Panel, Mini-panel and Study Group
Schizophrenia is a highly debilitating brain disorder with a heritability of up to 80% and a complex genetic architecture. A popular research strategy for the dissection of schizophrenia pathophysiology is imaging genetics, an approach founded on the idea that some neuroimaging phenotypes may bear a closer relationship to the genetic mechanisms of the disorder than the clinical phenotype itself. Here, much interest has been devoted to functional MRI (fMRI)-based phenotypes related to the
... risk for the disorder; in particular, functional connectivity of the DLPFC and hippocampus during working memory and ventral striatal activation during reward processing. Beyond the classical candidate variant approach, the imaging genetics methods repertoire has recently been extended to include more complex strategies to aid the hypothesis-free identification of variants, genes, and pathways associated with these risk-related neuroimaging phenotypes. Methods: In a series of studies in healthy individuals and unaffected first-degree relatives of schizophrenia patients we have established and confirmed the link of these phenotypes to the genetic liability for schizophrenia. We have further explored the genetic contributions to these phenotypes using a broader array of imaging genetics methods including single-variant approaches exploring the effects of candidate genes and genome-wide supported psychosis risk variants. Recently, we have utilized more complex strategies in order to examine numerous genetic variants simultaneously using reliability-optimized neuroimaging risk phenotypes, gene fine mapping approaches, and gene set enrichment analyses. Results: For DLPFC -hippocampus functional connectivity our analyses replicate prior associations of this phenotype with the genetic risk for the illness, highlight associations with genetic loci supported by prior meta-analysis and genome-wide association studies (e.g., NRG1, ZNF804A, CACNAB2, extended MHC genomic region), and provide evidence for the role of genes and biological pathways involved in neurodevelopmental and plasticity processes. For ventral striatal activation during reward processing our data provide the first evidence for a systems-level intermediate phenotype signaling increased genetic risk for schizophrenia, which demonstrates association with a genome-wide supported psychosis risk variant in ITIH3/4 as well as the enrichment of gene sets and pathways involved in dopamine neurotransmission. Conclusions: Our findings support the utility of fMRI-based neuroimaging phenotypes for the examination of genes and pathways associated with an increased genetic liability for schizophrenia. They further underscore the value of different imaging genetics analysis strategies, the reliabilitybased definition of neuroimaging risk phenotypes, the independent replication of findings, and the use of comparable data processing methods and analysis strategies across centers. Disclosure: Nothing to Disclose.