Decoding Mental Health With Advanced Brain Gene Maps

Groundbreaking maps reveal the complex gene regulation in brains with and without mental disorders, enhancing the understanding of mental illnesses and potential treatments.

A consortium of researchers has produced the largest and most advanced multidimensional maps of gene regulation networks in the brains of people with and without mental disorders. These maps detail the many regulatory elements that coordinate the brain's biological pathways and cellular functions. The research, supported by the National Institutes of Health (NIH), used postmortem brain tissue from over 2,500 donors to map gene regulation networks across different stages of brain development and multiple brain-related disorders.

"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," said Joshua A. Gordon, M.D., Ph.D., director of NIH's National Institute of Mental Health (NIMH). "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."

The research is published across 15 papers in Science, Science Advances, and Scientific Reports. The papers report findings along several key themes:

• Population-level analyses that link genetic variants, regulatory elements, and different molecular forms of expressed genes to regulatory networks at the cellular level, in both the developing brain and adult brain
• Single-cell-level maps of the prefrontal cortex from individuals diagnosed with mental disorders and neurodevelopmental disorders
• Experimental analyses validating the function of regulatory elements and genetic variants associated with quantitative trait loci (segments of DNA that are linked with observable traits)

The analyses expand on previous findings, exploring multiple cortical and subcortical regions of the human brain. These brain areas play key roles in a range of essential processes, including decision-making, memory, learning, emotion, reward processing, and motor control.

Approximately 2% of the human genome is composed of genes that code for proteins. The remaining 98% includes DNA segments that help regulate the activity of those genes. To better understand how brain structure and function contribute to mental disorders, researchers in the NIMH-funded PsychENCODE Consortium are using standardized methods and data analysis approaches to build a comprehensive picture of these regulatory elements in the human brain.

In addition to these discoveries, the papers also highlight new methods and tools to help researchers analyze and explore the wealth of data produced by this effort. These resources include a web-based platform offering interactive visualization data from diverse brain cell types in individuals with and without mental disorders, known as PsychSCREEN. Together, these methods and tools provide a comprehensive, integrated data resource for the broader research community.

The papers focus on the second phase of findings from the PsychENCODE Consortium. This effort aims to advance our understanding of how gene regulation impacts brain function and dysfunction.

"These PsychENCODE Consortium findings shed new light on how gene risk maps onto brain function across developmental stages, brain regions, and disorders," said Jonathan Pevsner, Ph.D., chief of the NIMH Genomics Research Branch. "The work lays a strong foundation for ongoing efforts to characterize regulatory pathways across disorders, elucidate the role of epigenetic mechanisms, and increase the ancestral diversity represented in studies."

The PsychENCODE papers published in Science and Science Advances are presented as a collection on the Science website.

About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure.