The schizophrenia and bipolar twin study in Sweden (STAR)

Abstract

The schizophrenia and bipolar twin study in Sweden (STAR) is a large nation-wide cohort of monozygotic (MZ) and dizygotic (DZ) same-sex twins with schizophrenia or bipolar disorder and healthy control pairs, extensively characterized with brain imaging, neuropsychological tests, biomarkers, genetic testing, psychiatric symptoms and personality traits. The purpose is to investigate genetic and environmental mechanisms that give rise to schizophrenia and bipolar disorder as well as the intermediate phenotypes. This article describes the design, recruitment, data collection, measures, collected twins' characteristics, diagnostic procedures as well as ongoing and planned analyses. Identification of biomarkers, genetic and epigenetic variation and the development of specific and common endophenotypes for schizophrenia and bipolar disorder are potential gains from this cohort.

Introduction

Schizophrenia and bipolar disorder are among the most chronic and debilitating of psychiatric syndromes and, with a lifetime prevalence of about 1% each, represent major public health concerns (McGrath et al., 2008; Merikangas et al., 2007). Both are genetic disorders with heritability estimated to approximately 80% in schizophrenia (Cannon et al., 1998; Cardno et al., 1999; Chou et al., 2017; Sullivan et al., 2003) and slightly lower in bipolar disorder (Edvardsen et al., 2008; Kieseppa et al., 2004; Song et al., 2015). Recent work has revealed substantial epidemiological overlap between schizophrenia and bipolar disorder (Lichtenstein et al., 2009), as well as shared associations within genomic regions (Smoller et al., 2013; Sullivan et al., 2012).

Anatomically, patients with schizophrenia show reductions in prefrontal, medial temporal, and superior temporal gray matter volumes and enlarged ventricles (Pantelis et al., 2005; Shenton et al., 2001). Decreased cortical thickness in prefrontal regions has been found to vary with genetic loading for schizophrenia among the non-ill co-twins of patients, while probands have further reductions in gray matter in dorsolateral prefrontal, superior temporal, and parietal regions compared with their non-ill co-twins (Cannon et al., 2002). Decreased cortical thickness in prefrontal regions have also been found in bipolar disorder and unaffected first-degree relatives (Hibar et al., 2018). Neurocognitively, patients with schizophrenia show impairments across all major domains of functioning, including attention, verbal abilities, spatial abilities, learning and memory, and processing speed (Cannon et al., 2000). Across all of these domains, individuals at genetic risk for schizophrenia have been found to perform at a level intermediate between that of probands with schizophrenia and the general population (Cannon et al., 2000). Cognitive impairments are also present in bipolar disorder across several domains although not as pronounced as in schizophrenia (Raucher-Chene et al., 2017).

Elucidating the specific genetic and neural mechanisms influencing susceptibility to and expression of schizophrenia and bipolar disorder, and explaining the nature of the overlap between them, is critical to understand the necessary and sufficient conditions for overt psychosis and to the development of more effective treatment and prevention strategies. To gain traction on these issues, we have established a twin cohort to investigate the inheritance of neural dysfunctions in schizophrenia and bipolar disorder in samples of monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for these two conditions along with healthy control pairs. We use this information to determine which brain abnormalities vary in dose dependent fashion with increasing genetic loading for each of these disorders, to examine DNA variations that may contribute to these abnormalities, to isolate non-genetic influences associated with each illness, and to clarify the extent of overlap between the two syndromes. The goal of the present report is to provide an overview of the sampling approach of the study, assessment methods, and findings to date, along with a brief description of work in progress.