Integrative functional genomic analysis of human brain development and neuropsychiatric risks

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.

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

“…Such cis-regulatory structural variants associated with autism have been recently described (53). FEZF2 is also part of a developing human brain gene co-expression network enriched for neurodevelopmental disorder risk genes that includes ASD high-risk genes such as TBR1, CTTNBP2, and DSCAM (44). Previously, genetic association has been found between FEZF2 and ASD (54) and rare mutations in the FEZF2 gene were identified in distinct ASD cohorts (55,56).…”

“…Interestingly, in each FEZF2 allele-linked family we identified a mutation in a gene that is part of the FEZF2 'red ensemble' and a mutation in a gene that is part of the KATNAL2 'black ensemble' (Figure 5 and Supplementary Figure 2). Genes of the FEZF2 'red ensemble' that are expressed at midgestation in deep layers of the cortex may be involved in social interaction impairment as demonstrated for CDH8 (44). In contrast, genes of the KATNAL2 'black ensemble' that are highly expressed at postnatal stages in the striatum may be responsible for stereotypies (60,61).…”

“…We took advantage of t-distributed stochastic neighbor embedding methods by applying BrainScope (43) to explore high-dimensional data (dual t-SNE) across multiple brain regions and developmental periods from the BrainSpan consortium (44).…”

“…We took advantage of t-distributed stochastic neighbor embedding methods by applying BrainScope (43) to explore high-dimensional data (dual t-SNE) across multiple brain regions and developmental periods from the BrainSpan consortium (44). With this approach, we were able to distinguish different clusters for the 65 ASD risk genes defined by Sanders et al 2015 suggesting that they display distinct spatiotemporal trajectories (Figure 7A-B).…”

From Sanger Sequencing to Genome Databases and Beyond

“…In a recent multicenter study, the genomic data from over 2000 human brains were compiled to form the most complete picture of how regions that regulate DNA expression can influence the brain and its function [4]. With special focus on schizophrenia, autism and bipolar disorder, the PsychENCODE study combined data from DNA and RNA sequencing methods toidentify the genome and the transcriptome withinformation regarding the DNA structure, transcription factors [5] and enhancer regions.…”