Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIα gene (PIP5K2A) with schizophrenia

S. G. Schwab, M. Knapp, P. Sklar, G. N. Eckstein, C. Sewekow, M. Borrmann-Hassenbach, M. Albus, T. Becker, J. F. Hallmayer, B. Lerer, W. Maier, D. B. Wildenauer

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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.

Original languageEnglish
Pages (from-to)837-846
Number of pages10
JournalMolecular Psychiatry
Volume11
Issue number9
DOIs
StatePublished - Sep 2006
Externally publishedYes

Keywords

  • Candidate gene
  • Linkage disequilibrium
  • Non-synonymous amino-acid exchange
  • Phosphoinositide cell signalling
  • Single nucleotide polymorphism

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