It's all relative: A cross-disorder approach into brain structure, cognition, and familial risk in schizophrenia and bipolar disorder

Schizophrenia and bipolar disorder are two severe psychiatric disorders with shared symptoms and a strong genetic component that is partly shared between the disorders; however, which factors lead to these illnesses is mostly still unknown. Both disorders are considered neurodevelopment disorders. This means that a disruption during brain development may lead to clinical symptoms later on in life. In this thesis, three important neurodevelopmental components of schizophrenia and bipolar disorder were investigated: brain structure, cognition and risk genes. To increase insight into the biological underpinnings underlying the development of each disorder, this thesis examines which of those components, and to what degree, are related to risk of developing schizophrenia or bipolar disorder, and whether these are shared components or unique to either illness. Through investigating first-degree relatives of patients with schizophrenia or bipolar disorder, and using a cross-disorder approach, this thesis shows that schizophrenia and bipolar disorder have differential neurodevelopmental trajectories. One of the main findings indicating different neurodevelopment, was a divergent finding for intracranial volume (ICV; i.e., an approximation of head size). In a collaborative study through the ENIGMA consortium, with over 6,000 participants, we showed that ICV was not different in first-degree relatives of patients with schizophrenia, but that it was larger in first-degree relatives of patients with bipolar disorder compared to a healthy control group. Follow-up studies described in this thesis showed that there is likely a genetic component leading to the positive relationship between bipolar disorder and ICV, that is independent of IQ. Together, these studies provide further evidence that early life brain development is different in those at risk for the disorders. Important next steps are longitudinal studies to explore when the neurodevelopmental trajectories start to divert and to investigate the effect of the environment on the risk of developing a disorder. The ultimate goal is to correctly identify who is at risk of developing the disorder, thereby allowing for early identification, intervention or even preventing someone from becoming ill.