Greg W.H. Wong

Linkage of M5 Muscarinic and α7-Nicotinic Receptor Genes on 15q13 to Schizophrenia

Most antipsychotic drugs act on the forebrain by blocking dopamine receptors. In rodents, the M5 muscarinic receptor (CHRM5) is important for prolonged dopamine release. We typed polymorphisms in CHRM5 and α7-nicotinic receptor (CHRNA7) genes on 15q13 in 82 Canadian families having at least 1 schizophrenic patient. Using the Family-Based Association Test, we performed haplotype analysis of the 2 loci and found biased transmission in schizophrenia (z = –2.651, p = 0.008). In the families tested, the 2 cholinergic genes interacted to affect schizophrenia in combination, while neither was sufficiently alone to confer susceptibility. Our present study provided the first line of direct evidence suggesting that the CHRM5 gene combined with the CHRNA7 gene may be linked to schizophrenia.

Investigation of polymorphism in the MDR1 gene and antidepressant-induced mania

ABSTRACTThe involvement of the multi-drug-resistant 1 P-glycoprotein gene (MDR1 P-gp) in the transport of antidepressants across the blood–brain barrier makes it a good candidate for the prediction of antidepressant response and side effects. We investigated the role of the MDR1 P-gp gene in predicting the induction of mania in bipolar patients (BP) treated with proserotonergic drugs. Participants met the DSM-IV criteria for BP or BPII and had at least one depressive episode treated with proserotonergic antidepressants. The first group (n=26) included patients with at least one DSM-IV manic/hypomanic episode developed during antidepressant treatment; the second group (N=29) included patients with no antidepressant-induced switches. The common polymorphism of the MDR1 was genotyped for both groups and comparison was made with respect to the presence/absence of induced mania between the two groups. No association between antidepressant-induced mania and the MDR1 alleles or genotypes was found (χ2=1.85, 2 df, P=0.39; χ2=0.13, 1 df, P=0.72).

Association study between the novel functional polymorphism of the serotonin transporter gene and suicidal behaviour in schizophrenia

A serotonin transporter gene linked polymorphic region (5-HTTLPR) has been investigated in several genetic association studies, including studies of schizophrenia and suicidality. The current study was designed to examine whether the new long (A/G) variant polymorphism of the 5-HTT gene may be associated with suicide attempts of 290 Caucasian schizophrenic patients. Among these patients, 92 had a history of suicide attempt. No association with history of suicide attempt was found in the multiallelic 5-HTTLPR (p = 0.305), however we found significant association with the intron 2 VNTR polymorphism (p = 0.018). When we performed a haplotype analysis, we found association between suicide attempt and haplotype distribution (p = 0.031). These findings suggest that the intron 2 VNTR polymorphism in serotonin transporter gene may influence suicidal behaviour in schizophrenia.

Polymorphisms in glutamate decarboxylase genes: analysis in schizophrenia.

The decrease of glutamic acid decarboxylase (GAD) has been reported as an important neurochemical alteration of the inhibitory GABAergic interneurons in schizophrenia. To our knowledge no studies have investigated the genetic variants influencing GAD expression. To search for markers contributing to the genetic susceptibility of schizophrenia, we typed two polymorphisms by polymerase chain reaction-restriction fragment length polymorphism in both GAD1 and GAD2 genes in 112 triad families and 46 case-controls. We used the Transmission Disequilibrium Test to perform the qualitative family-based analyses and found negative results (GAD1, χ2=0.273, 1 degree of freedom, P=0.60; GAD2, χ2=0, 1 degree of freedom, P=1). In addition there were no associations with GAD1 and GAD2 and quantitative measures of suicide behaviour in this sample. Although our results are negative, this was the first study to investigate GAD genes in schizophrenia, and further studies of these genes, particularly with schizophrenia subtypes, may prove valuable.

Genetic study of the myelin oligodendrocyte glycoprotein (MOG) gene in schizophrenia

Schizophrenia (SCZ) is a neuropsychiatric disorder that affects approximately 1% of the general population. The human leukocyte antigen (HLA) system has been implicated in several genetic studies of SCZ. The myelin oligodendrocyte glycoprotein (MOG) gene, which is located close to the HLA region, is considered a candidate for SCZ due to its association with white matter abnormalities and its importance in mediating the complement cascade. Four polymorphisms in the MOG gene (CA)n (TAAA)n, and two intronic polymorphisms, C1334T and C10991T, were investigated for the possibility of association with SCZ using 111 SCZ proband and their families. We examined the transmission of the alleles of each of these polymorphisms with the transmission disequilibrium test. We did not observe significant evidence for biased transmission of alleles at the (CA)n (χ2 = 2.430, 6 df, P = 0.876) (TAAA)n (χ2 = 3.550, 5 df, P = 0.616), C1334T (χ2 = 0.040, 1 df, P = 0.841) and C10991T (χ2 = 0.154, 1 df, P = 0.695) polymorphisms. Overall haplotype analysis using the TRANSMIT program was also not significant (χ2 = 7.954, 9 df, P = 0.539). Furthermore, our results comparing mean age at onset in the genotype groups using the Kruskal–Wallis Test were not significant. Our case‐control analyses (182 cases age‐, sex‐ and ethnicity‐matched with healthy controls) and combined z‐score [(CA)n: z‐score =−1.126, P = 0.130; (TAAA)n: z‐score = −0.233, P = 0.408; C1334T: z‐score = 0.703, P = 0.241; C10991T: z‐score = 0.551, P = 0.291] were also not significant. Although our data are negative, the intriguing hypothesis for MOG in SCZ may warrant further investigation of this gene.

Untranslated region haplotype in dysbindin gene: analysis in schizophrenia.

Summary.Genome-scans performed in schizophrenia families have provided evidence for region 6p24-21 where variability may confer susceptibility to schizophrenia. Recent studies have implicated that gene DTNBP1 (dysbindin) in this region is strongly associated with schizophrenia. In a family based association study we investigated three markers located in the untranslated region of the DTNBP1 gene: rs909706, rs1047631 and rs742106. The sample size of our study is 117 families. No biased transmission towards the disorder was detected by haplotype analysis using TRANSMIT.

No association between the Pro197Leu polymorphism in the glutathione peroxidase (GPX1) gene and schizophrenia.

Objective Oxidative stress such as free radical-mediated neuronal dysfunction may be involved in the pathophysiology of schizophrenia. The human glutathione peroxidase (GPX1) is a selenium-dependent enzyme, which plays an important role in the detoxification of free radicals. We therefore hypothesized that the GPX1 gene, which is located on chromosome 3p21.3, may be involved in the pathophysiology of schizophrenia. The aim of this study is to examine whether a potentially functional polymorphism, a proline (Pro) to leucine (Leu) substitution at codon 197 (Pro197Leu) of the human GPX1 gene, is associated with susceptibility to schizophrenia. Methods We genotyped the Pro197Leu polymorphism in a total of 113 nuclear families that had a proband with schizophrenia. Genetic association was tested using the transmission disequilibrium test (TDT), the sib transmission disequilibrium test (STDT), and the family-based association test (FBAT). Results The minor allele (Leu) frequency was calculated to be 0.282. We could not find significant transmission disequilibrium of the alleles for the Pro197Leu polymorphism in the GPX1 gene in association with the presence of schizophrenia in our family sample (TDT, χ2=0.03, degrees of freedom=1, P=0.86; combined TDT–STDT, Z′=−0.052, P=0.47; FBAT, Z=0.000, P=1.000). Conclusion The results of this study suggest that the GPX1 polymorphism is unlikely to be associated with susceptibility to schizophrenia.