This RO3 application proposes to investigate the genetic topography (GT) of the cortex in a large cohort of schizophrenia, familial high risk to develop psychosis and healthy control subjects (3257 subjects) from the GENUS Consortium. GT offers a novel perspective by delineating the cortex according to genetic influences instead of traditional anatomical boundaries. Our preliminary data indicate that in healthy controls, cortical clusters obtained by GT exhibit better discoverability and higher heritability, i.e. are superior endophenotypes compared to cortical units obtained with other commonly used atlases, such as the Desikan-Killiany, the Glasser and the Yeo. Thus, genetic clusters obtained according to GT in healthy controls associate with a significantly higher number of common genetic variants. GT has shown as well that there is significant overlapping between genetic clusters of surface area and traditionally defined anatomical surface area regions, while GT clusters of cortical thickness do not necessarily follow anatomical boundaries. For example, there is shared genetic influence between the non-adjacent temporal and prefrontal cortexes, regions that are commonly affected in SZ, and that together contribute to important cognitive functions such as language, an important clue in the study of mental illnesses. By applying a novel software tool compatible with the commonly used and anatomically based FreeSurfer segmentation, we will determine for the first time the genetic mapping of the cortex in schizophrenia and in subjects at familial risk to develop schizophrenia. We will also examine SZ polygenic risk score for genetic association with GT clusters and compare to Yeo and Glasser atlases in SZ. Indeed, the genetic mapping of the cortex has not been carried out before in any mental disease. Cognitive measures, in particular cognitive measures of language, available for the full cohort of subjects will be used for correlation with genetically defined cortical regions as well as with anatomically defined ones, and correlations compared. Ultimately, the present proposal aims at establishing cortical genetic clusters as highly discoverable and highly heritable discreet units to be used in future GWAS of mental disease.