Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia.

Hdl Handle:
http://hdl.handle.net/10147/238793
Title:
Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia.
Authors:
Jablensky, A; Angelicheva, D; Donohoe, G J; Cruickshank, M; Azmanov, D N; Morris, D W; McRae, A; Weickert, C S; Carter, K W; Chandler, D; Alexandrov, B; Usheva, A; Morar, B; Verbrugghe, P L; Filipovska, A; Rackham, O; Bishop, A R; Rasmussen, K Ø; Dragovic, M; Cooper, M; Phillips, M; Badcock, J; Bramon-Bosch, E; Almeida, O P; Flicker, L; Gill, M; Corvin, A; Macgregor, S; Kalaydjieva, L
Affiliation:
1] Centre for Clinical Research in Neuropsychiatry, The University of Western Australia, Perth, WA, Australia [2] School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, WA, Australia.
Citation:
Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia. 2011: Mol. Psychiatry
Journal:
Molecular psychiatry
Issue Date:
4-Oct-2011
URI:
http://hdl.handle.net/10147/238793
DOI:
10.1038/mp.2011.129
PubMed ID:
21968932
Abstract:
In a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 Mb interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated with CD scores and memory performance. The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins. The two tagging SNPs with strongest evidence of association were located around the overlapping putative promoters, with rs2224391 predicted to alter a transcription factor binding site (TFBS). Sequencing the promoter region identified 22 SNPs, many predicted to affect TFBSs, in a tight linkage disequilibrium block. Luciferase reporter assays confirmed promoter activity in the predicted promoter region, and demonstrated marked downregulation of expression in the LYRM4 direction under the haplotype comprising the minor alleles of promoter SNPs, which however is not driven by rs2224391. Experimental evidence from LYRM4 expression in lymphoblasts, gel-shift assays and modelling of DNA breathing dynamics pointed to two adjacent promoter SNPs, rs7752203-rs4141761, as the functional variants affecting expression. Their C-G alleles were associated with higher transcriptional activity and preferential binding of nuclear proteins, whereas the G-A combination had opposite effects and was associated with poor memory and high CD scores. LYRM4 is a eukaryote-specific component of the mitochondrial biogenesis of Fe-S clusters, essential cofactors in multiple processes, including oxidative phosphorylation. LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis.Molecular Psychiatry advance online publication, 4 October 2011; doi:10.1038/mp.2011.129.
Item Type:
Article
Language:
en
ISSN:
1476-5578

Full metadata record

DC FieldValue Language
dc.contributor.authorJablensky, Aen_GB
dc.contributor.authorAngelicheva, Den_GB
dc.contributor.authorDonohoe, G Jen_GB
dc.contributor.authorCruickshank, Men_GB
dc.contributor.authorAzmanov, D Nen_GB
dc.contributor.authorMorris, D Wen_GB
dc.contributor.authorMcRae, Aen_GB
dc.contributor.authorWeickert, C Sen_GB
dc.contributor.authorCarter, K Wen_GB
dc.contributor.authorChandler, Den_GB
dc.contributor.authorAlexandrov, Ben_GB
dc.contributor.authorUsheva, Aen_GB
dc.contributor.authorMorar, Ben_GB
dc.contributor.authorVerbrugghe, P Len_GB
dc.contributor.authorFilipovska, Aen_GB
dc.contributor.authorRackham, Oen_GB
dc.contributor.authorBishop, A Ren_GB
dc.contributor.authorRasmussen, K Øen_GB
dc.contributor.authorDragovic, Men_GB
dc.contributor.authorCooper, Men_GB
dc.contributor.authorPhillips, Men_GB
dc.contributor.authorBadcock, Jen_GB
dc.contributor.authorBramon-Bosch, Een_GB
dc.contributor.authorAlmeida, O Pen_GB
dc.contributor.authorFlicker, Len_GB
dc.contributor.authorGill, Men_GB
dc.contributor.authorCorvin, Aen_GB
dc.contributor.authorMacgregor, Sen_GB
dc.contributor.authorKalaydjieva, Len_GB
dc.date.accessioned2012-08-15T14:08:54Z-
dc.date.available2012-08-15T14:08:54Z-
dc.date.issued2011-10-04-
dc.identifier.citationPromoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia. 2011: Mol. Psychiatryen_GB
dc.identifier.issn1476-5578-
dc.identifier.pmid21968932-
dc.identifier.doi10.1038/mp.2011.129-
dc.identifier.urihttp://hdl.handle.net/10147/238793-
dc.description.abstractIn a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 Mb interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated with CD scores and memory performance. The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins. The two tagging SNPs with strongest evidence of association were located around the overlapping putative promoters, with rs2224391 predicted to alter a transcription factor binding site (TFBS). Sequencing the promoter region identified 22 SNPs, many predicted to affect TFBSs, in a tight linkage disequilibrium block. Luciferase reporter assays confirmed promoter activity in the predicted promoter region, and demonstrated marked downregulation of expression in the LYRM4 direction under the haplotype comprising the minor alleles of promoter SNPs, which however is not driven by rs2224391. Experimental evidence from LYRM4 expression in lymphoblasts, gel-shift assays and modelling of DNA breathing dynamics pointed to two adjacent promoter SNPs, rs7752203-rs4141761, as the functional variants affecting expression. Their C-G alleles were associated with higher transcriptional activity and preferential binding of nuclear proteins, whereas the G-A combination had opposite effects and was associated with poor memory and high CD scores. LYRM4 is a eukaryote-specific component of the mitochondrial biogenesis of Fe-S clusters, essential cofactors in multiple processes, including oxidative phosphorylation. LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis.Molecular Psychiatry advance online publication, 4 October 2011; doi:10.1038/mp.2011.129.en_GB
dc.languageENG-
dc.language.isoenen
dc.rightsArchived with thanks to Molecular psychiatryen_GB
dc.titlePromoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia.en_GB
dc.typeArticleen
dc.contributor.department1] Centre for Clinical Research in Neuropsychiatry, The University of Western Australia, Perth, WA, Australia [2] School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, WA, Australia.en_GB
dc.identifier.journalMolecular psychiatryen_GB
dc.description.provinceLeinsteren

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