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

Molecular Psychiatry volume 17, pages 1328–1339 (2012)Cite this article

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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.

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Acknowledgements

We thank patients, family members and volunteer controls for their participation. The study was supported by National Health and Medical Research Council of Australia Grant Nos. 37580400 and 37580900 to AJ and LK and Training Fellowship 634551 to DNA, with funding contribution from the North Metropolitan Health Area, Perth, Western Australia. Recruitment and genotyping of the Irish sample was supported by the Wellcome Trust and Science Foundation Ireland (SFI). Research performed at Los Alamos National Laboratory was carried out under the auspices of the National Nuclear Security Administration of the US Department of Energy under Contract No. DE-AC52-06NA25396. GD was supported by an NARSAD Young Investigator Award, and EB-B by an MRC (UK) Young Investigator Award. CSW is supported by the Schizophrenia Research Institute, utilising funds from the Macquarie Group Foundation and NSW Health. The SH-SY5Y cell line was a kind gift from Dr B Meloni (CNND, UWA) and the pcDNA3.1 (+) vector plasmid from Dr K Pfleger (WAIMR, UWA).

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Author notes

  1. M Cruickshank

    Present address: 15Current address: 3 Early Life Epigenetics, Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.,

Authors and Affiliations

  1. Centre for Clinical Research in Neuropsychiatry, The University of Western Australia, Perth, WA, Australia

    A Jablensky, M Dragovic & J Badcock

  2. School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, WA, Australia

    A Jablensky & O P Almeida

  3. Centre for Medical Research/Western Australian Institute for Medical Research, The University of Western Australia, Perth, WA, Australia

    D Angelicheva, D N Azmanov, D Chandler, B Morar, P L Verbrugghe, A Filipovska, O Rackham, M Phillips & L Kalaydjieva

  4. Institute of Molecular Medicine and Department of Psychiatry, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Trinity College, Dublin, Ireland

    G J Donohoe, D W Morris, M Gill & A Corvin

  5. School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Perth, WA, Australia

    M Cruickshank

  6. Queensland Institute for Medical Research, Brisbane, QLD, Australia

    A McRae & S MacGregor

  7. Schizophrenia Research Institute, School of Psychiatry, University of New South Wales and Neuroscience Research Australia, Randwick, NSW, Australia

    C S Weickert

  8. Telethon Institute for Child Health Research, Perth, WA, Australia

    K W Carter & M Cooper

  9. Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, USA

    B Alexandrov, A R Bishop & K Ø Rasmussen

  10. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    A Usheva

  11. Institute of Psychiatry, Kings College, London, UK

    E Bramon-Bosch

  12. NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust, London, UK

    E Bramon-Bosch & L Flicker

  13. Western Australian Centre for Health and Aging, Centre for Health Research, The University of Western Australia, Perth, WA, Australia

    O P Almeida

  14. School of Medicine and Pharmacology, The University of Western Australia, Perth, WA, Australia

    L Flicker

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Jablensky, A., Angelicheva, D., Donohoe, G. et al. Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia. Mol Psychiatry 17, 1328–1339 (2012). https://doi.org/10.1038/mp.2011.129

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