This is a second revision for the competitive continuation application for the Jerusalem Perinatal Cohort Schizophrenia Study (JPSS), a population-based research resource based on 92,408 offspring born in 1964- 76. It has unique information on antenatal maternal health, prenatal exposures, parental health and history, birth defects and pediatric health. We achieved all of the aims of the initial R01: we linked the cohort data to the Psychiatric Registry, finding a cumulative incidence of schizophrenia (SCZ) of 0.96 percent by age 34. We made seminal findings on the relationship of SCZ to paternal age, since replicated by many groups, and showed effects of circumscribed prenatal stress on the risks for SCZ and the psychiatric disorders, depending on gender and gestational age. We translated the NIMH Diagnostic Interview for Genetic Studies (DIGS) into Hebrew, validated the diagnoses in the Israeli Case Registry, and developed systems to ascertain, recruit and obtain consent to study treated cases and their relatives from hospitals throughout Israel, with structured interviews and DNA collection. With government researchers, we linked the cohort to military induction data at age 17, showing effects of late paternal age on adolescent IQ. This revised application, in full accord with the critique, has revised and greatly more detailed genetic sections. The genomic analyses are now focused only on schizophrenia related to paternal age, thereby integrating the molecular aspects of the study with its principal epidemiologic finding. The project aims to elucidate the mechanisms that underlie the relationship between advancing paternal age and SCZ. It includes expertise in molecular genetics (MC King) and biostatistics (Ian McKeague) in addition to the noted epidemiological strengths of the initial project team. This project will create an enlarged anonymous data base, anticipating 800 cases of SCZ and will recruit, interview and obtain DNA from up to 400 families with one or more SCZ cases. Complementary epidemiology studies will examine the antecedents and features of SCZ associated with late paternal age. The project is directly relevant to public health. SCZ is a costly disease, afflicting 10 percent of disabled people. Its heterogeneity of SCZ limits research in etiology, preventoin, and the discovery of optimal treatments. This project may establish paternal age related SCZ as a separate and common variant, explaining a quarter or more of cases, with known genetic causes, setting the stage for specific interventions. ? ? ? ?
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