Integrative functional genomic analysis of human brain development and neuropsychiatric risks

Mingfeng Li et.al

Science. 2018 Dec 14

Abstract

Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.

Graphical Abstract

Disruption of this regulation can lead to neuropsychiatric disorders.

RATIONALE:

The regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types.

RESULTS:

Here we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood.

Moreover, genes including MEF2C, SATB2, and TCF4, with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity.

CONCLUSION:

We generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease.

Cellular and temporal convergence of neuropsychiatric disease risks

At the gene level, multiple genes in ME37 identified using our less stringent criteria for interaction were associated with up to four or more different traits and disorders, including MEF2C, ZNF184, TCF4, and SATB2, all genes critical for neurodevelopment and/or implicated in neurodevelopmental disorders (57–65) (Fig. 7, B and C).