Abstract

Background: Recent discovery of hundreds of common gene variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. It is hypothesized that normal variation in genetic risk of schizophrenia should be associated with MRI changes in brain morphometry and tissue composition. Methods: We used the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large sample of adults from the UK Biobank (Nmax = 29,878) who had multiple micro- and macro-structural MRI metrics measured at each of 180 cortical areas and seven subcortical structures. Linear mixed effect models were used to investigate associations between schizophrenia PRS and brain structure at global and regional scales, controlled for multiple comparisons. Results: Micro-structural phenotypes were more robustly associated with schizophrenia PRS than macro-structural phenotypes. Polygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, and five subcortical structures. Other micro-structural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with schizophrenia PRS . Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate and prefrontal cortical areas, insula, and hippocampus. (Preprint: https://www.medrxiv.org/content/10.1101/2021.02.06.21251073v1)