Abstract
Human endogenous retroviruses (HERVs) are remnants of infections that took place several million years ago and represent around 8% of the human genome. Despite evidence implicating increased expression of HERV type W envelope (HERV-W ENV) in schizophrenia and bipolar disorder, it remains unknown whether such expression is associated with distinct clinical or biological characteristics and symptoms. Accordingly, we performed unsupervised two-step clustering of a multivariate data set that included HERV-W ENV protein antigenemia, serum cytokine levels, childhood trauma scores, and clinical data of cohorts of patients with schizophrenia (n = 29), bipolar disorder (n = 43) and healthy controls (n = 32). We found that subsets of patients with schizophrenia (~41%) and bipolar disorder (~28%) show positive antigenemia for HERV-W ENV protein, whereas the large majority (96%) of controls was found to be negative for ENV protein. Unsupervised cluster analysis identified the presence of two main clusters of patients, which were best predicted by the presence or absence of HERV-W ENV protein. HERV-W expression was associated with increased serum levels of inflammatory cytokines and higher childhood maltreatment scores. Furthermore, patients with schizophrenia who were positive for HERV-W ENV protein showed more manic symptoms and higher daily chlorpromazine (CPZ) equivalents, whereas HERV-W ENV positive patients with bipolar disorder were found to have an earlier disease onset than those who were negative for HERV-W ENV protein. Taken together, our study suggest that HERV-W ENV protein antigenemia and cytokines can be used to stratify patients with major mood and psychotic disorders into subgroups with differing inflammatory and clinical profiles.
Highlights
Within the context of precision medicine, the use of biological markers to reformulate/redefines complex diseases have revolutionized many medical fields, but, as of yet, classification and treatment of psychiatric disorders still rely on clinical symptomatology
We found that subsets of patients with schizophrenia (~41%) and bipolar disorder (~28%) show positive antigenemia for human endogenous retroviruses (HERVs)-W ENV protein, whereas the large majority (96%) of controls was found to be negative for ENV protein
Unsupervised cluster analysis identified the presence of two main clusters of patients, which were best predicted by the presence or absence of HERV-W ENV protein
Summary
Within the context of precision medicine, the use of biological markers to reformulate/redefines complex diseases have revolutionized many medical fields, but, as of yet, classification and treatment of psychiatric disorders still rely on clinical symptomatology. “Psychosis” could be a final endpoint for multiple etiologies, while a useful complementary approach may include the identification of biological pathways enabling to identify homogeneous subgroups. The identification of biologically-based psychiatric diseases represents a considerable challenge for psychiatry today and solving it would represent a major step towards characterizing homogeneous subgroups. Within the field of Immuno-Psychiatry [2], immune-related loci and mobile genetic elements are emerging as central players in the etiology of psychotic disorders [3,4,5]. Mobile genetic elements include the human endogenous retroviruses (HERVs), which are remnants of infections that took place million years ago and represent around 8% of the human genome [6]. The human genome harbors many distinct families of HERVs, including copies that can be transcribed under certain conditions [14]. Transcribable HERVs, including HERV-W, HERV-K, and HERV-H, are usually silenced by epigenetic machineries [15, 16], but can be activated/reactivated following infectious challenges and other pathological conditions of cellular stress [17, 18]
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