Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder

Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type ‘W’ family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (Po10–4) and in SZ (P1⁄4 0.012) as compared with HC, but with higher values in BD than in SZ group (Po0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P1⁄4 0.0016) or SZ (Po0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders. Translational Psychiatry (2012) 2, e201; doi:10.1038/tp.2012.125; published online 4 December 2012

[1]  F. Zhu,et al.  Implication of the env gene of the human endogenous retrovirus W family in the expression of BDNF and DRD3 and development of recent-onset schizophrenia. , 2011, Schizophrenia bulletin.

[2]  D. Rujescu,et al.  Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder , 2011, Molecular Psychiatry.

[3]  J. Rothstein,et al.  Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis , 2011, Annals of neurology.

[4]  N. Bannert,et al.  Retroelements and the human genome: New perspectives on an old relation , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[5]  M. Leboyer,et al.  Endogenous Retrovirus Type W GAG and Envelope Protein Antigenemia in Serum of Schizophrenic Patients , 2008, Biological Psychiatry.

[6]  Tyrone D. Cannon,et al.  Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study , 2009, The Lancet.

[7]  P. Rieckmann,et al.  Regulation of human endogenous retrovirus W protein expression by herpes simplex virus type 1: Implications for multiple sclerosis , 2006, Journal of NeuroVirology.

[8]  C. Feschotte,et al.  Endogenous viruses: insights into viral evolution and impact on host biology , 2012, Nature Reviews Genetics.

[9]  H. Perron,et al.  The multiple sclerosis-associated retrovirus and its HERV-W endogenous family: a biological interface between virology, genetics, and immunology in human physiology and disease , 2009, Journal of NeuroVirology.

[10]  B. Pearce,et al.  The Relationship Between Toxoplasma Gondii Infection and Mood Disorders in the Third National Health and Nutrition Survey , 2012, Biological Psychiatry.

[11]  M. Perucho,et al.  Frequent somatic demethylation of RAPGEF1/C3G intronic sequences in gastrointestinal and gynecological cancer. , 2011, International journal of oncology.

[12]  S. Kay,et al.  The positive and negative syndrome scale (PANSS) for schizophrenia. , 1987, Schizophrenia bulletin.

[13]  J. Seigneurin,et al.  Herpes simplex virus ICP0 and ICP4 immediate early proteins strongly enhance expression of a retrovirus harboured by a leptomeningeal cell line from a patient with multiple sclerosis. , 1993, The Journal of general virology.

[14]  R. Yolken,et al.  Toxoplasma gondii as a Risk Factor for Early-Onset Schizophrenia: Analysis of Filter Paper Blood Samples Obtained at Birth , 2007, Biological Psychiatry.

[15]  I. Ferrier,et al.  Magnetic resonance imaging abnormalities in young euthymic patients with bipolar affective disorder , 2006, British Journal of Psychiatry.

[16]  Y. Teo,et al.  Genome wide association studies (GWAS) and copy number variation (CNV) studies of the major psychoses: What have we learnt? , 2012, Neuroscience & Biobehavioral Reviews.

[17]  B. Horne,et al.  Evaluation of C-reactive protein, an inflammatory marker, and infectious serology as risk factors for coronary artery disease and myocardial infarction. , 1998, Journal of the American College of Cardiology.

[18]  M. Leboyer,et al.  Human endogenous retrovirus type W (HERV-W) in schizophrenia: A new avenue of research at the gene–environment interface , 2013, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[19]  D. Mager,et al.  Potential mechanisms of endogenous retroviral-mediated genomic instability in human cancer. , 2010, Seminars in cancer biology.

[20]  Mara Cercignani,et al.  White matter abnormalities in bipolar disorder: a voxel-based diffusion tensor imaging study. , 2008, Bipolar disorders.

[21]  R. Yolken,et al.  Altered transcriptional activity of human endogenous retroviruses in neuroepithelial cells after infection with Toxoplasma gondii. , 2006, The Journal of infectious diseases.

[22]  M. Åsberg,et al.  A New Depression Scale Designed to be Sensitive to Change , 1979, British Journal of Psychiatry.

[23]  Jan Paces,et al.  High copy number in human endogenous retrovirus families is associated with copying mechanisms in addition to reinfection. , 2005, Molecular biology and evolution.

[24]  W. Seifarth,et al.  Influence of Antipsychotic Drugs on Human Endogenous Retrovirus (HERV) Transcription in Brain Cells , 2012, PloS one.

[25]  Jianxin Shi,et al.  Common variants on chromosome 6p22.1 are associated with schizophrenia , 2009, Nature.

[26]  R. Yolken,et al.  HERV-W-related RNA detected in plasma from individuals with recent-onset schizophrenia or schizoaffective disorder , 2004, Molecular Psychiatry.

[27]  W. Schulz,et al.  Methylation of endogenous human retroelements in health and disease. , 2006, Current topics in microbiology and immunology.

[28]  David J Griffiths,et al.  Endogenous retroviruses in the human genome sequence , 2001, Genome Biology.

[29]  G. Paranhos-Baccala,et al.  Molecular cloning and characterization of MSRV-related sequences associated with retrovirus-like particles. , 1999, Virology.

[30]  S. Hiebert,et al.  The enemy within: dormant retroviruses awaken , 2010, Nature Medicine.

[31]  Zhongming Zhao,et al.  A bias-reducing pathway enrichment analysis of genome-wide association data confirmed association of the MHC region with schizophrenia , 2011, Journal of Medical Genetics.

[32]  P. Kreczmański.  Neuropathology of schizophrenia : a new vistas , 2009 .

[33]  Alan S. Brown,et al.  Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. , 2010, The American journal of psychiatry.

[34]  L. Duret,et al.  Molecular Characterization and Placental Expression of HERV-W, a New Human Endogenous Retrovirus Family , 1999, Journal of Virology.

[35]  R. C. Young,et al.  A Rating Scale for Mania: Reliability, Validity and Sensitivity , 1978, British Journal of Psychiatry.

[36]  J Schröder,et al.  Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[37]  R. Yolken,et al.  Transactivation of elements in the human endogenous retrovirus W family by viral infection , 2006, Retrovirology.

[38]  Babak A. Ardekani,et al.  A Voxel-Based Diffusion Tensor Imaging Study of White Matter in Bipolar Disorder , 2008, Neuropsychopharmacology.

[39]  J. Ruijter,et al.  Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS. , 2001, Human molecular genetics.

[40]  Gao-Hua Wang,et al.  Human endogenous retroviral pol RNA and protein detected and identified in the blood of individuals with schizophrenia , 2006, Schizophrenia Research.

[41]  N. Brockdorff,et al.  Global hypomethylation of the genome in XX embryonic stem cells , 2005, Nature Genetics.

[42]  H. Perron,et al.  The Human Endogenous Retrovirus Link between Genes and Environment in Multiple Sclerosis and in Multifactorial Diseases Associating Neuroinflammation , 2010, Clinical reviews in allergy & immunology.

[43]  D. Rujescu,et al.  Toxoplasma gondii antibody titers and history of suicide attempts in patients with schizophrenia , 2011, Schizophrenia Research.

[44]  R. Yolken,et al.  Toxoplasma gondii and other risk factors for schizophrenia: an update. , 2012, Schizophrenia bulletin.

[45]  L. Farinelli,et al.  Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease , 2012, Multiple sclerosis.

[46]  B. Gutiérrez,et al.  Infectious agents associated with schizophrenia: A meta-analysis , 2012, Schizophrenia Research.

[47]  Combined diffusion tensor imaging and transverse relaxometry in early-onset bipolar disorder. , 2010, Journal of the American Academy of Child and Adolescent Psychiatry.

[48]  Leonard Ming Wei. Tham,et al.  White matter abnormalities in major depression. , 2010 .

[49]  W. Tsai,et al.  Increased C-reactive protein is associated with future development of diabetes mellitus in essential hypertensive patients , 2010, Heart and Vessels.

[50]  Pall I. Olason,et al.  Common variants conferring risk of schizophrenia , 2009, Nature.

[51]  C. Nellåker,et al.  Elevated levels of human endogenous retrovirus‐W transcripts in blood cells from patients with first episode schizophrenia , 2007, Genes, brain, and behavior.

[52]  D. Collier,et al.  Association study of CHRFAM7A copy number and 2bp deletion polymorphisms with schizophrenia and bipolar affective disorder , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[53]  H. Perron,et al.  Endogenous retroviral genes, Herpesviruses and gender in Multiple Sclerosis , 2009, Journal of the Neurological Sciences.

[54]  C. Viret,et al.  The Envelope Protein of a Human Endogenous Retrovirus-W Family Activates Innate Immunity through CD14/TLR4 and Promotes Th1-Like Responses1 , 2006, The Journal of Immunology.

[55]  Jerzy K. Kulski,et al.  Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease , 1999, Immunological reviews.

[56]  P. Fusar-Poli,et al.  Brain structural abnormalities at the onset of schizophrenia and bipolar disorder: a meta-analysis of controlled magnetic resonance imaging studies. , 2012, Current pharmaceutical design.

[57]  Novel reliable real-time PCR for differential detection of MSRVenv and syncytin-1 in RNA and DNA from patients with multiple sclerosis. , 2009, Journal of virological methods.

[58]  D. Drubach.  Abnormal Corpus Callosum Integrity in Bipolar Disorder: A Diffusion Tensor Imaging Study , 2009 .

[59]  R. Yolken,et al.  Are some cases of psychosis caused by microbial agents? A review of the evidence , 2008, Molecular Psychiatry.

[60]  R. Hehlmann,et al.  Human Endogenous Retrovirus Expression Profiles in Samples from Brains of Patients with Schizophrenia and Bipolar Disorders , 2005, Journal of Virology.

[61]  I. Myin-Germeys,et al.  REVIEW: Genome‐Wide Findings in Schizophrenia and the Role of Gene–Environment Interplay , 2010, CNS neuroscience & therapeutics.

[62]  T. Kuijpers,et al.  High-throughput analysis of the C4 polymorphism by a combination of MLPA and isotype-specific ELISA's. , 2009, Molecular immunology.

[63]  J. Nurnberger,et al.  Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. , 1994, Archives of general psychiatry.

[64]  M. D. Del Bigio,et al.  Aboriginals with multiple sclerosis , 2001, Neurology.

[65]  M. Munch,et al.  The association between multiple sclerosis and infection with Epstein-Barr virus and retrovirus. , 2000, Journal of neurovirology.

[66]  E. Taylor,et al.  Retroviruses, ascorbate, and mutations, in the evolution of Homo sapiens. , 1998, Free radical biology & medicine.

[67]  H. Stefánsson,et al.  Genome-Wide Analysis Shows Increased Frequency of Copy Number Variation Deletions in Dutch Schizophrenia Patients , 2011, Biological Psychiatry.

[68]  J. Seigneurin,et al.  Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal Vbeta16 T-lymphocyte activation. , 2001, Virology.

[69]  F. Dickerson,et al.  Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. , 2003, Archives of general psychiatry.

[70]  E. Torrey,et al.  Serum antibodies reactive with non-human primate retroviruses identified in acute onset schizophrenia. , 2000, Journal of neurovirology.

[71]  C. Voisset,et al.  Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[72]  Rudi A. Dierckx,et al.  Neuroinflammation in Schizophrenia-Related Psychosis: A PET Study , 2009, Journal of Nuclear Medicine.

[73]  Thalita Cristina Figueiredo,et al.  Reconsidering the Association Between the Major Histocompatibility Complex and Bipolar Disorder , 2011, Journal of Molecular Neuroscience.

[74]  C. Wheeler,et al.  CpG Methylation of Human Papillomavirus Type 16 DNA in Cervical Cancer Cell Lines and in Clinical Specimens: Genomic Hypomethylation Correlates with Carcinogenic Progression , 2003, Journal of Virology.

[75]  E. Torrey,et al.  Molecular characterization of a MSRV-like sequence identified by RDA from monozygotic twin pairs discordant for schizophrenia. , 1999, Genomics.

[76]  K. Bechter.  Updating the mild encephalitis hypothesis of schizophrenia , 2013, Brain, behavior, and immunity.

[77]  F. Dickerson,et al.  Additive effects of elevated C-reactive protein and exposure to Herpes Simplex Virus type 1 on cognitive impairment in individuals with schizophrenia , 2012, Schizophrenia Research.

[78]  Allen W. Song,et al.  White matter abnormalities in bipolar disorder: insights from diffusion tensor imaging studies , 2010, Journal of Neural Transmission.

[79]  H. Stefánsson,et al.  Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness. , 2011, The American journal of psychiatry.

[80]  Thomas G Schulze,et al.  Molecular genetic overlap in bipolar disorder, schizophrenia, and major depressive disorder , 2014, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[81]  J. Addington,et al.  Assessing Depression in Schizophrenia: The Calgary Depression Scale , 1993, British Journal of Psychiatry.

[82]  P. Alliel,et al.  Particle-associated retroviral RNA and tandem RGH/HERV-W copies on human chromosome 7q: possible components of a 'chain-reaction' triggered by infectious agents in multiple sclerosis? , 2000, Journal of neurovirology.

[83]  T. Crow,et al.  Isolation and phylogeny of endogenous retrovirus sequences belonging to the HERV-W family in primates. , 1999, The Journal of general virology.