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

Hervé Perron ,Raphaël Faucard ,G Ollagnier ,Hélène Moins‐Teisserenc ,Nora Hamdani ,Robert H Yolken ,Ryad Tamouza ,Rajagopal Krishnamoorthy ,Sophie Sarrazin ,Anne Dumaine ,Corinne Bernard ,Dominique Charron ,Djaouïda Bengoufa ,Claire Daban-Huard ,K Le Dudal ,Marine Delavest ,Andreas Gombert ,Josselin Houenou ,Nadège Gehin ,Marta García-Montojo ,Stéphane Jamain ,A Henrion ,Alexandra Madeira ,Mohamed Lajnef ,Ingrid Burgelin ,Erell Leguen ,Marion Leboyer

doi:10.1038/tp.2012.125

Abstract

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 (P<10–4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) 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.

Highlights

IntroductionSchizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric disorders involving complex interactions between genetic and environmental factors.[1,2] Environmental factors, such as winter birth, urban environment and maternal infection during pregnancy, in particular caused by Influenza virus, Herpesviruses or T. gondii, are associated with an increased risk for SZ and for BD.[3,4,5] Particular viruses or parasites have been thought to have a role in the pathogenesis of SZ or BD but, as most studies were based on serology that essentially detects an ‘immunological scar’ represented by the presence of specific immunoglobulin G antibody, the period of infection is debated and may occur at variable times, as reviewed.[6,7] association of BD or SZ with infectious agents quite always represent subgroups of patients and may, play different or additional roles, or may constitute different etiological causes or contributors as suggested by various studies.[8,9,10] Genetic studies revealed an overlapped involvement of loci involved in the inflammatory/immune pathways including the major histocompatibility complex region in both SZ and BD,[11,12,13,14] among other candidate genes.[15,16,17] Structural genomic studies highlighted significant modifications in psychotic patients, Creteil, France
We have further investigated the genetic features and the ex-vivo transcriptional activity of Human Endogenous Retrovirus type-W (HERV-W) envelope copies, as reflected in appropriate blood cells, in patients with SZ and bipolar disorder (BD) in comparison with healthy controls (HC)
The study group consisted of 136 patients (91 with BD and 45 with SZ) and 73 HC

Summary

Introduction

Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric disorders involving complex interactions between genetic and environmental factors.[1,2] Environmental factors, such as winter birth, urban environment and maternal infection during pregnancy, in particular caused by Influenza virus, Herpesviruses or T. gondii, are associated with an increased risk for SZ and for BD.[3,4,5] Particular viruses or parasites have been thought to have a role in the pathogenesis of SZ or BD but, as most studies were based on serology that essentially detects an ‘immunological scar’ represented by the presence of specific immunoglobulin G antibody, the period of infection is debated and may occur at variable times, as reviewed.[6,7] association of BD or SZ with infectious agents quite always represent subgroups of patients and may, play different or additional roles, or may constitute different etiological causes or contributors as suggested by various studies.[8,9,10] Genetic studies revealed an overlapped involvement of loci involved in the inflammatory/immune pathways including the major histocompatibility complex region in both SZ and BD,[11,12,13,14] among other candidate genes.[15,16,17] Structural genomic studies highlighted significant modifications in psychotic patients, Creteil, France

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Conclusion