Search for missing schizophrenia genes will require a new developmental neurogenomic perspective

Even the most powerful experimental designs in search of genetic causes of schizophrenia have not met the desired goal. It is imperative to review the reasons for such an outcome and to formulate novel strategies for the future direction of this research in the new era of individual genomes. Here, we will review aspects of neurodevelopmental hypothesis of schizophrenia in the light of novel genomic and epigenomic insights. Specifically, we will argue for the involvement of de novo mutations and epigenetic modifications during neurodevelopment that may result in schizophrenia. Our conclusion is that the successful elucidation of hereditary mechanisms in neuropsychiatric disorders must begin with attention to discrete endophenotypes; consideration of ontogeny, forethought of genome structure including temporal and spatial patterns of (epi) mutations and the use of judicious techniques that go beyond association studies.