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

Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
The International Journal of Neuropsychopharmacology (Impact Factor: 5.26). 07/2011; 15(6):727-37. DOI: 10.1017/S1461145711001179
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Distinctions along the dorsal-ventral axis of medial prefrontal cortex (mPFC), between anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) sub-regions, have been proposed on a variety of neuroanatomical and neurophysiological grounds. Conventional lesion approaches (as well as some electrophysiological studies) have shown that these distinctions relate to function in that a number behavioral dissociations have been demonstrated, particularly using rodent models of attention, learning, and memory. For example, there is evidence to suggest that AC has a relatively greater role in attention, whereas IL is more involved in executive function. However, the well-established methods of behavioral neuroscience have the limitation that neuromodulation is not addressed. The neurotoxin 6-hydroxydopamine has been used to deplete dopamine (DA) in mPFC sub-regions, but these lesions are not selective anatomically and noradrenalin is typically also depleted. Microinfusion of drugs through indwelling cannulae provides an alternative approach, to address the role of neuromodulation and moreover that of specific receptor subtypes within mPFC sub-regions, but the effects of such treatments cannot be assumed to be anatomically restricted either. New methodological approaches to the functional delineation of the role of mPFC in attention, learning and memory will also be considered. Taken in isolation, the conventional lesion methods which have been a first line of approach may suggest that a particular mPFC sub-region is not necessary for a particular aspect of function. However, this does not exclude a neuromodulatory role and more neuropsychopharmacological approaches are needed to explain some of the apparent inconsistencies in the results.
    Frontiers in Systems Neuroscience 09/2014; DOI:10.3389/fnsys.2014.00160
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Transcriptome sequencing of brain samples provides detailed enrichment analysis of differential expression and genetic interactions for evaluation of mitochondrial and coagulation function of schizophrenia. It is implicated that schizophrenia genetic and protein interactions may give rise to biological dysfunction of energy metabolism and hemostasis. These findings may explain the biological mechanisms responsible for negative and withdraw symptoms of schizophrenia and antipsychotic-induced venous thromboembolism. Published BA22 RNA-Seq brain data of 9 schizophrenic patients and 9 controls samples were analyzed. The differentially expressed genes in the BA22 brain samples of schizophrenia are proposed as schizophrenia candidate marker genes (SCZCGs). The genetic interactions between mitochondrial genes and many under-expressed SCZCGs indicate the genetic predisposition of mitochondria dysfunction in schizophrenia. The biological functions of SCZCGs, as listed in the Pathway Interaction Database (PID), indicate that these genes have roles in DNA binding transcription factor, signal and cancer-related pathways, coagulation and cell cycle regulation and differentiation pathways. It is implicated that the energy metabolism and hemostatic process have important roles in the pathogenesis for schizophrenia. The cross-talk of genetic interaction by these co-expressed genes and reached candidate genes may address the key network in disease pathology. The accuracy of candidate genes evaluated from different quantification tools could be improved by crosstalk analysis of overlapping genes in genetic networks.
    BMC Genomics 12/2014; 15(Suppl 9):S6. DOI:10.1186/1471-2164-15-S9-S6 · 4.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Accumulating evidence has shown that alterations in one carbon metabolism might play an important role in the pathogenesis of schizophrenia (SZ). Nicotinamide-N-methyltransferase (NNMT) is one of the key enzymes of one-carbon metabolism. To examine whether NNMT gene was associated with SZ in Han Chinese population, we selected seven single nucleotide polymorphisms (SNPs) in NNMT gene, and investigated its association with SZ from a cohort of 42 SZ patients and 86 healthy controls by Mass-ARRAY technology. Statistical analyses revealed that one (rs694539) of the SNPs in the female subgroup showed significant difference between SZ patients and controls both in genotypic (p= 0.0170) and allelic frequencies (p = 0.0059). We also found that the frequency of haplotype 'A G G C T C T' in the female patients was significantly higher than in controls (p=0.0015). Our results suggest that NNMT rs694539 may have a role in the etiology of SZ in a Han Chinese female population.
    International journal of medical sciences 09/2014; 11(12):1234-9. DOI:10.7150/ijms.9426 · 1.55 Impact Factor