Stauffer EM, Bethlehem RAI, Warrier V, et al. - Findings from this study suggest the possibility of a correlation of cortical, subcortical, and white matter microstructure with the genetic mechanisms of schizophrenia.

• Using the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls), polygenic risk scores (PRS) for schizophrenia were calculated in a large sample of adults from the UK Biobank (N_max = 29,878).

• The adults had multiple micro- and macrostructural MRI metrics measured at each of 180 cortical areas, seven subcortical structures, and 15 major white matter tracts.

• There appeared a significant association of polygenic risk with lowered neurite density index (NDI) at global brain scale, at 149 cortical regions, five subcortical structures, and 14 white matter tracts.

• Preliminary evidence supporting a causal relationship between (reduced) thalamic NDI and (increased) risk of schizophrenia was generated in post-hoc bidirectional Mendelian randomization analyses.

• For reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks, a plausible indicator is risk-related reduction in NDI.