Discovery of genomic loci of the human cerebral cortex using genetically informed brain atlases

Abstract

To determine the impact of genetic variants on the brain, we used genetically informed brain atlases in genome-wide association studies of regional cortical surface area and thickness in 39,898 adults and 9136 children. We uncovered 440 genome-wide significant loci in the discovery cohort and 800 from a post hoc combined meta-analysis. Loci in adulthood were largely captured in childhood, showing signatures of negative selection, and were linked to early neurodevelopment and pathways associated with neuropsychiatric risk. Opposing gradations of decreased surface area and increased thickness were associated with common inversion polymorphisms. Inferior frontal regions, encompassing Broca's area, which is important for speech, were enriched for human-specific genomic elements. Thus, a mixed genetic landscape of conserved and human-specific features is concordant with brain hierarchy and morphogenetic gradients.

Fig.1.. Manhattan plots of genetic variants underlying cortical thickness and area.

Results are shown separately for surface area (Panel A) and cortical thickness (Panel B). Numbers on brain atlases represent each brain region. Plots are color-coded for brain atlas region. Number of significant genetic loci are listed in Manhattan subplot titles, with the horizontal dotted line denoting genome-wide significance. Vertical bar charts show breakdown of genomic position of SNPs, with corresponding legend at top of Panel A.

Fig.2.. Genetic architecture of the cortex.

Cortical phenotypes generally have low polygenicity, medium/high heritability and are under strong negative selection. Vertical black lines on each plot are average reference lines for relevant estimates of commonly studied traits taken from (16). Numbering of regions follows labels in Fig.1. Abbreviations: SA: Surface Area. CT: Cortical Thickness. π: polygenicity. S: selection. h²: heritability.

Fig.3.. Partitioned heritability and Gene Ontology (GO) enrichment.

Panel A. Heritability of cortical phenotypes are significantly enriched for conserved, developmental, and regulatory annotations. The river plot depicts mapping between significant annotations (18) and cortical phenotypes. Color-coding of river plot is based on -log10 enrichment p-values. Panel B. Significantly enriched GO terms from MAGMA gene-set analysis for surface area (top) and cortical thickness (bottom).

Fig. 4.. Three-dimensional genetic characterization of cortex.

Panel A. Phenotypic and genotypic correlations between 24 regions, ordered by hierarchical clustering that shows A-P divisions for area, and D-V divisions for thickness. Phenotypic correlations are in bottom left triangle and genetic correlations in upper right. Panel B. Pleiotropic SNP counts for each pair of regions, using the same ordering as Panel A. Agonistic or same direction of effects are in lower red triangle; antagonistic or opposing effects are in upper blue triangle. Panel C: Brain maps of standardized effects of each latent factor (F1 and F2) derived from genomic SEM on each brain region. Detailed statistics are in Fig.S7.

Fig.5.. Enrichment of cell type-specific accessible chromatin sites and fine-mapping to regulatory regions of genes.

Panel A. Heatmap of enrichment for cortical phenotypes and cell type-specific accessible chromatin peaks. Phenotypes also include 3 metabolic (blood glucose, body mass index, blood pressure) and 3 cortical-related (multiple sclerosis, Alzheimer’s Disease, depression) controls. Vertical black line differentiates M1 cell types (left) from organoid developmental stages (right). Significant values are based on the bias-corrected enrichment statistic from g-chromVAR (12). Panel B. Mapped genes and the regulatory region (blue=enhancer; red=promoter) of the causal SNPs carried forward by positively enriched M1 cell type-cortical phenotype pairs (z>2.36, p<0.01). Size of dot reflects probability of SNP being causal. Colors represent peak to gene coaccessibilities, where a score of 1 reflects a peak being in the gene’s promoter region. Panel C. A selected pleiotropic SNP (rs2696555) influencing both orbitofrontal area and ventral frontal thickness, mapped to target genes based on co-accessibility with M1. Cell types are outlined in Table S23.