| 1 | Am. J. Hum. Genet. 2007 Apr 80: 664-72 |
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| PMID | 17357072 |
| Title | A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia. |
| Abstract | Previous linkage analyses of families with multiple cases of schizophrenia by us and others have confirmed the involvement of the chromosome 11q22-24 region in the etiology of schizophrenia, with LOD scores of 3.4 and 3.1. We now report fine mapping of a susceptibility gene in the 11q22-24 region, determined on the basis of a University College London (UCL) sample of 496 cases and 488 supernormal controls. Confirmation was then performed by the study of an Aberdeen sample consisting of 858 cases and 591 controls (for a total of 2,433 individuals: 1,354 with schizophrenia and 1,079 controls). Seven microsatellite or single-nucleotide polymorphism (SNP) markers localized within or near the FXYD6 gene showed empirically significant allelic associations with schizophrenia in the UCL sample (for D11S1998, P=.021; for rs3168238, P=.009; for TTTC20.2, P=.048; for rs1815774, P=.049; for rs4938445, P=.010; for rs4938446, P=.025; for rs497768, P=.023). Several haplotypes were also found to be associated with schizophrenia; for example, haplotype Hap-F21 comprising markers rs10790212-rs4938445-rs497768 was found to be associated with schizophrenia, by a global permutation test (P=.002). Positive markers in the UCL sample were then genotyped in the Aberdeen sample. Two of these SNPs were found to be associated with schizophrenia in the Scottish sample (for rs4938445, P=.044; for rs497768, P=.037). The Hap-F21 haplotype also showed significant association with schizophrenia in the Aberdeen sample, with the same alleles being associated (P=.013). The FXYD6 gene encodes a protein called "phosphohippolin" that is highly expressed in regions of the brain thought to be involved in schizophrenia. The protein functions by modulating the kinetic properties of Na,K-ATPase to the specific physiological requirements of the tissue. Etiological base-pair changes in FXYD6 or in associated promoter/control regions are likely to cause abnormal function or expression of phosphohippolin and to increase genetic susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Neurosci. Lett. 2008 Jun 438: 70-5 |
| PMID | 18455306 |
| Title | A genetic association study of the FXYD domain containing ion transport regulator 6 (FXYD6) gene, encoding phosphohippolin, in susceptibility to schizophrenia in a Japanese population. |
| Abstract | The FXYD domain containing ion transport regulator 6 (FXYD6) gene is located within a region of chromosome 11 (11q23.3) that has been shown by a number of genome scans to be one of the most well-established linkages to schizophrenia. FXYD6 encodes the protein phosphohippolin, which is primarily expressed in the brain. Phosphohippolin modulates the kinetic activity of Na,K-ATPase and has long-term physiological importance in maintaining cation homeostasis. A recent study reported that FXYD6 was associated with schizophrenia in the United Kingdom samples. Applying the gene-based association concept, we carried out an association study regarding FXYD6 and schizophrenia in a Japanese population, with a sample consisting of 2026 subjects (906 schizophrenics and 1120 controls). After linkage disequilibrium analysis, 23 single nucleotide polymorphisms (SNPs) were genotyped using 5'-exonuclease allelic discrimination assay. We found a significant association of two SNPs (rs11216573; genotypic P value: 0.022 and rs555577; genotypic P value: 0.026, allelic P value: 0.011, uncorrected). Nominal P values did not survive correction for multiple testing (rs11216573; genotypic P value: 0.47 and rs555577; genotypic P value: 0.55, allelic P value: 0.24, after SNPSpD correction). No association was observed between schizophrenia patients and controls in allelic, genotypic and haplotypic analyses. Our findings suggest that FXYD6 is unlikely to be related to the development of schizophrenia in a Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Neurosci. Lett. 2008 Jun 438: 70-5 |
| PMID | 18455306 |
| Title | A genetic association study of the FXYD domain containing ion transport regulator 6 (FXYD6) gene, encoding phosphohippolin, in susceptibility to schizophrenia in a Japanese population. |
| Abstract | The FXYD domain containing ion transport regulator 6 (FXYD6) gene is located within a region of chromosome 11 (11q23.3) that has been shown by a number of genome scans to be one of the most well-established linkages to schizophrenia. FXYD6 encodes the protein phosphohippolin, which is primarily expressed in the brain. Phosphohippolin modulates the kinetic activity of Na,K-ATPase and has long-term physiological importance in maintaining cation homeostasis. A recent study reported that FXYD6 was associated with schizophrenia in the United Kingdom samples. Applying the gene-based association concept, we carried out an association study regarding FXYD6 and schizophrenia in a Japanese population, with a sample consisting of 2026 subjects (906 schizophrenics and 1120 controls). After linkage disequilibrium analysis, 23 single nucleotide polymorphisms (SNPs) were genotyped using 5'-exonuclease allelic discrimination assay. We found a significant association of two SNPs (rs11216573; genotypic P value: 0.022 and rs555577; genotypic P value: 0.026, allelic P value: 0.011, uncorrected). Nominal P values did not survive correction for multiple testing (rs11216573; genotypic P value: 0.47 and rs555577; genotypic P value: 0.55, allelic P value: 0.24, after SNPSpD correction). No association was observed between schizophrenia patients and controls in allelic, genotypic and haplotypic analyses. Our findings suggest that FXYD6 is unlikely to be related to the development of schizophrenia in a Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Sep 153B: 1221-7 |
| PMID | 20468077 |
| Title | Failure to confirm genetic association of the FXYD6 gene with schizophrenia: the Japanese population and meta-analysis. |
| Abstract | The FXYD domain-containing ion transport regulator 6 (FXYD6) gene encodes phosphohippolin that regulates cellular ion transport by altering the kinetic properties of Na,K-ATPase. Phosphohippolin is highly expressed in brain regions that are relevant to schizophrenia. The FXYD6 gene is located at chromosome 11q22-24, one of the most established linkage regions for schizophrenia. Therefore, it may be possible that genetic variants in FXYD6, including the regulatory genomic elements could cause abnormal function or expression of phosphohippolin and increase the genetic risk for schizophrenia. A previous study suggested that polymorphisms in FXYD6 are associated with schizophrenia in UK samples. However, conflicting results have been reported in the Japanese population. In this study, we aimed to test the prior genetic association findings using different samples from the ethnically homogeneous Japanese population (1,060 schizophrenic patients and 1,060 age- and sex-matched controls). From the FXYD6 gene, we examined six single nucleotide polymorphisms (rs11216573, rs555577, rs1815774, rs4938445, rs4938446, and rs497768), all of which were previously analyzed for association. We did not detect any significant allelic, genotypic or haplotypic association in our Japanese samples. Meta-analysis incorporating previous and the present studies also showed that the FXYD6 gene is not associated with schizophrenia. We conclude that the FXYD6 gene does not have a major influence on susceptibility to schizophrenia across populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Sep 153B: 1221-7 |
| PMID | 20468077 |
| Title | Failure to confirm genetic association of the FXYD6 gene with schizophrenia: the Japanese population and meta-analysis. |
| Abstract | The FXYD domain-containing ion transport regulator 6 (FXYD6) gene encodes phosphohippolin that regulates cellular ion transport by altering the kinetic properties of Na,K-ATPase. Phosphohippolin is highly expressed in brain regions that are relevant to schizophrenia. The FXYD6 gene is located at chromosome 11q22-24, one of the most established linkage regions for schizophrenia. Therefore, it may be possible that genetic variants in FXYD6, including the regulatory genomic elements could cause abnormal function or expression of phosphohippolin and increase the genetic risk for schizophrenia. A previous study suggested that polymorphisms in FXYD6 are associated with schizophrenia in UK samples. However, conflicting results have been reported in the Japanese population. In this study, we aimed to test the prior genetic association findings using different samples from the ethnically homogeneous Japanese population (1,060 schizophrenic patients and 1,060 age- and sex-matched controls). From the FXYD6 gene, we examined six single nucleotide polymorphisms (rs11216573, rs555577, rs1815774, rs4938445, rs4938446, and rs497768), all of which were previously analyzed for association. We did not detect any significant allelic, genotypic or haplotypic association in our Japanese samples. Meta-analysis incorporating previous and the present studies also showed that the FXYD6 gene is not associated with schizophrenia. We conclude that the FXYD6 gene does not have a major influence on susceptibility to schizophrenia across populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | J Psychiatr Res 2010 Apr 44: 409-12 |
| PMID | 20149392 |
| Title | No association between the FXYD6 gene and schizophrenia in the Chinese Han population. |
| Abstract | Choudhury et al. identified FXYD6 as a susceptible gene for schizophrenia in the London and Aberdeen populations. We genotyped D11S1998 and 8 SNPs (rs869789, rs11216567, rs10790212, rs876797, rs4938445, rs497768, rs11216598, rs11605223) in a Chinese sample consisting of 1514 schizophrenia patients and 1514 healthy controls. We also compared the expression levels of FXYD6 in lymphocytes in 86 schizophrenia patients and 94 controls. No association was detected either in D11S1998 or the 8 SNPs. No difference was found in expression level between patients and controls. Our study suggests that FXYD6 does not play a role in schizophrenia in the Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2011 Oct 28: 539-42 |
| PMID | 21983730 |
| Title | [A family-based association study of FXYD6 gene polymorphisms and schizophrenia]. |
| Abstract | To study the association between the single nucleotide polymorphisms (SNPs) in FXYD6 gene and schizophrenia in a family-trios population. Six SNPs (rs10790212, rs11544201, rs555577, rs1815774, rs4938446 and rs497768) in the FXYD6 gene were genotyped by allele-specific PCR method in 101 nuclear families, and transmission disequilibrium test (TDT) was performed. SNPs rs10790212 and rs11544201 showed significant association with schizophrenia (P<0.05). Furthermore, significant association of schizophrenia with the haplotype rs10790212-rs11544201 was found (P<0.05). FXYD6 gene might play an important role in schizophrenia susceptibility and functional analysis of FXYD6 are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Biochem. Biophys. Res. Commun. 2011 Feb 405: 118-21 |
| PMID | 21216238 |
| Title | A novel replicated association between FXYD6 gene and schizophrenia. |
| Abstract | FXYD6 gene is located in chromosome region 11q22-q24 where previous studies have shown an association with schizophrenia. However, the subsequent studies failed to replicate this finding. To investigate the relationship between FXYD6 locus and schizophrenia in Chinese population, we genotyped six single-nucleotide polymorphisms (SNPs) in this region of FXYD6 in 1142 Han Chinese subjects (576 cases and 566 controls), and performed an association analysis. Significant associations with schizophrenia and the marker rs11544201 (P=0.0028) and the haplotype rs10790212-rs11544201 (global P=0.005) were found. Our results support that FXYD6 is a susceptibility gene of schizophrenia. Replication of larger samples and functional analysis of FXYD6 are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | PLoS ONE 2015 -1 10: e0133404 |
| PMID | 26193471 |
| Title | Network-Based Analysis of Schizophrenia Genome-Wide Association Data to Detect the Joint Functional Association Signals. |
| Abstract | schizophrenia is a common psychiatric disorder with high heritability and complex genetic architecture. Genome-wide association studies (GWAS) have identified several significant loci associated with schizophrenia. However, the explained heritability is still low. Growing evidence has shown schizophrenia is attributable to multiple genes with moderate effects. In-depth mining and integration of GWAS data is urgently expected to uncover disease-related gene combination patterns. Network-based analysis is a promising strategy to better interpret GWAS to identify disease-related network modules. We performed a network-based analysis on three independent schizophrenia GWASs by using a refined analysis framework, which included a more accurate gene P-value calculation, dynamic network module searching algorithm and detailed functional analysis for the obtained modules genes. The result generated 79 modules including 238 genes, which form a highly connected subnetwork with more statistical significance than expected by chance. The result validated several reported disease genes, such as MAD1L1, MCC, SDCCAG8, VAT1L, MAPK14, MYH9 and FXYD6, and also obtained several novel candidate genes and gene-gene interactions. Pathway enrichment analysis of the module genes suggested they were enriched in several neural and immune system related pathways/GO terms, such as neurotrophin signaling pathway, synaptosome, regulation of protein ubiquitination, and antigen processing and presentation. Further crosstalk analysis revealed these pathways/GO terms were cooperated with each other, and identified several important genes, which might play vital roles to connect these functions. Our network-based analysis of schizophrenia GWASs will facilitate the understanding of genetic mechanisms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |