Department of Economics and Business Economics

COMT Val158Met and MTHFR C677T moderate risk of schizophrenia in response to childhood adversity

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  • J-C Debost
  • M Debost, Department of Internal Medicine, Randers Regional Hospital, Randers NØ, Denmark.
  • ,
  • J Grove
  • O Mors
  • D M Hougaard, Danish Centre for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
  • ,
  • A D Børglum
  • P B Mortensen
  • L Petersen, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research

OBJECTIVE: Mesolimbic dopamine sensitization has been hypothesized to be a mediating factor of childhood adversity (CA) on schizophrenia risk. Activity of catechol-O-methyltransferase (COMT) Val158Met increases mesolimbic dopamine signaling and may be further regulated by methylenetetrahydrofolate reductase (MTHFR) C677T. This study investigates the three-way interaction between CA, COMT, and MTHFR.

METHODS: We conducted a nested case-control study on individuals born after 1981, linking population-based registers to study the three-way interaction. We included 1699 schizophrenia cases and 1681 controls, and used conditional logistic regression to report incidence rate ratios (IRRs).

RESULTS: Childhood adversity was robustly associated with schizophrenia. No main genetic effects were observed. MTHFR C677T increased schizophrenia risk in a dose-dependent manner per MTHFR T allele (P = 0.005) consequent upon CA exposure. After inclusion of the significant (P = 0.03) COMT × MTHFR × CA interaction, the risk was further increased per high-activity COMT Val allele. Hence, exposed COMT Val/Val and MTHFR T/T carriers had an IRR of 2.76 (95% CI, 1.66-4.61). Additional adjustments for ancestry and parental history of mental illness attenuated the results with the interaction being only marginally significant.

CONCLUSION: MTHFR C677T and COMT Val158Met interact with CA to increase risk of schizophrenia.

Original languageEnglish
JournalActa Psychiatrica Scandinavica
Pages (from-to)85-95
Publication statusPublished - 29 May 2017

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  • Journal Article

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