From Genes To Neural Mechanisms: Characterizing The Effects Of Genetic Risk Variation In Schizophrenia

Recent large-scale patient studies have identified rare and common genetic variants that confer risk of schizophrenia independently or as aggregated polygenic risk. However, the biological implications of these genetic risk variants are mostly unknown. Elucidating the function of genetic risk variants in schizophrenia is an essential step towards understanding the disease pathophysiology, and may highlight novel mechanism-based targets for developing new treatments. This symposium will present recent research yielding insights into the function of genetic risk variants in schizophrenia using different analytical approaches and patient populations. The presentations include a statistical evaluation of gene-set analysis as a promising method for investigating the contribution of common genetic variation to disease, including which factors affect detection of gene sets and valid interpretation of results. Gene set results will be presented from the new CLOZUK and PGC meta-analysis (40,675 schizophrenia cases and 64,643 controls). The presentations also include studies linking genetic risk variants with brain phenotypes relevant to schizophrenia, including neurocognitive deficits and structural and functional imaging abnormalities. Specifically, the functional effects of genetic risk scores, based on either whole genome data or particular pathways and gene sets (e.g., risk variants interacting with MIR137), will be described in relation to cognition and brain structure/function in well powered schizophrenia phenotypic samples, including the GENUS Consortium dataset consisting of over 8,000 patients, controls, and familial-high risk individuals. The overall objective of this symposium is to highlight the potential for accelerating mechanistic insight into schizophrenia through investigating the biological implications of genetic risk variation underlying this disorder.