title: Epistasis effects of COMT and MTHFR on inter-individual differences in mental health: under the inverted U-shaped prefrontal dopamine model.
abstract: Higher cognitive performance, maintenance of mental health and psychological well-being require adequate prefrontal cortex (PFC) function. "Inverted U-shaped" dopamine model indicates optimal PFC dopamine level is important to attain its function while high or low levels have adverse effects. Catechol-O-methyltransferase (COMT) and methylenetetrahydrofolate reductase (MTHFR) may be involved in this complex non-linear PFC dopamine regulation. We addressed whether genetic variation reflecting COMT and MTHFR activities can explain the inter-individual mental health differences in healthy Japanese men (n=188). The mental health was measured by Mental Health Inventory (MHI)-5 score. The rs4633-rs4818-rs4680 haplotypes were used to represent the multilevel COMT activities, while for MTHFR, the functional single polymorphism, rs1801133 (C677T), was used. We examined the effectiveness of haplotype-based association analysis of COMT on mental health together with studying its interaction with MTHFR-C677T. As a result, the relation between activity-ranked COMT genotype and MHI-5 score showed a tendency to fit into an "inverted U-shaped" quadratic curve (P=0.054). This curvilinear correlation was significant in the subjects with MTHFR-CC (P<0.001), but not with MTHFR T-allele carriers (P=0.793). Our pilot study implies a potential influence of COMT and MTHFR genotypic combination on normal variation of mental health.
authors.affiliation: Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; Department of Nutritional Education, National Institute of Health and Nutrition, Tokyo, Japan.
authors.forename: Nay Chi
authors.initials: NC
authors.lastname: Htun
authors.affiliation: Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; Department of Clinical Research and Informatics, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyaki
authors.affiliation: Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Muramatsu
authors.affiliation: Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: nsato.epi@mri.tmd.ac.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Sato
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D004298:Dopamine / Q000502:physiology*; D004843:Epistasis, Genetic / Q000502:physiology*; D005838:Genotype; D006801:Humans; D007206:Individuality; D008297:Male; D008603:Mental Health; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000502:physiology*
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002394:Catechol O-Methyltransferase; D004298:Dopamine
keywords: COMT haplotypes; Epistasis; Genetic polymorphisms; Inverted U-shaped dopamine effects; MTHFR C677T; Mental health