The vast majority of the human genome, a staggering 98%, is composed not of genes encoding proteins but of DNA that regulates gene activity. These regulatory sequences are pivotal to human health and could significantly affect mental health, though much about their operation in the human brain is yet to be fully grasped. To delve deeper into this mystery, the NIH initiated the PsychENCODE Consortium in 2015, an endeavor that aims to demystify the complexities of gene regulation and expression within the brain.
Initially, the consortium’s work, revealed five years prior, shed light on complex regulatory networks with potential links to various psychiatric conditions. Building upon this foundation, the recent findings have employed cutting-edge methodologies, capitalizing on postmortem brain tissue from a diverse set of over 2,500 donors, including different age groups and both individuals with and without mental disorders, such as schizophrenia and bipolar disorder. This rich spectrum of samples has enabled scientists to chart gene regulation networks across varying cell types and life stages, encompassing states of both health and disease.
A collection of over a dozen research papers, detailing these groundbreaking insights, graced the period between May 23 and 29, 2024, in Science and affiliated journals. These studies provide an unprecedented map of the regulatory landscape within the human brain, marking a significant advance in our understanding of genetic regulation and mental health.
In an innovative fusion of high-throughput experimentation and advanced machine learning, researchers embarked on an exploration of DNA regulatory elements that influence gene expression in the developing human brain. This pioneering study successfully pinpointed over 46,000 enhancers – pivotal gene regulatory elements – that command the expression of specific genes. Furthermore, the team illuminated that upwards of 160 variants, previously implicated in psychiatric disorders, significantly impact gene regulation. The methodologies conceived in this investigation pave the way for fellow researchers to swiftly and precisely forecast the impact of noncoding DNA on gene regulation within maturing brain cells. This holds immense promise for propelling forward the development of therapeutic strategies for psychiatric conditions.
Another facet of the research delved into the intricacies of gene regulation across various brain cell populations. This segment of the study included samples from 388 adults spanning a diversity of backgrounds, among them individuals diagnosed with schizophrenia, bipolar disorder, autism spectrum disorder, PTSD, and Alzheimer’s disease, as well as others with no mental disorder diagnosis. Undertaking single-cell analytic procedures on an expansive collection of over 2.8 million brain cells, the researchers cataloged over half a million regulatory elements unique to 28 distinct cell types and identified more than 1.4 million expression quantitative trait loci (eQTLs) correlating with gene expression variability. This treasure trove of data empowers the scientific community to pinpoint relevant genes and prospective drug targets associated with various maladies. Concurrently, the creation of BrainSCOPE — a robust scientific database — offers unparalleled access to raw datasets and supplementary resources to researchers worldwide.
This array of studies unveiled a wealth of discoveries pertaining to schizophrenia, autism spectrum disorders, and other mental health conditions. Complementing these breakthroughs, several publications introduced innovative methodologies and instruments which peers in the field can now employ to dissect the prodigious data yielded by this initiative. Among them is ‘PsychSCREEN,’ an intuitive, web-based interface designed for scientists to navigate the fresh data with ease.
Dr. Joshua A. Gordon, the director of NIH’s National Institute of Mental Health, articulates the significance of this research, stating, “These pioneering insights deepen our comprehension of the geographical, procedural, and temporal aspects of genetic susceptibility in mental disorders like schizophrenia, PTSD, and depression.” He further emphasizes the value of these openly shared tools, remarking, “These vital instruments will not only enable the research community to identify genetic variations with a probable causal link to mental illnesses but will also aid in the discovery of new molecular targets for future treatments.”
The backing of NIA grant U19AG060909, along with contributions from the NIH National Institute of Mental Health (NIMH), the NIH National Human Genome Research Institute (NHGRI), the NIH National Institute on Drug Abuse (NIDA), and the NIH National Institute of Neurological Disorders and Stroke (NINDS), were instrumental in supporting this research.