Nicotinamide-N-methyltransferase (NNMT) in schizophrenia: Genetic association and decreased frontal cortex mRNA levels

Anna Bromberg, Elad Lerer, Madhara Udawela, Elizabeth Scarr, Brian Dean, R. H. Belmaker, Richard Ebstein, Galila Agam

    Research output: Contribution to journalArticlepeer-review

    23 Scopus citations

    Abstract

    Emerging evidence suggests impaired one-carbon metabolism in schizophrenia. Homocysteine is one of the key components of one-carbon metabolism. Elevated plasma homocysteine levels were reported in schizophrenia. A linkage study found that nicotinamide-N-methyltransferase (NNMT), an enzyme involved in one-carbon metabolism, is a determinant of plasma homocysteine levels. In an association study the rs694539 NNMT single nucleotide polymorphism (SNP) was found significantly associated with hyperhomocysteinaemia. Aiming to assess the possible involvement of NNMT in the aetiology of schizophrenia we (1) performed an association study of eight NNMT tagged SNPs in 202 families sharing the same ethnic origin including healthy parents and a schizophrenia proband; (2) assessed NNMT mRNA levels in post-mortem frontal cortex of schizophrenia patients. Genotyping was performed using the ABI SNaPshot and the HRM methods. Individual SNPs and haplotypes were analysed for association using the family-based association test (UNPHASED software). NNMT mRNA levels were measured using RT real-time PCR. In the single SNP analysis, rs694539, previously reported to be associated with hyperhomocysteinaemia, and rs1941404 were significantly associated with schizophrenia (p<0.004 and p=0.033, respectively, following permutation test adjustment). Several haplotypes were also significantly associated with schizophrenia (global p values <0.05 following permutation test adjustment). This is the first study demonstrating an association of NNMT with schizophrenia. Post-mortem frontal cortex NNMT mRNA levels were ∼35% lower in schizophrenia patients vs. control subjects. Our study favours the notion that NNMT is involved in the aetiology of schizophrenia.

    Original languageEnglish
    Pages (from-to)727-737
    Number of pages11
    JournalInternational Journal of Neuropsychopharmacology
    Volume15
    Issue number6
    DOIs
    StatePublished - 1 Jul 2012

    Keywords

    • Frontal cortex
    • genetic association
    • mRNA levels
    • nicotinamide-N- methyltransferase (NNMT)
    • schizophrenia

    ASJC Scopus subject areas

    • Pharmacology
    • Psychiatry and Mental health
    • Pharmacology (medical)

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