Genetic control of the brain – comprehensive cell maps published

Fifteen studies comprehensively mapping the genes responsible for regulation of activity and development of the brain have been published.

Neurodevelopmental conditions such as autism, and mental illnesses such as schizophrenia are common, yet their underlying mechanisms are poorly understood. The PsychENCODE Consortium is a multi-institutional collaboration funded by the US National Institute of Mental Health (NIMH) aimed at understanding gene regulation's impact on brain function and dysfunction, including what occurs during neuropsychiatric diseases. It published 11 papers in 2018, and this publication of 15 new papers, represents the second phase of the project.

Dr Daniel Geschwind, senior author of one of the studies from the University of California Los Angeles, said: 'This collection of manuscripts from PsychENCODE, both individually and as a package, provides an unprecedented resource for understanding the relationship of disease risk to genetic mechanisms in the brain.'

The studies were published across Science, Science Advances, and Scientific Reports, included characterisation of donated human brain tissue across different brain regions, studied several neuropsychiatric diseases as well as the neurotypical developing human brain, and used standardised methods to create multidimensional maps of gene regulation networks.

In one study published in Science, researchers developed a transcriptomic atlas of the prefrontal cortex from individuals with and without schizophrenia and identified cell type-specific transcriptional changes associated with schizophrenia, revealing that genetic risk variants for schizophrenia predominantly target genes in cells known as excitatory neurons.

For a study on autism, researchers analysed genetic expression in the brain tissues of 66 people, 33 people with autism and 33 controls to better understand the mechanisms underpinning genetic risk factors associated with autism. They discovered known risk genes played a role in regulating transcription of genes associated with stress response in immune cells found in the brain, and synaptic gene expression. Overall they found substantial gene expression changes across 35 different cell types in the brain. Results were published in Science.

Researchers characterised molecular alterations across three different brain regions from individuals with post-traumatic stress disorder and major depressive disorder compared with control subjects, in another study published in Science. They identified brain region-specific molecular differences.

Lastly, researchers presented a new tool called PsychSCREEN, an interactive web-based platform to allow for easy visualisation of the data from diverse brain cell types in individuals with and without mental disorders generated by the PsychENCODE consortium, in a paper in Science Advances.

The director of the NIMH, Dr Joshua Gordon, said: 'These groundbreaking findings advance our understanding of where, how, and when genetic risk contributes to mental disorders such as schizophrenia, post-traumatic stress disorder, and depression... Moreover, the critical resources, shared freely, will help researchers pinpoint genetic variants that are likely to play a causal role in mental illnesses and identify potential molecular targets for new therapeutics.'