Scientists Find Clues to the Genetics of Mental Illness

The studies in Phase II bear out the extensive variety of genes and cells that may be involved in psychiatric disorders. One study by researchers at multiple PsychENCODE labs assessed the activity of DNA regions that may affect gene expression in developing brain cells. The researchers identified more than 46,000 gene regulatory elements called enhancers—DNA sequences that affect the expression of specific genes. The team also identified 164 variants within these enhancers that alter how genes are regulated in fetal cortical cells and are associated with psychiatric disorders.

In another paper, researchers from multiple consortium labs described their processes for analyzing single-cell sequencing data of different types of brain cells from 388 adults, including donors who had schizophrenia, bipolar disorder, ASD, PTSD, or Alzheimer’s disease. They identified more than 550,000 regulatory elements specific to 28 different types of cells. All told, they identified more than 1.4 million gene regions associated with variation in gene expression called expression quantitative trait loci. This enabled them to evaluate links between genetic regulatory elements and brain disorders and integrate them into a model to predict phenotypes and suggest drug targets.

“If you want to design a treatment, it’s useful to know which cells the genes [responsible] are in and how they’re acting up to prompt the disorder,” said coauthor Mark Gerstein, Ph.D., the Albert L. Williams Professor of Biomedical Informatics and a professor of molecular biophysics and biochemistry, of computer science, and of statistics and data science at Yale.

Gerstein said that because the team analyzed different cell types, they could also study how cells communicated. He likened the brain to a computer in which cells such as neurons are akin to wires that make complicated electrical circuits. Some of the neurons are excitatory, meaning they activate other neurons and propagate electrical signals throughout the brain, while others are inhibitory, meaning they make other neurons less likely to fire signals of their own.

“But there’s not just one type of ‘wire.’ There are all sorts of wires that have different excitatory and inhibitory functions, and a lot of neurons also have help from other types of cells like glial cells,” Gerstein said. “When you look at all of this together—how gene expression changes, how cells communicate—that could suggest a potential target for a drug.”

The Gerstein Lab also created the BrainSCOPE Resource for sharing its raw data files and other information with other scientists.

Collaboration and sharing data openly are hallmarks of PsychENCODE, according to Zhiping Weng, PhD., the Li Weibo Chair in Biomedical Research and professor and chair of genomics and computational biology at UMass Chan Medical School. Weng is the corresponding author of a paper describing how researchers integrated epigenetic data from the PsychENCODE Consortium and other published sources to construct an atlas of active gene regulatory elements in the brain.

As part of their work, the team collaborated with other UMass labs to create PsychSCREEN, a web-based platform that offers interactive visualization of PsychENCODE-generated genetic and epigenetic data from diverse brain-cell types in individuals with and without psychiatric disorders. Although PsychSCREEN is geared toward researchers and others in the scientific and medical communities who understand genetics, the platform is public.

“We decided that it’s important to make the notations from all of these massive data analyses available to the world,” Weng said. “We put the entire data set up, genome-wide—each gene, each locus [on the chromosome], and each sample, per genetic variant.”

Weng noted the labor-intensiveness of the undertaking. “Each data set is easy,” she said, “but if you multiply it by each locus on each gene in each sample, it becomes a challenge.”

Collaboration was essential to the team’s success. “People are very open to sharing data within the consortium, even before publication,” Weng said. “When I asked people if they wanted me to include their results in PsychSCREEN, everyone gave it to me, from data sets to preprints [of journal articles]. That made everything easier.”

Researchers who would like to access and use data from the PsychENCODE Consortium are free to request it through the NIMH Repository & Genomics Resource. So far, roughly 300 investigators have received access to the data.

The PsychENCODE project is entering its final stage, with some grants funded through 2026. Weng estimated that there are about three years left for data production, and said her team and other PsychENCODE labs are thinking of ways to publish their additional findings.

Pevsner said he hopes for more breakthroughs, not only from the consortium teams, but from the outside researchers who have received PsychENCODE data and are using it in their own work, perhaps as a foundation for one day developing new ways of treating and preventing psychiatric disorders. “What we’re doing now is basic research,” Pevsner said. “This basic research can help us understand disease etiology, that is, the molecular cause of disease.

“The long-term goal is for basic research findings to extend to translational research, but one cannot begin translational research without understanding basic aspects and information about genes.” ■