The neurodevelopmental origins of schizophrenia in the penumbra of genomic medicine
Authors: Daniel R. Weinberger
Journal: World Psychiatry (2017)

The notion that schizophrenia has its origins long before the emergence of the clinical syndrome dates back at least to Kraepelin, who proffered that behavior peculiarities in children who later manifest dementia praecox were an expression of the "morbid pathology" at that time of life. In the 1920s, E. Southard, Harvard Professor of Psychiatry and Neuropathology, interpreted his neuropathological findings in brain tissue from patients with schizophrenia as being of developmental origin. L. Bender, an influential Boston psychiatrist and neuropathologist of the 1940s, labeled schizophrenia a "congenital encephalopathy". B. Fish of the University of California at Los Angeles started in the 1960s a series of landmark studies of high risk children and described neurological "dysmaturation" as a hallmark of these individuals during early childhood. In 1986, in a paper entitled The pathogenesis of schizophrenia: a neurodevelopmental theory1, I elaborated on these earlier ideas in the context of two traditional neurological principles: neuroanatomical localization of function and the implications of the state of brain maturation for clinical translation. I argued that the "lesion" in schizophrenia occurred early in development and involved distributed neural circuitries, that no single etiology had a monopoly on the underlying pathology, and that clinical and biological heterogeneity reflects inter-individual variation in the extent of this pathology. I attempted to espouse a further amplification of these principles a year later in the paper Implications of normal brain development for the pathogenesis of schizophrenia2, by arguing that, while the pathology associated with schizophrenia may occur during early brain development, it was not a sufficient explanation for the condition. I highlighted the deterministic role of brain maturation for the clinical expression of psychosis and suggested that what is unique about schizophrenia is neither its pathology nor its cause, but the interaction of the pathology with the normal course of maturation of the brain systems affected by it. I also raised the provocative possibility that the pathology in schizophrenia "may not reflect a discrete event or illness process at all, but rather one end of the developmental spectrum that for genetic and/or other reasons 0.5% of the population will fall into". In other words, rather than being an illness in a traditional sense, schizophrenia may reflect a quantitative developmental physiological deficit, a "liability factor that seems to be inherited". The association of specific genes with schizophrenia allowed for a more detailed approach to this story, which P. Levitt and I discussed in 20113. Studies of structural chromosomal defects, such as velocardiofacial syndrome, Klinefelter's syndrome and NRXN1 deletions, illustrated the variable clinical expressivity ("pleiotropy") of these genetic factors, such that cases of schizophrenia, autism and intellectual disability were associated with each of them. We proffered that, as schizophrenia is not something someone has, but a diagnosis that someone is given, it made sense to consider the syndrome not as a disease, but rather as a state of brain development and function based on an altered developmental trajectory with changing repercussions throughout life, much like autism and intellectual disability. The more granular insights about genetics and epigenetics prompted us to observe that schizophrenia appears to be on a developmental continuum with other behavioral disorders with onset in childhood, including autism, intellectual disability and epilepsy, arising perhaps from overlapping biological risk factors that may each have distinct covariates. Schizophrenia reflects the relatively least "noise" burden of this group of developmental disturbances. We expropriated the concepts of C. Waddington in further suggesting that, as individuals on a particular developmental trajectory move forward, "the subtle course corrections from early cell differentiation and circuit construction become increasingly amplified and compounded as the phenotypic endpoint becomes increasingly mature and the circuits involved take on increasingly complex functions". Schizophrenia, we suggested, involved alterations in molecular trajectories that converge on relatively late maturating mechanisms for tuning cortical microcircuitry, involving the interplay between glutamate and GABA neurons (now popularly referred to as "excitatory-inhibitory balance"). From the background of this perspective, I found the paper by Owen and O'Donovan4 appearing in this issue of the journal to be most timely and informative. These investigators have been at the leading edge of a generation of landmark genetic studies, based on rapidly developing molecular techniques for surveying genetic variation across the genome and the availability of large samples of case and control subjects generated by teams of investigators sharing data across many international research centers. The results of this work have permanently transformed the landscape of psychiatric research, from its long history principally of phenomenology into a mainstream scientific discipline with objective insights about basic causative mechanisms. At the core of their discussion is the notion of a neurodevelopmental gradient, with genetic and biological overlap between schizophrenia and other neurodevelopmental disorders, including autism, attention-deficit/hyperactivity disorder, intellectual disability and epilepsy. This evolving idea is now strengthened by evidence which they review of relatively rare, but putatively deleterious, variations in the same genes and genomic regions being associated with each of these syndromes, and the burden of deleterious variation being greater in intellectual disability than autism, which is greater than in schizophrenia. These are potentially seminal insights. It is also noteworthy that the shared genetic associations in each of these disorders span large fractions of the genome, implicating many and diverse pathways to risk. Overall, consistent with their conclusions, these findings would seem to implicate a relative burden of developmental "noise" that is a common factor in neurodevelopmental disorders, in which more "noise" has a greater impact on function and adaptation. Less consistent with this notion, however, is the overlap between common variants and this spectrum of developmental disorders. Current data suggest that most genetic risk for schizophrenia is accounted for by common variants, and the overlap here with more traditional neurodevelopmental disorders, such as intellectual disability and autism, is less strong5. It is also important to note that sharing genetic components with disorders that arise early in development, while suggestive, does not establish a neurodevelopmental origin for schizophrenia. A more direct test of this possibility is differential expression analysis in fetal and postnatal brain of genes associated with schizophrenia and other neurodevelopmental disorders. Jaffe et al6 have shown that genes associated with schizophrenia, autism and intellectual disability are preferentially expressed during fetal life, in contrast to genes associated with bipolar disorder and neurodegenerative disorders, which are preferentially expressed after birth. Surprisingly, these authors also found that epigenetic changes associated with fetal life are enriched for positive schizophrenia genome-wide association study (GWAS) loci and that epigenetic changes in brain associated with the manifest illness also are enriched for fetal epigenetic marks7. Epigenetic changes around the time of onset of schizophrenia were surprisingly not enriched for GWAS loci and were not enriched in the brains of deceased individuals who had schizophrenia at the time of their death. These surprising results suggest that both genetic and environmental events related to schizophrenia risk, at least those that leave epigenetic marks in the brains of patients with schizophrenia, are related principally to fetal life. However, these data are still circumstantial support for a neurodevelopmental origin of schizophrenia. Perhaps the strongest evidence to date for a "smoking gun" are recent data showing that a sizable fraction of the genes in the schizophrenia GWAS significant loci directly influence placental biology and placental health and can predict complicated pregnancy, a well-recognized risk factor for schizophrenia8. This may offer new opportunities for developing primary prevention strategies early in life. Finally, a recent highly provocative and influential publication by Boyle et al9 argues that "many complex traits are driven by enormously large numbers of variants of small effects, potentially implicating most regulatory variants that are active in disease-relevant tissue". The authors go on to suggest that disease risk is driven mostly by genes with no direct relevance to disease, but which act as modifiers of more fundamental biologic processes, perhaps related to individual genetic backgrounds and environmental experience. This proposal echoes the question of whether psychiatric disorders are really "diseases" rather than varying states of brain development that have a particular way of expressing difficulties in particular environmental contexts, based on genomic background, development and experience. If this is so, the primary public health challenge may not be in defining the genetics, but in defining the functional state of the brain when it matters most. Daniel R. Weinberger Lieber Institute for Brain Development; Departments of Psychiatry, Neurology and Neuroscience, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA