"The ambitious goal of this proposal is to identify causal mechanisms in schizophrenia, a devastating disease affecting about 1 percent of the population worldwide, and for which there is no current prevention or cure. If my team and I are successful, we will discover etiological factors that can be targets for preventive interventions on the general population level and in high-risk groups, as well as inform the development of novel treatments. I will use a truly unique population-based set of registers and biobanks, based upon a total national Danish birth cohort of more that 1.6 million individuals, and apply a novel combination of epidemiological design and methods and molecular biological techniques to the study of early risk factors for schizophrenia: I propose to combine cohort, nested case-control and case-sibling designs in studies of this total national birth cohort with detailed biological assessment of genetic and environmental risk factors operating during fetal life and around birth, in combination with detailed longitudinal information about the life course of cases, controls and their relatives. Together with my team, I will for the first time in a human population empirically test a range of novel and specific hypotheses, tied together by a common theoretical framework of inflammatory and immune mechanisms interacting with individual genetic vulnerability during fetal life. Specifically the focus will be on infectious agents, markers of inflammation, effects of maternal auto-antibodies, and interactions with maternal vitamin D as well as genes involved in apoptosis and other relevant pathways. All findings will be tested in independent replication samples from the same population and further validated by comparison to healthy sibling controls. Because my studies are performed in a total population birth cohort, we will be able to make risk prediction suitable for the identification of targets for preventive strategies."