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    Cummings 2010

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    Fahrunnisa Nurdin
    This document summarizes a study that investigated the relationship between a schizophrenia risk gene called ZNF804A and clinical symptomatology in 820 patients with psychotic disorders. The study found: 1) Carriers of the ZNF804A risk allele had significantly higher lifetime mania scores on a clinical assessment scale. 2) There was no significant association found between ZNF804A genotype and mania symptom factor scores derived from a checklist of lifetime symptoms. 3) Nominal evidence was found for an association between the risk allele and increased reports of "racing thoughts" and "reduced need for sleep" on the symptom checklist.

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    Cummings 2010

    Uploaded by

    Fahrunnisa Nurdin
    12 views3 pages
    This document summarizes a study that investigated the relationship between a schizophrenia risk gene called ZNF804A and clinical symptomatology in 820 patients with psychotic disorders. The study found: 1) Carriers of the ZNF804A risk allele had significantly higher lifetime mania scores on a clinical assessment scale. 2) There was no significant association found between ZNF804A genotype and mania symptom factor scores derived from a checklist of lifetime symptoms. 3) Nominal evidence was found for an association between the risk allele and increased reports of "racing thoughts" and "reduced need for sleep" on the symptom checklist.

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    This document summarizes a study that investigated the relationship between a schizophrenia risk gene called ZNF804A and clinical symptomatology in 820 patients with psychotic disorders. The study found: 1) Carriers of the ZNF804A risk allele had significantly higher lifetime mania scores on a clinical assessment scale. 2) There was no significant association found between ZNF804A genotype and mania symptom factor scores derived from a checklist of lifetime symptoms. 3) Nominal evidence was found for an association between the risk allele and increased reports of "racing thoughts" and "reduced need for sleep" on the symptom checklist.

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    © All Rights Reserved
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    12 views3 pages

    Cummings 2010

    Uploaded by

    Fahrunnisa Nurdin
    This document summarizes a study that investigated the relationship between a schizophrenia risk gene called ZNF804A and clinical symptomatology in 820 patients with psychotic disorders. The study found: 1) Carriers of the ZNF804A risk allele had significantly higher lifetime mania scores on a clinical assessment scale. 2) There was no significant association found between ZNF804A genotype and mania symptom factor scores derived from a checklist of lifetime symptoms. 3) Nominal evidence was found for an association between the risk allele and increased reports of "racing thoughts" and "reduced need for sleep" on the symptom checklist.

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    of 3

    Machine Translated by Google

    Schizophrenia Research 122 (2010) 273–275

    Contents lists available at ScienceDirect

    Schizophrenia Research
    journalh om epage : www. els ev ie r. c om /locate/schres

    Letter to the Editors


    Clinical symptomatology and the psychosis risk gene All genotypes were found to be concordant with either the available
    ZNF804A online HapMap data or each other for this SNP.
    An exploratory factor analysis using the 60 items relating to
    clinical signs and symptoms from the Operational Criteria Checklist
    Dear Editors, for Psychotic Illness yielded 44 items with loadings of 0.4 or more.
    A five factor solution gave an interpretable pattern of factors, namely
    The single nucleotide polymorphism (SNP) rs1344706, mapping manic, depressive, positive, disorganized and negative factors
    to the gene ZNF804A, has been implicated in schizophrenia (Supplementary Fig. 1, Supplementary Table 1). Factor score
    susceptibility (O'Donovan et al. 2008; Interna-tional Schizophrenia coefficients were then calculated in SPSS 16.0 using the regression
    Consortium, 2009; Stefansson et al. method. There were no significant differences observed between
    2009; Steinberg et al. 2010). The original study reported stronger the ZNF804A genotype groups with respect to current age, age at
    association when the phenotype was broadened to include bipolar onset, gender, diagnosis, medication and course of disorder
    disorder (p= 9.96× 10ÿ9 ) (O'Donovan et al. 2008), but the variant is (Supplementary Table 2).
    likely to have a modest effect on disease risk (OR= 1.12).
    Understanding the function of psychosis risk genes is a key step A MANOVA looking at the relationship between ZNF804A status
    towards understanding disease biology. Little is currently known and BADDS Scores showed a significant association between
    about the encoding protein, zinc finger protein 804A, except that it ZNF804A status and the BADDS score for mania (p= 0.014).
    is brain-expressed and predicted to be involved in regulation of Carriers of the previously identified risk allele had higher BADDS
    gene expression. Two recent studies suggest that the ZNF804A risk mania scores. Partial eta squared was 0.011, which suggested that
    allele is likely to influence brain function, both with respect to ZNF804A genotype was respon-sible for 1.1% of variance of this
    connectivity within and between the dorsolateral prefrontal cortex score (Table 1).
    and hippocampus (Esslinger et al. 2009) and on episodic and ZNF804A genotype status was not associated with higher Manic
    working memory (Walters et al. in press). Factor scores derived from the OPCRIT factor analysis (p= 0.169),
    (Supplementary Table 3). Examining the indi-vidual symptom items
    there was nominal evidence for association between the risk allele
    An unanswered question is whether this gene has an effect at and ‘reduced need for sleep’ (p= 0.014) and having ‘racing thoughts’
    the level of clinical symptomatology within patient populations. (p= 0.048).
    Specifically, does this risk variant delineate a specific form of illness Neither finding would withstand correction for the number of
    on the mood-psychosis spectrum (Craddock et al. 2006). For this symptoms examined, but in both instances, carriers of the risk allele
    study we investigated clinical symptom factors in a large sample experienced more symptoms.
    (n= 820) of Irish psychotic patients. The study included 820 patients This study suggests modest evidence that carriers of the
    with a DSM-IV diagnosis of schizophrenia (N= 568), schizoaffective rs1344706 risk allele score higher on a measure which weights for
    disorder (N= 127) or bipolar affective disorder (N= 125). the number and severity of lifetime manic episodes. This did not
    translate into association with a derived factor score based on a
    Because clinical symptoms can vary over time we analyzed two lifetime history of having specific manic symptoms, but there was
    measures of clinical symptomatology based on lifetime severity modest support for an increase in ‘racing thoughts’ and ‘reduced
    (BADDS) and presence of specific symptoms (Oper-ational Criteria need for sleep’.
    Checklist for Psychotic Illness, OPCRIT)
    (McGuffin et al. 1991). We attempted to address the difficulties inherent in measuring
    SNP rs1344706 was genotyped using a Taqman® SNP symptoms which fluctuate over time by using two different validated
    Genotyping Assay on a 7900HT Sequence Detection System lifetime measures to capture infor-mation on illness episodes and
    (Applied Biosystems) (n= 529) and the Sequenom iPLEX Gold illness factors based on discrete symptoms. Within a broad
    system (n= 291) (detailed in Walters et al. in press). psychosis population we may have undersampled patients with
    The call rate for both genotyping platforms was N95%. Both case/ manic symptomatol-ogy and the study may be underpowered.
    control samples were in Hardy–Weinberg Equilibrium (HWE; Further data, for example, using serial assessments in larger
    pN0.05). A number of HapMap CEU DNA samples (n= 90: samples may be required to address these possibilities. This would
    www.hapmap.org) and duplicates (n= 60) were genotyped across assume that the effect was driven exclusively by the subset of
    platforms for quality control purposes.

    0920-9964/$ – see front matter © 2010 Published by Elsevier B.V.


    doi:10.1016/j.schres.2010.05.022
    Machine Translated by Google

    274 Letter to the Editors

    Table 1
    Multivariate analysis of variance of ZNF804A genotype groups (CC vs AC vs AA) with BADDS dimension scores.

    BADDS dimension Mean (SD) CC Mean (SD) AC Mean (SD) AA Type III sum df Mean square F(CC vs AC vs AA) Sig. Partial and
    score of squares squared

    Mania 24.07 (28.81) 31.69 (31.26) 32.89 (31.25) 8209.327 2 4104.663 4.301 .014 .010
    Depression 44.23 (40.65) 39.49 (40.6 41.17 (41.75) 1533.638 2 766.819 .452 .636 .001
    Psychotic 40.33 (28.39) 38.50 (40.60) 39.73 (28.22) 396.802 2 198.401 .248 .781 .001
    Incongruence 56.50 (32.01) 58.69 (30.73) 60.80 (29.20) 1578.198 2 789.099 .929 .395 .002

    patients in the study with a diagnosis of bipolar disorder International Schizophrenia Consortium, 2009. Common polygenic variation
    (n= 125) or schizoaffective disorder (n= 127). However, contributes to risk of schizophrenia and bipolar disorder. Nature 460
    (7256), 748–752.
    when we restrict the analysis to patients with schizophrenia McGuffin, P., Farmer, A., Harvey, I., 1991. A polydiagnostic application of
    only (n= 568) the association between genotype and BADDS operational criteria in psychotic illness: development and reliability
    mania score remains significant (p= 0.05). A secondary of the OPCRIT system. Arch. Gen. Psychiatry 48 (8), 764–770.
    O'Donovan, M.C., Craddock, N., Norton, N., Williams, H., Peirce, T.,
    question is whether this association is independent of, or Moskvina, V., Nikolov, I., Hamshere, M., Carroll, L., Georgieva, L.,
    related to, the previous observation of relatively spared et al., 2008. Identification of loci associated with schizophrenia
    cognitive performance in patient carriers of the risk allele. by genome-wide association and follow-up. Nat. Genet. 40 (9),
    1053–1055.
    We have insufficient cognitive data available on bipolar
    Stefansson, H., Ophoff, R.A., Steinberg, S., et al., 2009. Common variants
    patients (or patients who score highly on BADDS mania) conferring risk of schizophrenia. Nature 460 (7256), 744–747.
    within our sample to address this question as part of the Steinberg, S., Mors, O., Børglum, AD, Gustafsson, O., Werge, T., Mortensen,
    current work. P.B., et al., 2010. Expanding the range of ZNF804A variants conferring
    risk of psychosis. Mol. Psychiatry. doi:10.1038/mp.2009.149 Electronic
    publication ahead of print January 5.
    Role of funding source Walters J.T.R., Corvin A., Williams H., Dragovic M., Quinn E.M., et al. In Press. The
    psychosis susceptibility gene ZNF804A is associated with less impaired
    This study was funded by the Wellcome Trust and Science Foundation
    cognitive performance in schizophrenia. Archives of General psychiatry.
    Ireland (SFI).

    Contributors
    Dr Elizabeth Cummings and Dr Aiden Corvin conducted data analyses E. Cummings
    and drafted the manuscript. Dr Gary Donohoe, contributed to the data
    Neuropsychiatric Genetics Research Group,
    analysis and writing of the paper. Dr. Aiden Corvin, Professor Michael Gill
    and Dr Derek Morris conceived the study. Dr Derek Morris conducted the
    Department of Psychiatry and Institute of Molecular Medicine,
    genotyping. Professors McDonald, Dinan, Murphy, Waddington, O'Neill and Trinity College Dublin, Ireland
    O'Callaghan were involved in the study design and recruitment of
    participants. All authors contributed to and have approved the final G. Donohoe
    manuscript.
    Neuropsychiatric Genetics Research Group,
    Department of Psychiatry and Institute of Molecular Medicine,
    Conflict of interest
    Trinity College Dublin, Ireland
    The authors declare no conflict of interests.
    Trinity Institute of Neuroscience, Trinity College, Dublin, Ireland

    Acknowledgements C. McDonald
    The authors sincerely thank all patients who contributed to this study
    Department of Psychiatry,
    and wish to thank the staff of Cavan–Monaghan, North Dublin, South Lee,
    Galway, St John of God's and St James' Mental Health Services and staff of National University of Ireland Galway, Galway, Ireland
    the Belfast Health and Social Care Trust for their contributions to this
    study. T.G. Dinan
    Department of Psychiatry , University College Cork,
    Appendix A. Supplementary data Cork, Ireland

    Supplementary data associated with this article can be found, FA O'Neill


    in the online version, at doi:10.1016/j.schres.2010.05.022. The Department of Psychiatry, The Queens University, Belfast,
    Northern Ireland
    E. O'Callaghan
    References Cloan Mhuire Family Center and Department of Psychiatry,
    University College Dublin, Dublin, Ireland
    Craddock, N., O'Donovan, M.C., Owen, M.J., 2006. Genes for schizophrenia
    and bipolar disorder? Implications for psychiatric nosology. Schizophr.
    Bull. 32 (1), 9–16. J.L. Waddington
    Esslinger, C., Walter, H., Kirsch, P., Erk, S., Schnell, K., Arnold, C., Haddad, Molecular & Cellular Therapeutics, Royal College of Surgeons in
    L., Mier, D., Opitz von Boberfeld, C., Raab, K., Witt, SH, Rietschel, Ireland, Dublin, Ireland
    M., Cichon, S., Meyer-Lindenberg, A., 2009. Neural mechanisms of
    a genome-wide supported psychosis variant. Science 324 (5927),
    Cavan-Monaghan Mental Health Service, St. Davnet's Hospital,
    605. Monaghan, Ireland
    Machine Translated by Google

    Letter to the Editors 275

    K.C. Murphy Trinity Institute of Neuroscience, Trinity College, Dublin, Ireland


    Molecular & Cellular Therapeutics, Royal College of Surgeons in ÿCorresponding author. Trinity Centre for Health Sciences, St
    Ireland, Dublin, Ireland James's Hospital, Dublin 8, Ireland. Tel.: +353 1 8962468; fax:
    The Department of Psychiatry, Royal College of Surgeons in +353 1 8963405.
    Ireland, Education and Research Centre, Beaumont E-mail address: acorvin@tcd.ie (A. Corvin).
    Hospital, Dublin, Ireland
    11 February 2010
    M. Gill
    D.W. Morris
    A. Corvinÿ
    Neuropsychiatric Genetics Research Group,
    Department of Psychiatry and Institute of Molecular Medicine,
    Trinity College Dublin, Ireland

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