Genetic insights into the neurodevelopmental origins of schizophrenia

Key Points Schizophrenia is a severe neuropsychiatric disorder with an unknown causative pathophysiology. Genome-wide association studies applied to schizophrenia have successfully identified discrete risk variants of common and rare frequency, but the functional characterization and neurobiological import of these loci remain to be elucidated. The neurodevelopmental model provides a translational context for schizophrenia genetics, positing that schizophrenia genetic and epigenetic risk factors converge on early brain development to perturb neurodevelopmental trajectories. Post-mortem studies of brain gene expression and DNA methylation suggest that risk factors for schizophrenia, both genetic and epigenetic variations that leave marks in the adult brain, occur principally during early brain development rather than during the tumultuous period of late adolescence or early adulthood, when the diagnosis is typically made. The diverse and protean effects of genetic and epigenetic risk of schizophrenia on brain development may be parsimoniously conceptualized as introducing developmental 'noise' — various subtle perturbations, including those to early brain circuits and synaptic organization — analogous to alterations in autism and intellectual disability but with lesser 'noise' burden or more amenable to compensation. Schizophrenia risk loci should be functionally characterized (spatially and temporally) in relevant neurodevelopmental models, including post-mortem brain across developmental stages and placenta and stem cell models. A causal explanation for the pathogenesis of schizophrenia is lacking. In this Review, Birnbaum and Weinberger explore recent genetic studies of schizophrenia and discuss how genetic and epigenetic risk of the disorder may converge to perturb key neurodevelopmental trajectories. Schizophrenia is a severe neuropsychiatric disorder with a longstanding history of neurobiological investigation. Although the underlying causal mechanisms remain unknown, early neurodevelopmental events have been implicated in pathogenesis, initially by epidemiological and circumstantial data but more recently by brain-specific molecular and genetic findings. Notably, genomic research has recently uncovered discrete risk variants and risk loci associated with schizophrenia, with the potential to elucidate disease mechanisms. This Review revisits the neurodevelopmental model of schizophrenia from a current genetics perspective, delineating the complex gene