Table 1 Summary of convergent results on the biological and clinical relevance of three human brain transcriptional programs

		C1: neuronal hierarchy	C2: cognitive metabolism	C3: adolescent plasticity
Normative	Biological processes (Fig. 1c)	Most genes are aligned, especially PVALB, SST	Metabolism Epigenetics	Synaptic plasticity Learning/memory Immunity
	Architectonics (Fig. 1d)	L4 L1, L2, L6	L4, L5, L6 L2	L2, L3, L4, L5, L6 L1, white matter
	Cell types (Fig. 1e)	Oligodendrocytes Astrocytes	Synapses Endothelial cells	Synapses, Neurons Oligodendrocytes, Microglia
	GWAS (Fig. 1f,g)	Educational attainment	Intelligence/cognition Educational attainment	Intelligence/cognition Educational attainment
	Imaging (Fig. 2)	fMRI degree T1w/T2w Cortical thickness	MEG theta power Aerobic glycolysis	Adolescent change in myelination
	Development (Fig. 3b,c)	Prenatal, greatest expression at birth	Prenatal, greatest expression in first decade	Adolescence, greatest expression in adulthood
Atypical	Imaging (Fig. 4a,b,g)	ASD volume shrinkage	ASD volume shrinkage	SCZ volume shrinkage and L2/L3-specific thinning
	RNA-seq of brain tissue (Fig. 4c,f)	ASD DEGs	ASD DEGs	SCZ DEGs, with L2, L3 enrichment
	GWAS (Fig. 4d,f)	ASD risk genes	ASD risk genes	SCZ risk genes, with L2, L3 enrichment

Each of three components of normative human brain gene expression (C1–C3; table columns) was biologically validated by testing for enrichment of gene weights on each component and for co-location of regional component scores with neuroimaging or other macroscale brain phenotypes, in healthy brain samples (normative) and in studies of neurodevelopmental disorders (atypical). Each row summarizes results for a distinct gene enrichment analysis (italicized) or spatial co-location analysis (plain font). Based on previous knowledge that theta oscillations are linked to intelligence and cognition⁹² as well as to glucose metabolism⁹³, the spatial alignments between C2 and maps of MEG theta power (Fig. 2d) and aerobic glycolysis (Fig. 2a) were convergent with the enrichment of C2 for genes linked to cognitive capacity (Fig. 1f,g) and metabolism (Fig. 1c). Similarly, previous knowledge implicates microglia and oligodendrocytes in the immune-mediated synaptic pruning and myelination that, over adolescence, gives rise to adult cognitive capacity^94,95, such that the spatial alignment between C3 and the map of adolescent myelination (Fig. 2d) was convergent with the enrichments of C3 for genes related to immunity, synaptic development and learning (Fig. 1c); oligodendrocytes, microglia and synapses (Fig. 1e); and cognitive capacity (Fig. 1f,g), among which one GWAS explicitly linked intelligence to myelination⁴¹. SCZ, schizophrenia.

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