This book was motivated by recent evidence that the origins of schizophrenia almost certainly encompass both environmental and genetic factors, which, through both independent and interactive neurodevelopmental mechanisms, appear to play important roles in this disorder. This theory is based on support from several domains of research. First, many new findings on potential environmental etiologies have emerged from epidemiologic studies. These investigations feature fundamental methodologic improvements over prior work, including birth cohort and other longitudinal approaches, prospective and more precise definitions of exposure status, control of confounding, and addressing bias due to attrition. These developments have markedly improved the validity and interpretability of this body of research and suggest potential novel preventive approaches. Second, rapid advances in molecular genetic and genomic approaches, including genomewide association studies, and the emerging fields of copy number variation and epigenetics, as well as new statistical methods and bioinformatic strategies, have markedly expanded the power to decipher the genetic variants and modifications that may alter brain development and contribute to susceptibility for schizophrenia. Third, a revolution in preclinical, translational models of schizophrenia has allowed the testing of several environmental and genetic candidates of these disorders, particularly those that act to modify neurodevelopmental processes. This has facilitated validation of clinical findings, enhanced the understanding of etiopathogenic mechanisms, and revealed potential treatment approaches that target the aberrant processes that are triggered by these insults. The reach of these studies has been further enhanced by improvements in behavioral assays, gene expression profiling, laser microdissection–real time polymerase chain reaction, and small-animal magnetic resonance imaging technologies. Finally, further developments in research on the biological basis of schizophrenia have yielded astounding insights into the neurodevelopmental and pathophysiologic basis of schizophrenia. These discoveries are having profound effects on epidemiologic, genetic, and translational approaches to schizophrenia, including the identification of candidate risk factors, the relevant functional effects of putative susceptibility genes, and the molecules, cellular pathways, and neurocircuits to be investigated in preclinical models. Several of these points are further elucidated by John Waddington in the Overview to this book.
This book is divided into two parts. Part 1, “Clinical Research on Risk Factors for Schizophrenia,” includes two sections, “Environmental Factors” and “Genetics and Epigenetics.” The first section consists of detailed discussion of emerging and prior research on the following putative risk factors: maternal infection, prenatal nutritional factors, obstetric complications, maternal stress, advancing paternal age, and cannabis use. The second section consists of a comprehensive and up-to-date review of the genetics of schizophrenia, including genomewide association studies, copy number variation, and epigenetics. Part 2, “Preclinical Research on Etiologies of Schizophrenia,” also contains two sections. In keeping with the translational theme of this volume, the first section, “Animal Models of Environmental Factors and Schizophrenia,” focuses on the methods and novel findings from preclinical studies of environmental factors, several of which are included in the first section of Part 1. These include animal models of maternal infection, developmental vitamin D deficiency, prenatal protein malnutrition, and maternal stress. The second section, “Animal Models of Genetic Factors and Schizophrenia,” consists of preclinical models of two of the most commonly cited candidate genes for schizophrenia, DISC1 (Disrupted-in-Schizophrenia 1) and neuregulin, which have been investigated extensively.
Although the material presented in this book is the product of several remarkable transformations in research on the epidemiology, genetics, and neurobiology of schizophrenia, and in spite of the high level of collective scientific wisdom that it contains, we must underscore the point that the field is a long way from a complete understanding of this complex and puzzling disorder. Conceivably, some of the findings presented here will fail to be replicated, or will be replaced by more satisfactory explanations, and undoubtedly new environmental risk factors, genes, and pathogenic mechanisms that involve gene-environment interactions will emerge. Moreover, we may not yet have a firm grasp on the pathophysiologic basis of schizophrenia, requiring the development of novel technologies and perhaps radically different approaches to understanding the structure and function of the normal and diseased brain, the relationships of these neurobiological findings to symptoms and behavior, and the developmental trajectories that give rise to this condition. These caveats aside, it is our view that the methods and findings presented here hold great promise toward the ultimate goal of eradicating this devastating illness, providing hope to the millions of afflicted individuals, to society, and to future generations.