Association study of Nogo‐related genes with schizophrenia in a Japanese case–control sample

Abstract

Many studies have suggested that myelin dysfunction may be causally involved in the pathogenesis of schizophrenia. Nogo (RTN4), myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG) all bind to the common receptor, Nogo-66 receptor 1 (RTN4R). We examined 68 single nucleotide polymorphisms (SNPs) (51 with genotyping and 17 with imputation analysis) from these four genes for genetic association with schizophrenia, using a 2,120 case-control sample from the Japanese population. Allelic tests showed nominally significant association of two RTN4 SNPs (P = 0.047 and 0.037 for rs11894868 and rs2968804, respectively) and two MAG SNPs (P = 0.034 and 0.029 for rs7249617 and rs16970218, respectively) with schizophrenia. The MAG SNP rs7249617 also showed nominal significance in a genotypic test (P = 0.017). In haplotype analysis, the MAG haplotype block including rs7249617 and rs16970218 showed nominal significance (P = 0.008). These associations did not remain significant after correction for multiple testing, possibly due to their small genetic effect. In the imputation analysis of RTN4, the untyped SNP rs2972090 showed nominally significant association (P = 0.032) and several imputed SNPs showed marginal associations. Moreover, in silico analysis (PolyPhen) of a missense variant (rs11677099: Asp357Val), which is in strong linkage disequilibrium with rs11894868, predicted a deleterious effect on Nogo protein function. Despite a failure to detect robust associations in this Japanese cohort, our nominally positive signals, taken together with previously reported biological and genetic findings, add further support to the "disturbed myelin system theory of schizophrenia" across different populations.

Myelin, myelin-related disorders, and psychosis

“…Many of these genes play an important role in brain development (Weinberger, 1986;Walsh et al, 2008). A number of smaller clinical studies have identified several OMR genes (Jungerius et al, 2008;Jitoku et al, 2011;Ayalew et al, 2012) and myelin-related pathways (Yu et al, 2014) that are associated with increased risk for schizophrenia. However, these latter findings should be looked upon with some skepticism, as the largest and most carefully curated meta-analysis of genetic risk for schizophrenia, the PGC study, did not find any statistical association with any of these loci (PGC-SWE; Ripke et al, 2013).…”

The Nogo-66 receptor family in the intact and diseased CNS

“…In Caucasian population samples, two studies have been able to measure a statistically significant, though modest, association between SNPs in the NgR1 gene and schizophrenia (Budel et al 2008) but another study did not find a statistically significant association in an Afrikaaner population (Hsu et al 2007). In other populations, no association has been shown, including Chinese Han (Meng et al 2007;Budel et al 2008), Japanese (Jitoku et al 2011), or African-American (Budel et al 2008). This would indicate that NgR1 has a fairly minor role in risk association to schizophrenia in selected Caucasian populations.…”

“…Decreases in white matter volume in the cortex in schizophrenic patients have been suggested to be involved in the disruption of connections of the prefrontal cortex that are proposed to cause some symptoms of schizophrenia (Davis et al 2003). Indeed, there has been investigation of associations of other myelin-associated genes with schizophrenia, including Nogo-A and MAG (Jitoku et al 2011). Secondly, the NgR1 gene is located on chromosome 22q11 and microdeletions in 22q11 have been associated with risk of severe mental illness, including increased risk of schizophrena.…”

Decreased Expression of α-Synuclein, Nogo-A and UCH-L1 in Patients with Schizophrenia: A Preliminary Serum Study

“…Hovewer, myelination of the prefrontal cortex typically reaches the highest level in late adolescence and early adulthood, happening together with the onset of schizophrenia. Myelin dysfunction is one of the strongly supported hypotheses for explaining pathogenesis of schizophrenia 16. Nogo-A is a necessary ligand for CNS construct at either beginning of the CNS building or later the maintenance in the adult, but at the same time an inhibitory factor to CNS recovery after injuries or disease, which mainly is expressed on the surface of the oligodendrocytes that myelinate the CNS neurons during development of the CNS, and may contribute to the neuron spreading direction and the neuron distribution pattern 17.…”