Abstract
Linkage studies in schizophrenia have identified a candidate region on chromosome 10p14–11 as reported for several independent samples. We investigated association of DNA sequence variants in a plausible candidate gene located in this region, the gene for phosphatidylinositol-4-phosphate 5-kinase IIα (PIP5K2A), in a sample of 65 sib-pair families for which linkage had been reported. Evidence for association was obtained for 15 polymorphisms spanning 73.6 kb in the genomic region of the gene between intron 4 and the 3′ untranslated region, a region with high degree of linkage disequilibrium. Single nucleotide polymorphism (SNP) rs10828317 located in exon 7 and causing a non-synonymous amino-acid exchange (asparagine/serine) produced a P-value of 0.001 (experiment-wide significance level 0.00275) for over-transmission of the major allele coding for serine, analysed by transmission disequilibrium test using FAMHAP. Association of this SNP with schizophrenia has been also described in a sample of 273 Dutch schizophrenic patients and 580 controls (P=0.0004). PIP5K2A is involved in the biosynthesis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), one of the key metabolic crossroads in phosphoinositide signalling. PI(4,5)P2 plays a role in membrane transduction of neurotransmitter signals as well as in intracellular signalling, pathways that may be impaired in schizophrenia.
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Acknowledgements
We are extremely thankful to Dr SC Bakker (Department of Psychiatry and Department of Biomedical Genetics, University Medical Center, Utrecht, The Netherlands) for communicating data before publication. We are very grateful to the patients and their family members without whose support and interest this study would not have been possible. We gratefully acknowledge support from the German–Israeli Foundation (to BL and DBW), Deutsche Forschungsgemeinschaft SFB 400 (to SGS, MK, WM and DBW) and DFG Grant Kn378/1-3 (to MK). DBW is recipient of a NARSAD Independent Investigator Award. SGS would like to thank Professor Eric Lander for hospitality during the initial phase of this work.
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Schwab, S., Knapp, M., Sklar, P. et al. Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIα gene (PIP5K2A) with schizophrenia. Mol Psychiatry 11, 837–846 (2006). https://doi.org/10.1038/sj.mp.4001864
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DOI: https://doi.org/10.1038/sj.mp.4001864
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