Transcriptional Cartography Integrates Multiscale Biology of the Human Cortex

The human cerebral cortex underlies many of our unique strengths and vulnerabilities as a species - but efforts to understand its organization are challenged by reliance on incompatible measurement methods at different spatial scales. Macroscale features such as cortical folding or functional activation are accessed through spatially dense neuroimaging maps, whereas microscale cellular and molecular features are typically measured with sparse postmortem sampling. Here, we integrate these distinct windows on brain organization by building upon existing postmortem data to impute, validate and analyze a library of ∼20,000 spatially dense neuroimaging-like maps of human cortical gene expression. These maps allow spatially unbiased discovery of cortical zones with extreme transcriptional profiles or unusually rapid transcriptional change indexing distinct microstructure. Comparison with neuroimaging shows these molecular transitions are aligned with cortical folding and functional specializations. Next, we define canonical cortex-wide gene co-expression patterns, and show that these integrate diverse spatial scales and temporal epochs of human brain organization - ranging from protein-protein interactions to large-scale systems for cognitive processing. These spatial modes of cortical gene expression are enriched for neuropsychiatric disorder risk genes, and - in the example of autism spectrum disorder - define a functionally enriched subset of risk genes that tags specific cyto-laminar features and predicts the location of altered cortical anatomy and gene expression in patients. Taken together, the methods, resources and findings described here advance our understanding of human cortical organization and offer flexible bridges to connect scientific fields operating at different spatial scales of human brain research.