A further study of a possible locus for schizophrenia on the X chromosome.

Several studies suggest that the X chromosome may contain a gene for schizophrenia. In the present study, we recruited 142 male schizophrenic patients and their biological mothers from all parts of the United Kingdom to detect a genetic association for the SYP/CACNA1F locus in the Xp11 region and the FACL4 locus in the Xq22.3-Xq23 region. The haplotype-based haplotype relative risk (HHRR) analysis showed allelic association for rs2071316 (chi2=6.85, P=0.009) and rs5905724 (chi2=5.3, P=0.021) at the CACNA1F locus, but not for rs5943414 and rs1324805 at the FACL4 locus and rs3817678 at the SYP locus. The haplotype analysis showed a weak association for the rs3817678-rs2071316-rs5905724 haplotypes (chi2=12.19, df=4, P=0.016) but did not show such an association for the rs5943414-rs1324805 haplotypes (chi2=3.96, df=2, P=0.138). Because the linkage disequilibrium signal was detected only at the CACNA1F locus, this gene should perhaps be considered as being a candidate for schizophrenia although further work is needed to draw firm conclusions.

A study of the combined effect of the CLDN5 locus and the genes for the phospholipid metabolism pathway in schizophrenia.

The present study attempts to test the combined effect of the CLDN5 gene and those for the phospholipid metabolism pathway, including PTGS1, PTGS2, PLA2G4A and PLA2G4C. We detected five single nucleotide polymorphisms (SNPs) present in these genes among 131 British family trios of schizophrenic patients. The transmission disequilibrium test (TDT) showed that BanI-SNP located in the 5'-flanking region of the PLA2G4A gene was associated with schizophrenia (chi(2) = 5.16, P = 0.023) although the others failed to show such allelic associations. The global P-value was 0.150 for 1000 permutations with the TDT analysis. The conditioning on genotype test, but not on allele test, revealed a strong association for the combination of the CLDN5 gene with the PLA2G4A gene (chi(2) = 10.17, df = 2, P = 0.006). The present results suggest that the PLA2G4A locus may be involved in schizophrenia and its combination with the CLDN5 gene may increase further the risk for the illness.

The KPNA3 gene may be a susceptibility candidate for schizophrenia.

The present study investigated the possible association of the KPNA3 locus in the 13q14 region with schizophrenia. We detected 7 single nucleotide polymorphisms (SNPs) on 13q14, one (rs6313) present at the HTR2A locus and the other 6 at the KPNA3 locus, among 124 British family trios consisting of mother, father and affected offspring with schizophrenia. The transmission disequilibrium test (TDT) showed allelic association for rs3736830 (chi(2)=8.66, P=0.003), rs2181185 (chi(2)=3.86, P=0.049) and rs626716 (chi(2)=5.82, P=0.016), but not for rs6313 (chi(2)=0.009, P=0.926). The global P-value was 0.029 for 1000 permutations with the TDT. The 2-SNP haplotype analysis showed a disease association for the rs2273816-rs3736830 haplotypes (chi(2)=7.63, d.f.=2, P=0.022), the rs3736830-rs2181185 haplotypes (chi(2)=10.30, d.f.=2, P=0.006) and the rs2181185-rs3782929 haplotypes (chi(2)=9.26, d.f.=2, P=0.01). The global P-value was 0.034 for 1000 permutations with the 2-SNP haplotype analysis. The 6-SNP haplotype system also showed a weak association with the illness (chi(2)=15.62, d.f.=8, P=0.048), although the 1-d.f. test did not show the association for nine individual haplotypes when a P-value was corrected by the Bonferroni corrections. The present study suggests that the KPNA3 may contribute genetically to schizophrenia in a small effect size.

Gene, gut and schizophrenia: the meeting point for the gene-environment interaction in developing schizophrenia.

Both schizophrenia and celiac disease involve a genetic component. Several lines of evidence have shown a genetic relationship between these two conditions. Celiac disease is characterized by damage to the microscopic finger-like projections called villi, which line the small intestine and play a significant role in digestion, due to an inflammatory condition caused by a reaction to wheat gluten or related rye and barley proteins. Celiac disease represents not only malabsorption leading to a poor nutritional condition but also an alteration of gut permeability. Individuals with a history of a childhood celiac condition have a raised risk of developing schizophrenia. Psychotic symptoms often occur in adult celiac disease. It can be hypothesized that apart from malnutrition, the meeting point for the gene-environment interaction may be an alteration in gut permeability, in which the gut may lose its capacity to block exogenous psychosis-causing substances that may enter the body thus causing the development of schizophrenia and other mental conditions. To support this hypothesis, the conditional test was conducted to look at the combined effect of the CLDN5 gene involved in forming permeability barriers and the DQB1 gene that has been found to be associated with celiac disease. The results demonstrate that these two genes possibly work together in conferring a susceptibility to schizophrenia.

The KPNB3 locus is associated with schizophrenia.

Seven single nucleotide polymorphisms (SNPs) present on 13q32 were detected among 124 British family trios consisting of fathers, mothers and affected offspring with schizophrenia. The transmission disequilibrium test (TDT) demonstrated that of these 7 SNPs, rs626716, a T to C base change at the KPNB3 locus, was the only SNP associated with schizophrenia (chi(2) = 7.71, P = 0.005) although the global P-value given by a permutation test was 0.04 for 100 permutations. Of 248 parents, 20 were heterozygous. These heterozygous parents had transmitted 4 T-alleles and 16 C-alleles to their affected offspring. To further validate the rs626716 association, we analysed a haplotype system composed of 3 SNPs at the KPNB3 locus. The result showed that the KPNB3 haplotypes were also associated with schizophrenia (chi(2) = 10.18, d.f. = 2, P = 0.006). Because the KPNB3 finding has been replicated in a Chinese population, it could be hypothesized that the KPNB3 locus may contain a disease-causing variant for schizophrenia.

Lack of a genetic association between the frizzled-3 gene and schizophrenia in a British population.

In recent studies, the frizzled-3 (FZD3) locus was found to be associated with schizophrenia in both Japanese and Chinese populations. To validate the initial finding, we detected three single nucleotide polymorphisms (SNPs) present in a 10-kb segment of DNA at the FZD3 locus, as described in a previous study with a Chinese population. We totally recruited 120 British family trios consisting of fathers, mothers and affected offspring with schizophrenia. The transmission disequilibrium test (TDT) did not show allelic association between these three SNPs and schizophrenia. The 3-SNP haplotype system was composed of only 3 individual haplotypes among the 120 family trios and these 3 SNPs were mainly carried by two distinct haplotypes, suggesting that these 3 SNPs may result from a single founding event in history. No association was shown between the 3-SNP haplotypes and schizophrenia. The present results imply that the FZD3 gene is less evolutionary in the British population than in the Chinese population. This may be a possible reason for the failure to replicate the FZD3 finding with the British sample.

Is NOTCH4 associated with schizophrenia?

The NOTCH4 locus was reported to be associated with schizophrenia in our previous study but the subsequent replication by other workers has been inconsistent. To find out possible reasons for the poor replication, the present work was undertaken to analyse four functional single nucleotide polymorphisms (SNPs) (rs367398, rs915894, rs520692 and rs422951) at the NOTCH4 locus among 141 schizophrenic family trios of Chinese Han descent. Of these four SNPs, rs520692 was the only one associated with schizophrenia (P = 0.017); the other three, however, did not show any association with the illness, including rs367398 located in the promoter region, which had shown a strong association with the illness in our previous study conducted with British samples. Although these four SNPs analysed lie within a less than 4 kb segment of genomic DNA, the pattern of linkage disequilibrium between them was unexpected. The strongest linkage disequilibrium was shown only between rs367398 and rs520692 and between rs520692 and rs422951 in both parent and patient groups. This study raises the possibility that there might be two or more disease-underlying variants at the NOTCH4 locus or at a nearby locus, and that the allelic or locus heterogeneity may be one of the possible reasons for the poor replication of the NOTCH4 finding.

Lack of a genetic association between the TNXB locus and schizophrenia in a Chinese population.

A recent study demonstrated that the tenascin X (TNXB) gene was associated with schizophrenia in a British population. To replicate the initial finding, we analysed two positive single nucleotide polymorphisms (SNPs), rs1009382 and rs204887 present at the TNXB locus, in a Chinese population by using PCR-based restriction fragment length polymorphism analysis. We recruited a total of 136 family trios consisting of fathers, mothers and affected offspring with schizophrenia. The transmission disequilibrium test did not show allelic association between these two SNPs and schizophrenia, and the rs1009382-rs204887 haplotypes were not associated with the illness either. The present results suggest that the TNXB locus does not appear to be associated with schizophrenia in the Chinese population. Because the TNXB gene is less than 100 kb away from the NOTCH4 locus that was also reported to be associated with schizophrenia, allelic and locus heterogeneity could be possible reasons for the failure to replicate the TNXB finding.