title: Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia.
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.
authors.affiliation: Centre for Clinical Research in Neuropsychiatry, The University of Western Australia, Perth, WA, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Jablensky
authors.forename: D
authors.initials: D
authors.lastname: Angelicheva
authors.forename: G J
authors.initials: GJ
authors.lastname: Donohoe
authors.forename: M
authors.initials: M
authors.lastname: Cruickshank
authors.forename: D N
authors.initials: DN
authors.lastname: Azmanov
authors.forename: D W
authors.initials: DW
authors.lastname: Morris
authors.forename: A
authors.initials: A
authors.lastname: McRae
authors.forename: C S
authors.initials: CS
authors.lastname: Weickert
authors.forename: K W
authors.initials: KW
authors.lastname: Carter
authors.forename: D
authors.initials: D
authors.lastname: Chandler
authors.forename: B
authors.initials: B
authors.lastname: Alexandrov
authors.forename: A
authors.initials: A
authors.lastname: Usheva
authors.forename: B
authors.initials: B
authors.lastname: Morar
authors.forename: P L
authors.initials: PL
authors.lastname: Verbrugghe
authors.forename: A
authors.initials: A
authors.lastname: Filipovska
authors.forename: O
authors.initials: O
authors.lastname: Rackham
authors.forename: A R
authors.initials: AR
authors.lastname: Bishop
authors.forename: K Ø
authors.initials: KØ
authors.lastname: Rasmussen
authors.forename: M
authors.initials: M
authors.lastname: Dragovic
authors.forename: M
authors.initials: M
authors.lastname: Cooper
authors.forename: M
authors.initials: M
authors.lastname: Phillips
authors.forename: J
authors.initials: J
authors.lastname: Badcock
authors.forename: E
authors.initials: E
authors.lastname: Bramon-Bosch
authors.forename: O P
authors.initials: OP
authors.lastname: Almeida
authors.forename: L
authors.initials: L
authors.lastname: Flicker
authors.forename: M
authors.initials: M
authors.lastname: Gill
authors.forename: A
authors.initials: A
authors.lastname: Corvin
authors.forename: S
authors.initials: S
authors.lastname: MacGregor
authors.forename: L
authors.initials: L
authors.lastname: Kalaydjieva
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D002460:Cell Line; D003072:Cognition Disorders / Q000150:complications / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005807:Genes, Overlapping / Q000235:genetics*; D056726:Genetic Association Studies / Q000706:statistics & numerical data; D006801:Humans; D035925:Iron-Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D010652:Phenylalanine-tRNA Ligase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012559:Schizophrenia / Q000150:complications / Q000235:genetics*; D012565:Schizophrenic Psychology
chemical_list: D035925:Iron-Regulatory Proteins; C544445:LYRM4 protein, human; D024101:Mitochondrial Proteins; D010652:Phenylalanine-tRNA Ligase