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: 4.01). 07/2011; 15(6):727-37. DOI: 10.1017/S1461145711001179
Source: PubMed


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.

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Available from: Robert H Belmaker, Sep 28, 2015
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    • "Giusti et al. [22] found an association of polymorphisms across the NNMT gene with abdominal aortic aneurism and De Jonge et al. suggested an association between NNMT and paediatric acute lymphoblastic leukaemia. In an Israeli population, NNMT gene was shown to be associated with SZ [23]. Recently, Ali Sazci et al. showed that NNMT gene is a genetic risk factor for bipolar disorder and nonalcoholic steatohepatitis (NASH) in the Turkish population [24] [25]. "
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    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 · 2.00 Impact Factor
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    • "The rs694539 variant of NNMT gene located at the 114133419th bp (GNA transition; dbSNP) is shown to be significantly associated with elevated homocysteine levels (Souto et al., 2005). This particular variant was found to be associated with schizophrenia in an Israeli population (Bromberg et al., 2012). The hypothesis is that whether the rs694539 variant of NNMT gene is associated with bipolar disorders as well. "
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    ABSTRACT: Here we report the association of the rs694539 variant of nicotinamide-N-methyltransferase gene with bipolar disorder in a case-control study of 95 bipolar disorder patients and 201 healthy controls (χ2=13.382, P=0.001). With the polymerase chain reaction restriction fragment length polymorphism method we developed we were able to show the association for the first time. This new finding may provide evidence to understand the mechanism of the disease.
    Gene 09/2013; 532(2). DOI:10.1016/j.gene.2013.08.077 · 2.14 Impact Factor
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    • "The NNMT gene, located on chromosome 11q23.1, is 16.703 bp in length and has three exons and two introns. The rs694539 NNMT variant is found at 114133419 bp (G > A transition) (dbSNP), is a single nucleotide polymorphism (SNP) that is found to be significantly associated with hyperhomocysteinemia (Souto et al., 2005; Bromberg et al., 2012) which causes steatosis. "
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormal hepatic steatosis in the absence of a history of alcohol use and with a prevalence of 15%-45% in developed nations. Nonalcoholic steatohepatitis (NASH) is an advanced stage of NAFLD with a pronounced major inflammatory component. The aim of this study was to investigate the possible role of nicotinamide-N-methyltransferase (NNMT) gene rs694539 variant in the development of NASH. Therefore, we analyzed 80 NASH patients and 183 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism method developed in our laboratory. The NNMT rs694539 variant was found to be significantly associated with NASH (χ(2)=9.349, p=0.009). The individuals with the GG genotype had protection against NASH (χ(2)=3.793, p=0.051, odds ratio [OR]=0.580, 95% confidence interval [CI]=0.334-1.006), whereas the individuals with the AA genotype showed statistically significant increased risk for NASH (χ(2)=7.748, p=0.005, OR=7.338, 95% CI=1.448-37.190). Moreover, the G allele was protective against NASH (χ(2)=7.748, p=0.005, OR=0.136, and 95% CI=0.027-0.691). On the other hand, the A allele was a risk factor for NASH (χ(2)=3.793, p=0.051, OR=1.725, and 95% CI=0.994-2.996). Consequently, the rs694539 variant of NNMT gene is a genetic risk factor for developing NASH.
    Genetic Testing and Molecular Biomarkers 08/2013; 17(11). DOI:10.1089/gtmb.2013.0309 · 1.46 Impact Factor
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