGMT  and glioma susceptibility were evaluated in a case–control study of 1056 individuals. The function of susceptibility locus for glioma was explored with a set of biochemical assays, including luciferase reporter gene, EMSA and supershift EMSA, ChIP, and siRNA knockdown.    Results  We found that rs11016798 TT genotype was associated with a significantly decreased risk of glioma (OR = 0.57, 95% CI 0.39–0.85;  P  = 0.006). Stratification analyses indicated that the association between rs11016798 and glioma was more pronounced in males (OR = 0.62, 95% CI 0.40–0.97;  P  = 0.035), older subjects (OR = 0.46, 95% CI 0.27–0.80;  P  = 0.006), WHO grade IV glioma (OR = 0.58, 95% CI 0.35–0.96;  P  = 0.033), and IDH wildtype glioma (OR = 0.43, 95% CI 0.21–0.88;  P  = 0.022). We characterized an insertion variant rs10659396 in the upstream of  MGMT  as a causative variant. The risk allele rs10659396 ins allele was demonstrated to downregulate  MGMT  expression by disrupting a STAT1 binding site. Knockdown of  STAT1  remarkably attenuated  MGMT  expression. Moreover, the rs10659396 allele-specific positive correlation was observed between the expression of  STAT1  and  MGMT  in population.    Conclusions  The study demonstrates that an insertion variant of  MGMT  rs10659396 confers susceptibility to glioma by downregulating MGMT expression through disrupting a STAT1 binding site.    Graphic abstractSupplementary Information  The online version contains supplementary material available at 10.1186/s12935-021-02211-4.

An insertion variant of MGMT disrupts a STAT1 binding site and confers susceptibility to glioma