Extended Data Fig. 4: Analysis of age-associated effects on gene expression levels.

(a) Quantile-quantile (QQ) plots of P values from initial efficient mixed model association (EMMA) tests show enrichment of low P values across nearly all brain regions tested (all EMMA tests are two-sided). (b) A multivariate adaptive shrinkage (MASH) approach substantially improves statistical power by leveraging shared patterns between tissue datasets, resulting in a greater number of genes passing a threshold (local false sign rate [LFSR] < 0.2) relative to a similar threshold applied to our EMMA results (false discovery rate [FDR] < 0.2). (c) The number of significant genes visualized over a range of LFSR thresholds shows extremely stable rank order of brain regions. (d) Whole-brain age-differentially expressed genes (wbaDEGs) cross-referenced with our gene trajectory results (Fig. 1d) demonstrate that the vast majority of wbaDEGs fall into four clusters, marked by asterisks (***). Most wbaDEGs decreasing in expression with age fall into trajectories associated with signaling-related functions, while most wbaDEGs increasing in expression with age fall into a trajectory associated with the immune response. In the bottom panel, the percentage of genes assigned to wbaDEGs is plotted on the y axis.