Integrative functional genomic analysis of human brain development and neuropsychiatric risks.
Li M., Santpere G., Imamura Kawasawa Y., Evgrafov OV., Gulden FO., Pochareddy S., Sunkin SM., Li Z., Shin Y., Zhu Y., Sousa AMM., Werling DM., Kitchen RR., Kang HJ., Pletikos M., Choi J., Muchnik S., Xu X., Wang D., Lorente-Galdos B., Liu S., Giusti-Rodríguez P., Won H., de Leeuw CA., Pardiñas AF., BrainSpan Consortium None., PsychENCODE Consortium None., PsychENCODE Developmental Subgroup None., Hu M., Jin F., Li Y., Owen MJ., O'Donovan MC., Walters JTR., Posthuma D., Reimers MA., Levitt P., Weinberger DR., Hyde TM., Kleinman JE., Geschwind DH., Hawrylycz MJ., State MW., Sanders SJ., Sullivan PF., Gerstein MB., Lein ES., Knowles JA., Sestan N.
To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. 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.