Psychiatric disorders like schizophrenia, bipolar disorder, and depression have a strong genetic signature. Through advanced transcriptome-wide association studies (TWAS), researchers can identify unique gene expressions to identify new drug targets to treat these disorders.

Results from a study “Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions” published today in Nature Communications by scientists at the Feinstein Institutes for Medical Research and King’s College London reveal new gene expression patterns linked to common mental health disorders, providing a roadmap for future therapeutic research.

Human endogenous retroviruses (HERVs) are non-coding sequences that make up about eight percent of the human genome. They originated from ancient retrovirus infections that infected our lineage millions of years ago and are thought to regulate nearby genes and have other biological functions. HERVs have been linked to psychiatric conditions, but their exact role has been unclear.

“Our HERV expression study suggests that HERVs play a role in causing psychiatric disorders,” said Douglas F. Nixon, MD, PhD, researcher at the Feinstein Institutes for Medical Research and co-senior author of the paper. “This and future studies, including further translational research and clinical trials, could lead to potential new ways for treating psychiatric disorders.”

Focus on neurological HERV expression

The research, partly funded by the United Kingdom’s National Institute for Health and Care Research (NIHR) and the U.S. NIH, focused on neurological HERV expression and found unique patterns associated with genetic risks for major psychiatric disorders. The team also found co-expression networks connecting standard genes with HERVs, helping understand their functions better.

“Here, we perform specialized transcriptome-wide association studies that consider HERV expression quantified to precise genomic locations, using RNA sequencing and genetic data from 792 post-mortem brain samples. In Europeans, we identify 1,238 HERVs with expression regulated in cis, of which 26 represent expression signals associated with psychiatric disorders, with ten being conditionally independent from neighboring expression signals,” write the investigators.

“Of these, five are additionally significant in fine-mapping analyses and thus are considered high confidence risk HERVs. These include two HERV expression signatures specific to schizophrenia risk, one shared between schizophrenia and bipolar disorder, and one specific to major depressive disorder. No robust signatures are identified for autism spectrum conditions or attention deficit hyperactivity disorder in Europeans, or for any psychiatric trait in other ancestries, although this is likely a result of relatively limited statistical power.

“Ultimately, our study highlights extensive HERV expression and regulation in the adult cortex, including in association with psychiatric disorder risk, therefore providing a rationale for exploring neurological HERV expression in complex neuropsychiatric traits.”

It’s still unclear how HERVs are involved in psychiatric disorders. The research proposes that differences in HERV expression in psychiatric cases might be due to immune responses against current or past infections, that can trigger inflammation. However, some HERV expression directly contributes to the cause of these disorders rather than being a response to infections or environmental factors.

“Dr. Nixon’s groundbreaking research opens a new vista in finding new treatments for disease,” said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes and Karches Family Distinguished Chair in Medical Research. “By probing the so-called ‘dark genome,’ Dr. Nixon is shining a new light on the mystery, and giving a source of hope for patients with psychiatric disorders who lack sufficient effective therapies.”

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