Integrative functional genomic analysis of human brain development and neuropsychiatric risks
B. Lorente-Galdos, H.J. Kang, N. Sestan, D.H. Geschwind, O.V. Evgrafov, X. Xu, F.O. Gulden, P. Giusti-Rodríguez, Yu-Ping Zhu, M.B. Gerstein, D.M. Werling, S.M. Sunkin, S. Pochareddy, C.A. De Leeuw, F. Jin, M. Pletikos, G. Santpere, S. Muchnik, J.A. Knowles, Y.I. Kawasawa, J.T.R. Walters, Daniëlle Posthuma, Yao-Tai Li, M.J. Owen, MINGAN LI, D.R. Weinberger, Hoyoun Won, Jennifer Ja-Yoon Choi, Pat Levitt, BrainSpan Consortium, PsychENCODE Consortium, PsychENCODE Developmental Subgroup, M. Hu, S.J. Sanders, T.M. Hyde, E.S. Lein, M.W. State, Yen-Yu Ian Shin, A.M.M. Sousa, Sai Liu, Z. Li, J.E. Kleinman, M.J. Hawrylycz, D. Wang, A.F. Pardiñas, R.R. Kitchen, P.F. Sullivan, M.C. O apos Donovan
Abstract
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.