Abstract
A recent ‘mega-analysis’ combining genome-wide association study data from over 40 000 individuals identified novel genetic loci associated with schizophrenia (SCZ) at genome-wide significance level. The strongest finding was a locus within an intron of a putative primary transcript for microRNA MIR137. In the current study, we examine the impact of variation at this locus (rs1625579, G/T; where T is the common and presumed risk allele) on brain activation during a sentence completion task that differentiates individuals with SCZ, bipolar disorder (BD), and their relatives from controls. We examined three groups of individuals performing a sentence completion paradigm: (i) individuals at high genetic risk of SCZ (n=44), (ii) individuals at high genetic risk of BD (n=90), and (iii) healthy controls (n=81) in order to test the hypothesis that genotype at rs1625579 would influence brain activation. Genotype groups were assigned as ‘RISK−’ for GT and GG individuals, and ‘RISK+’ for TT homozygotes. The main effect of genotype was significantly greater activation in the RISK− individuals in the posterior right medial frontal gyrus, BA 6. There was also a significant genotype*group interaction in the left amygdala and left pre/postcentral gyrus. This was due to differences between the controls (where individuals with the RISK− genotype showed greater activation than RISK+ subjects) and the SCZ high-risk group, where the opposite genotype effect was seen. These results suggest that the newly identified SCZ locus may influence brain activation in a manner that is partly dependent on the presence of existing genetic susceptibility for SCZ.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Ambros V (2004). The functions of animal microRNAs. Nature 431: 350–355.
Andreasen NC, Paradiso S, O’Leary DS (1998). ‘Cognitive dysmetria’ as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? Schizophr Bull 24: 203–218.
Arts B, Jabben J, Krabbendam L, van Os J (2008). Meta-analyses of cognitive functioning in euthymic bipolar patients and their first-degree relatives. Psychol Med 38: 771–785.
Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ (2011). Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry 15: 1176–1189.
Bitan T, Burman DD, Chou T, Lu D, Cone NE, Cao F et al (2007). The interaction between orthographic and phonological information in children: an fMRI Study. Hum Brain Mapp 28: 880–891.
Bloom PA, Fischler I (1980). Completion norms for 329 sentence contexts. Mem Cognt 8: 631–642.
Bokat CE, Goldberg TE (2003). Letter and category fluency in schizophrenic patients: a meta-analysis. Schizophr Res 64: 73–78.
Burgess P, Shallice T (1997). The Hayling and Brixton Tests. Thames Valley Test Company Limited: Bury St Edmunds.
Craddock N, O’Donovan MC, Owen MJ (2005). The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 42: 193–204.
Dazzan P, Morgan KD, Orr KG, Hutchinson G, Chitnis X, Suckling J et al (2004). The structural brain correlates of neurological soft signs in AESOP first-episode psychoses study. Brain 127: 143–153.
Exner C, Weniger G, Schmidt-Samoa C, Irle E (2006). Reduced size of the pre-supplementary motor cortex and impaired motor sequence learning in first-episode schizophrenia. Schizophr Res 84: 386–396.
First MB, Spitzer RL, Miriam G, Williams JBW (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). Biometrics Research, New York State Psychiatric Institute: New York.
Forero DA, van der Ven K, Callaerts P, Del-Favero J (2010). miRNA genes and the brain: implications for psychiatric disorders. Hum Mutat 31: 1195–1204.
Fusar-Poli P, Perez J, Broome M, Borgwardt S, Placentino A, Caverzasi E et al (2007). Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis. Neurosci Biobehav Rev 31: 465–484.
Geekiyanage H, Chan C (2011). MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid beta, novel targets in sporadic Alzheimer's disease. J Neurosci 31: 14820–14830.
Glahn DC, Laird AR, Ellison-Wright I, Thelen SM, Robinson JL, Lancaster JL et al (2008). Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis. Biol Psychiatry 64: 774–781.
Gountouna VE, Job DE, McIntosh AM, Moorhead TW, Lymer GK, Whalley HC et al (2011). Functional magnetic resonance imaging (fMRI) reproducibility and variance components across visits and scanning sites with a finger tapping task. Neuroimage 49: 552–560.
Gourovitch ML, Goldberg TE (1996). Cognitive deficits in schizophrenia: attention, executive functions, memory and language processing. In: Pantelis C, Nelson HE, Barnes TRE (eds). Schizophrenia A Neuropsychological Perspective. Wiley: Chichester, UK. pp 72–86.
Gur RE, McGrath C, Chan RM, Schroeder L, Turner T, Turetsky BI et al (2002). An fMRI study of facial emotion processing in patients with schizophrenia. Am J Psychiatry 159: 1992–1999.
Hall J, Whalley HC, McKirdy JW, Romaniuk L, McGonigle DJ, McIntosh AM et al (2008). Overactivation of fear systems to neutral faces in schizophrenia. Biol Psychiatry 64: 70–73.
Heinrichs RW, Zakzanis KK (1998). Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12: 426–445.
Hodges A, Byrne M, Grant E, Johnstone E (1999). People at risk of schizophrenia. Sample characteristics of the first 100 cases in the Edinburgh High-Risk Study [see comment]. Br J Psychiatry 174: 547–553.
Holt DJ, Kunkel L, Weiss AP, Goff DC, Wright CI, Shin LM et al (2006). Increased medial temporal lobe activation during the passive viewing of emotional and neutral facial expressions in schizophrenia. Schizophr Res 82: 153–162.
Honey GD, Pomarol-Clotet E, Corlett PR, Honey RA, McKenna PJ, Bullmore ET et al (2005). Functional dysconnectivity in schizophrenia associated with attentional modulation of motor function. Brain 128: 2597–2611.
Jansma JM, Ramsey NF, Coppola R, Kahn RS (2000). Specific vs nonspecific brain activity in a parametric N-back task. Neuroimage 12: 688–697.
Jardri R, Pouchet A, Pins D, Thomas P (2011). Cortical activations during auditory verbal hallucinations in schizophrenia: a coordinate-based meta-analysis. Am J Psychiatry 168: 73–81.
Job DE, Whalley HC, McConnell S, Glabus M, Johnstone EC, Lawrie SM (2002). Structural gray matter differences between first-episode schizophrenics and normal controls using voxel-based morphometry. Neuroimage 17: 880–889.
Johnstone EC, Abukmeil SS, Byrne M, Clafferty R, Grant E, Hodges A et al (2000). Edinburgh high risk study—findings after four years: demographic, attainment and psychopathological issues. Schizophr Res 46: 1–15.
Kim AH, Reimers M, Maher B, Williamson V, McMichael O, McClay JL et al (2010). MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders. Schizophr Res 124: 183–191.
Kircher TT, Liddle PF, Brammer MJ, Williams SC, Murray RM, McGuire PK (2001). Neural correlates of formal thought disorder in schizophrenia: preliminary findings from a functional magnetic resonance imaging study. Arch Gen Psychiatry 58: 769–774.
Lawrie SM, Abukmeil SS (1998). Brain abnormality in schizophrenia. A systematic and quantitative review of volumetric magnetic resonance imaging studies.[see comment]. Br J Psychiatry 172: 110–120.
Lichtenstein P, Yip BH, Bjork C, Pawitan Y, Cannon TD, Sullivan PF et al (2009). Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373: 234–239.
Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH (2003). An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 19: 1233–1239.
McGuffin P, Farmer A, Harvey I (1991). A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Arch Gen Psychiatry 48: 764–770.
McGuire PK, Silbersweig DA, Wright I, Murray RM, David AS, Frackowiak RS et al (1995). Abnormal monitoring of inner speech: a physiological basis for auditory hallucinations. Lancet 346: 596–600.
McIntosh A, Whalley HC, McKirdy J, Hall J, Sussmann J, Shankar P et al (2008a). Differences in dorsal and ventral prefrontal function separate bipolar disorder from schizophrenia. Schizoprenia Research 98: 40.
McIntosh AM, Whalley HC, McKirdy J, Hall J, Sussmann JE, Shankar P et al (2008b). Prefrontal function and activation in bipolar disorder and schizophrenia. Am J Psychiatry 165: 378–384.
Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC (2009). Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry 66: 811–822.
Nachev P, Kennard C, Husain M (2008). Functional role of the supplementary and pre-supplementary motor areas. Nat Rev Neurosci 9: 856–869.
Nelson H (1982). The National Adult Reading Test Manual. Windsor: NFER-Nelson.
Nenadic I, Smesny S, Schlosser RG, Sauer H, Gaser C (2010). Auditory hallucinations and brain structure in schizophrenia: voxel-based morphometric study. Br J Psychiatry 196: 412–413.
Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA et al (2007). microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol 8: R27.
Phillips ML, Drevets WC, Rauch SL, Lane R (2003). Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry 54: 515–528.
Phillips ML, Williams L, Senior C, Bullmore ET, Brammer MJ, Andrew C et al (1999). A differential neural response to threatening and non-threatening negative facial expressions in paranoid and non-paranoid schizophrenics. Psychiatry Res 92: 11–31.
Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF et al (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460: 748–752.
Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA et al (2011). Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43: 969–976.
Romaniuk L, Honey GD, King JR, Whalley HC, McIntosh AM, Levita L et al (2010). Midbrain activation during Pavlovian conditioning and delusional symptoms in schizophrenia. Arch Gen Psychiatry 67: 1246–1254.
Rypma B, Prabhakaran V, Desmond JE, Glover GH, Gabrieli JD (1999). Load-dependent roles of frontal brain regions in the maintenance of working memory. Neuroimage 9: 216–226.
Schneider F, Weiss U, Kessler C, Salloum JB, Posse S, Grodd W et al (1998). Differential amygdala activation in schizophrenia during sadness. Schizophr Res 34: 133–142.
Schwartz CE, Wright CI, Shin LM, Kagan J, Whalen PJ, McMullin KG et al (2003). Differential amygdalar response to novel vs newly familiar neutral faces: a functional MRI probe developed for studying inhibited temperament. Biol Psychiatry 53: 854–862.
Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V (2004). Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 5: R13.
Shenton ME, Dickey CC, Frumin M, McCarley RW (2001). A review of MRI findings in schizophrenia. Schizophr Res 49: 1–52.
Shi Y, Zhao X, Hsieh J, Wichterle H, Impey S, Banerjee S et al (2010). MicroRNA regulation of neural stem cells and neurogenesis. J Neurosci 30: 14931.
Smith S, Jenkinson M, Beckmann C, Miller K, Woolrich M (2007). Meaningful design and contrast estimability in FMRI. Neuroimage 34: 127–136.
Smrt RD, Szulwach KE, Pfeiffer RL, Li X, Guo W, Pathania M et al (2010). MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 28: 1060–1070.
Strakowski SM, Delbello MP, Adler CM (2005). The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Mol Psychiatry 10: 105–116.
Suckling J, Barnes A, Job D, Brennan D, Lymer K, Dazzan P et al (2012). The neuro/PsyGRID calibration experiment: identifying sources of variance and bias in multicenter MRI studies. Hum Brain Mapp 33: 373–386.
Sun J, Ming GL, Song H (2011). Epigenetic regulation of neurogenesis in the adult mammalian brain. Eur J Neurosci 33: 1087–1093.
Surguladze S, Russell T, Kucharska-Pietura K, Travis MJ, Giampietro V, David AS et al (2006). A reversal of the normal pattern of parahippocampal response to neutral and fearful faces is associated with reality distortion in schizophrenia. Biol Psychiatry 60: 423–431.
Szulwach KE, Li X, Smrt RD, Li Y, Luo Y, Lin L et al (2010). Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol 189: 127–141.
Tanskanen P, Ridler K, Murray GK, Haapea M, Veijola JM, Jaaskelainen E et al (2010). Morphometric brain abnormalities in schizophrenia in a population-based sample: relationship to duration of illness. Schizophr Bull 36: 766–777.
Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N et al (2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15: 273–289.
Wessa M, Linke J (2009). Emotional processing in bipolar disorder: behavioural and neuroimaging findings. Int Rev Psychiatry 21: 357–367.
Whalley HC, Simonotto E, Flett S, Marshall I, Ebmeier KP, Owens DG et al (2004). fMRI correlates of state and trait effects in subjects at genetically enhanced risk of schizophrenia. [see comment]. Brain 127: 478–490.
Whalley HC, Sussmann JE, Chakirova G, Mukerjee P, Peel A, McKirdy J et al (2011). The neural basis of familial risk and temperamental variation in individuals at high risk of bipolar disorder. Biol Psychiatry 70: 343–349.
Whalley HC, Whyte MC, Johnstone EC, Lawrie SM (2005). Neural correlates of enhanced genetic risk for schizophrenia. Neuroscientist 11: 238–249.
Williams LM, Das P, Harris AW, Liddell BB, Brammer MJ, Olivieri G et al (2004). Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia. Am J Psychiatry 161: 480–489.
Zhou SY, Suzuki M, Hagino H, Takahashi T, Kawasaki Y, Matsui M et al (2005). Volumetric analysis of sulci/gyri-defined in vivo frontal lobe regions in schizophrenia: precentral gyrus, cingulate gyrus, and prefrontal region. Psychiatry Res 139: 127–139.
Acknowledgements
We thank all of the participants who took part in the study and the radiographers who acquired the MRI scans. This study was conducted at the Scottish Brain Imaging Research Centre, which is supported by SINAPSE (Scottish Imaging Network, a Platform for Scientific Excellence, www.sinapse.ac.uk). The investigators also acknowledge the financial support of National Health Service (NHS) Research Scotland, through the Scottish Mental Health Research Network (http://www.smhrn.org.uk) who provided assistance with subject recruitment and cognitive assessments.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author HCW is supported by a Dorothy Hodgkin Fellowship from the Royal Society of Edinburgh (DH080018). MP and ES are supported by a studentship from the Medical Research Council. JH is supported by a Scottish Senior Clinical Fellowship from the Chief Scientists Office in Scotland. JES is supported by a Clinical Research Training Fellowship from the Wellcome Trust. AMM was supported by the Health Foundation through a Clinician Scientist Fellowship (Ref: 2268/4295) and by the National Alliance for Research on Schizophrenia and Depression through an Independent Investigator Award. The investigators also acknowledge the financial support of National Health Service (NHS) Research Scotland through the Scottish Mental Health Research Network (http://www.smhrn.org.uk), which provided assistance with subject recruitment and cognitive assessments. All imaging aspects also received financial support from the Dr Mortimer and Theresa Sackler Foundation. HCW, ES, JH, SML, and AMM have received financial support from Pfizer (formerly Wyeth) in relation to imaging studies of people with SCZ and BD. SML, ECJ, and AMM have done consultancy work for Roche Pharmaceuticals in connection with a possible new treatment for SCZ. ECJ has also done consultancy work for Novartis. SML has also received honoraria for lectures, chairing meetings, and consultancy work from Janssen in connection with brain imaging and therapeutic initiatives for psychosis. The authors MP, LR, KLE, HPB, and JES have no competing interests to declare.
Additional information
Supplementary accompanies the paper on the Neuropsychopharmacology website
Supplementary information
PowerPoint slides
Rights and permissions
About this article
Cite this article
Whalley, H., Papmeyer, M., Romaniuk, L. et al. Impact of a microRNA MIR137 Susceptibility Variant on Brain Function in People at High Genetic Risk of Schizophrenia or Bipolar Disorder. Neuropsychopharmacol 37, 2720–2729 (2012). https://doi.org/10.1038/npp.2012.137
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2012.137
Keywords
This article is cited by
-
MiR-137: an important player in neural development and neoplastic transformation
Molecular Psychiatry (2017)
-
Polymorphisms in MIR137HG and microRNA-137-regulated genes influence gray matter structure in schizophrenia
Translational Psychiatry (2016)
-
A pilot study on commonality and specificity of copy number variants in schizophrenia and bipolar disorder
Translational Psychiatry (2016)
-
MIR137 variants identified in psychiatric patients affect synaptogenesis and neuronal transmission gene sets
Molecular Psychiatry (2015)
-
MicroRNAs in Schizophrenia: Implications for Synaptic Plasticity and Dopamine–Glutamate Interaction at the Postsynaptic Density. New Avenues for Antipsychotic Treatment Under a Theranostic Perspective
Molecular Neurobiology (2015)
