Schizophrenia is an often devastating neuropsychiatric illness whose etiology remains unknown despite considerable study. Genetic factors have been strongly and consistently implicated in its etiology. Currently, there are multiple positive and plausible findings, but no finding currently meets a rigorous but appropriate definition of proof. There is considerable uncertainty about which of the findings in the literature represent true findings upon which to build the next generation of schizophrenia research. Our goals are extremely ambitious but attainable. We wish to help research into the genetics of schizophrenia move to a solid empirical foundation that can withstand rigorous scrutiny. We have designed a well-functioning international collaboration to attain these aims: (1) We have identified ~29,000 cases via record linkage who could be contacted immediately. (2) We seek to biobank DMA samples from 7,500 cases with schizophrenia and 7,500 well-matched controls ascertained via high-quality Swedish national hospitalization and population registries. Both cases and controls will be population-based and of Scandinavian ancestry. Neurocognitive endophenotypes will be collected. (3) We will rigorously evaluate 10 candidate genes for schizophrenia. (3a) Following a comprehensive quantitative literature review, a pluralistic expert panel will select the 10 most promising genes. (3b) Genotype all cases and controls for 768 SNPs in these genes to capture genetic variation comprehensively, analyze, and with the expert panel select two genes for resequencing entire genomic transcripts for both common variants (N=48 cases, Aim 3c) and functional genomic regions for rare variants (N=1000 cases, Aim 3d). (3e) Complete the evaluation of these genes by conducting additional genotyping in cases and controls for SNPs identified in re-sequencing and finalize the analyses by investigating the relevance of neurocognition, birth insults (GxE interactions), family history (covariate indexing genetic risk), and age 18 conscription data (males only, possible endophenotypes) using prospective register data. A full-scale pilot study has proven that we can achieve these aims and strongly supports the validity of our assumptions. We have improved our diagnostic procedures and have shown that power will not be substantially altered by misclassification of either cases or controls. This research team is committed to collaborative """"""""open-source"""""""" genetic research. All phenotypes, genotypes, and DMA samples will be made available via the Kl BioBank. Application procedures will be straight-forward and require a brief page application that documents: a reasonable scientific plan, a timeline for completion and return of all unused samples, commitment to depositing all data created on these samples into a central repository at the Kl upon completion, and agreement to uphold the ethical and altruistic principles fundamental to this project. On the short-term, completion of this work will provide strong and possibly definitive evidence of the relevance of the best current set of 10 candidate genes for schizophrenia. For the long-term, establishment of this sample will provide an accessible resource for the psychiatric research community. Future projects could include whole genome association and nested case-control studies. ? ? ?
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