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.

Establishment of a Predictive Genetic Model for Estimating Chemotherapy Sensitivity of Colorectal Cancer with Synchronous Liver Metastasis

“…TGFB1I1 is involved in the differentiation of prostate cancer cells, and it upregulated in response to chronic stimulation with tumor necrosis factor, which can augment sensitivity to anti-androgen therapy. 19 Conversely, downregulated TGFB1I1 expression can promote prostate cancer cell proliferation and invasion; thus, TGFB1I1 is believed to a predictive factor for prostate cancer.…”

Failure to confirm genetic association of the FXYD6 gene with schizophrenia: The Japanese population and meta‐analysis

“…The aim of this study was to replicate a previous report of significant association between the FXYD6 gene and schizophrenia in UK samples [Choudhury et al, 2007]. The FXYD protein family contains seven members [Sweadner and Rael, 2000].…”

“…We genotyped the six SNPs, rs11216573, rs555577, rs1815774, rs4938445, rs4938446, and rs497768, which were previously reported to be significantly associated with schizophrenia [Choudhury et al, 2007;Ito et al, 2008]. The following two SNPs were included in the study of Ito et al [2008], but not in that of Choudhury et al [2007]: one, rs11216573 is located in the 3' downstream region and the other, rs497768 in the 5' upstream region of the gene.…”

“…The following two SNPs were included in the study of Ito et al [2008], but not in that of Choudhury et al [2007]: one, rs11216573 is located in the 3' downstream region and the other, rs497768 in the 5' upstream region of the gene. SNP genotyping was performed using the TaqMan system (Applied Biosystems, Foster City, CA) according to manufacturer's recommendation.…”

“…Recently, fine mapping of the 11q22-24 region performed in University College London samples (496 cases and 488 controls from English, Scottish, and Welsh populations) has implicated FXYD6 as a schizophrenia susceptibility gene [Choudhury et al, 2007]. In that study, seven genetic variations (D11S1998, rs3168238, TTTC20.2, rs1815774, rs4938445, rs4938446, and rs497768) at the FXYD6 locus were found to be associated with schizophrenia.…”