Radically different
Schizophrenia’s genetic landscape just expanded dramatically. A new study in Nature Genetics identifies 641 previously unrecognized genes associated with schizophrenia, thanks to a modeling framework that captures how distant genetic variants regulate gene expression through co‑expression networks. The work reframes schizophrenia not as a collection of isolated genetic hits, but as a disorder shaped by long‑range regulatory relationships across the brain. The study is titled, “Co‑expression‑based models improve eQTL predictions for transcriptome‑wide association studies and highlight new schizophrenia‑associated genes.”
The research team, led by Giulio Pergola, PhD, at the Lieber Institute for Brain Development (LIBD), developed two trans‑aware predictive models—INGENE and MODULE—that quantify how variants far from a gene influence its expression through co‑regulated partners. Traditional transcriptome‑wide association studies (TWAS) focus almost exclusively on cis‑expression quantitative trait loci (cis–eQTLs), variants within ±1 Mb of a gene. But as the paper noted, “Most transcriptome‑wide association approaches primarily model local (cis) genetic effects, leaving much of gene regulation unexplained.” By contrast, the new models incorporate distal (trans) regulatory effects, capturing regulatory relationships that behave more like social networks than neighborhood blocks.
Using RNA‑seq data from six human post‑mortem brain regions and genetic data from more than 102,000 individuals, the team integrated cis‑based predictors (CIS, EpiXcan) with their new trans‑based frameworks. The combined approach improved gene‑expression prediction for 18,744 genes, and when applied to Psychiatric Genomics Consortium (PGC3) datasets, it identified 766 schizophrenia‑associated genes, including 641 not previously detected by TWAS.
Pergola said the field has been “looking for the light under the lamppost, focusing only on genes close to disease‑associated DNA variants.” By illuminating long‑range interactions, he explained, “we’ve essentially turned on lights across the entire neighborhood, revealing how distant genetic variants coordinate to build the genetic basis of schizophrenia.”
The findings converge on pathways involved in glutamate signaling, neuronal communication, immune processes, and neurodevelopment—biological systems repeatedly implicated in psychiatric risk. MODULE‑derived trans‑single nucleotide polymorphisms (SNPs) showed particularly strong enrichment for schizophrenia‑associated variants, and many overlapped with cis‑eQTLs for transcription factors such as GATAD2A, RERE, IRF3, and SP4, all previously prioritized in schizophrenia GWAS.
Daniel Weinberger, MD, CEO and director of LIBD, emphasized the shift in perspective: “Schizophrenia risk isn’t just about individual genes acting one after another—it’s about how networks of genes work together. Understanding these coordinated genetic programs brings us closer to precision psychiatry.”
By demonstrating that trans‑regulatory architecture is both detectable and biologically meaningful, the study provides a roadmap for expanding TWAS beyond local effects. It also underscores the importance of integrating multi‑region brain transcriptomics with large‑scale genetic cohorts to reveal disease‑relevant regulatory relationships.
The post Long‑Range Gene Networks Uncover 641 New Schizophrenia‑Associated Genes appeared first on GEN – Genetic Engineering and Biotechnology News.
The Trump administration released a memo last week that seeks to upend landmark disability laws and court rulings that prioritize people with disabilities receiving care while living in their community instead of at institutions like nursing homes.
The memo — written by the Department of Justice Office of Legal Counsel in response to an inquiry from White House officials — breaks with decades of disability law and practice and argues that the “integration mandate” is not actually a mandate, especially for people with “severe mental illness or disabilities.”
Pfizer said Monday that an experimental drug it hoped could replace a widely used chemotherapy in one of the most common forms of lung cancer fell short in a clinical trial.
Expectations had been high that the drug, sigvotatug vedotin, could replace docetaxel, a chemotherapy initially approved in 1996. Last year, Pfizer’s CEO, Albert Bourla, said on an earnings call the drug “could be a driver of growth later this decade.” In a note to investors in May, Leerink analyst David Risinger called the upcoming data readout a “major oncology catalyst” and said he had spoken to a doctor who was “optimistic” about its potential.
Pfizer acquired sigvotatug vedotin when it bought the biotechnology firm Seagen for $43 billion in 2023.
A University of California, Riverside-led research team has developed a gene therapy that restored production of a missing brain protein, corrected abnormalities in brain circuitry, and improved behavior in a mouse model of Fragile X syndrome (FXS). The study, published in the journal Molecular Therapy Nucleic Acids, tested an adeno-associated virus (AAV)-based therapy carrying a normal human version of the FMR1 gene to produce the Fragile X messenger ribonucleoprotein (FMRP) and found that early treatment normalized several measures of brain activity while improving social behavior, exploratory behavior, and cognitive flexibility.
“In a typical brain, FMRP acts like a brake or a volume control,” said senior author Iryna Ethell, PhD, a professor of biomedical sciences at the UC Riverside School of Medicine. “Without it, neural circuits become overactive and less efficient, which contributes to many of the developmental and behavioral challenges associated with FXS.”
FXS is the most common single-gene cause of autism spectrum disorder. According to the researchers, the disorder typically manifests from expansion of CGG repeats in the 5′ untranslated region of FMR1. The mutation causes methylation and silencing of the gene, leading to a major reduction or complete loss of FMRP, an RNA-binding protein that regulates numerous messenger RNAs involved in synapse formation, maturation, and function. Loss of the protein can lead to abnormal synaptic activity and increased cortical hyperexcitability.
FXS can produce sensory hypersensitivity, seizures, anxiety, intellectual disability, developmental delays, repetitive behaviors, and social communication difficulty. Current treatments for this syndrome don’t seek to cure it, rather they are aimed at managing the associated symptoms of anxiety, hyperactivity, irritability, aggression, depression, and seizures.
The therapy developed by the research team was designed to replace missing FMRP rather than repair the original mutation. To do this, the researchers used an AAV9 viral vector to deliver human FMR1 isoform 7, one of the most abundant forms of the protein found in the brain. The therapy was tested in newborn mice lacking FMRP via intracerebroventricular injections at either a low or high doses.
The work built on earlier research that explored the potential of AAV-mediated restoration of FMRP in rodent models. These prior studies used a range of viral serotypes, promoters, delivery routes, and FMRP isoforms and showed they could partially or completely correct specific biochemical, physiological, and behavioral abnormalities. The researchers noted that studies involving mouse and rat FMRP homologs had shown that restoring the protein could improve a range of Fragile X-related deficits.
The current study showed that high-dose treatment produced the strongest positive effects in the mouse models. Electroencephalography showed normalization of baseline gamma power, improvements in responses to sound, reduced background neural activity, and improved habituation to repeated auditory stimuli. The therapy also restored abnormal patterns of brain-wave coupling that have been associated with Fragile X-related dysfunction.
Behavioral testing showed that these improvements persisted into adulthood. Mice receiving the higher dose displayed normalized exploratory behavior, improved social preference, and better performance in probabilistic reversal learning, a measure of cognitive flexibility that requires adapting when previously rewarded behaviors stop producing rewards.
“Fragile X mice tend to persist with an old solution even after the rules change,” Ethell said. “After treatment, they became much better at adapting, performing similarly to mice with normal FMR1 function.”
The researchers noted that their work showed the importance of delivering at therapy for FXS early in its development. They said that widespread distribution of the potential new gene therapy throughout the brain was necessary to achieve a therapeutic benefit. There was a clear relationship between the proportion of neurons expressing the therapeutic gene and the degree of functional recovery, which indicated that restoring FMRP in a sufficient number of cortical cells is critical for correcting any behavioral deficits.
While a promising step, the investigators said that the work was a preclinical study and that future research will now focus on developing delivery methods that can of have broad distribution across the human brain. The team also believes their approach could have broader applications.
“Beyond FXS, the findings may provide a roadmap for treating other genetic neurodevelopmental disorders caused by the loss of a single critical protein,” Ethell said. “Our study shows it may be possible to restore function across complex brain networks by replacing a missing gene. That gives us reason to be optimistic about the future of genetic medicine.”
The post Gene Therapy Restores Brain Function and Behavior in Fragile X Syndrome appeared first on Inside Precision Medicine.
by Annabella Hagen, LCSW
When I met Marie, she shared how faith and her connection with a Higher Power had always been important in her life. Her parents taught her that faith could be an anchor during hard times.
But Marie also had a genetic predisposition to obsessive compulsive disorder (OCD). When doubts and fears began to take over, she slowly lost confidence that she could ever feel peace again. Without knowing it, the more she tried to reason with the thoughts, fight them, or seek reassurance, the stronger they became.
Her OCD changed themes as she grew up. The voice within whispered different fears at different times:
“You may hurt the kids you’re babysitting.”
“You caused your granny’s pneumonia because you didn’t wash your hands well enough.”
“Am I going blind?”
“Why do these ugly images come into my head in sacred places? I must stop them.”
She tried to “fix” her doubts. But the more she focused on them, the more they grew. They distracted her from what mattered most — including her relationship with her Higher Power. She blamed herself for not feeling close to God. She felt ashamed and spiritually broken.
Many people with OCD blame themselves for their unwanted thoughts. They panic.
“Why would I think this?”
“What does this say about me?”
“Am I a terrible person?”
No matter what Marie did, she could not find certainty. She could not get enough reassurance. She wished she could control her thoughts and feelings. Because she couldn’t, she became very hard on herself. Her self-compassion slowly disappeared.
But here is something important: every human being — whether they have OCD or not — experiences disturbing thoughts, images, or impulses at times. Research going back decades, including studies like Rachman and de Silva (1978), shows that intrusive thoughts are common in the general population.
The difference is not the content of the thoughts. The difference is how often they come, how intense they feel, and how much distress they cause.
When someone without OCD has a strange thought, they may feel uncomfortable and say, “That was weird,” and move on.
But someone with OCD feels a strong need to solve the doubt. They may analyze it, argue with it, pray repeatedly, seek reassurance, or try to push it away. Without realizing it, these efforts make the thoughts louder and more frequent. This is how the OCD cycle grows.
Understanding this can bring hope. It means the problem is not your faith. It is the pattern.
And the good news is that OCD is not only genetic or neurological. It is also behavioral. That means you can learn to respond differently!
Thoughts and feelings are like the weather. They come and go. When we fight them or try to control them, they often stay longer.
You can learn to let them be.
Through Exposure and Response Prevention (ERP), you can practice moving toward what matters most — your faith, your family, your values — even when doubt is present. Instead of trying to silence the thoughts, you can choose not to follow the urge to fix them.
The first step is awareness.
You may already notice the unwanted thoughts. But can you notice how you respond?
Ask yourself gently:
These small moments of awareness begin to weaken the cycle.
As you practice new responses, you can begin shaping new pathways in your brain. Slowly, you can move closer to the connection with your Higher Power that you have been longing for.
Thoughts come and go. What matters most is what you choose to do.
You can act in faith and trust your Higher Power, even when the OCD voice is loud. That voice feels powerful, but it is not your identity. It does not define your relationship with God.
Change takes time. It takes practice. But it is possible. And it is worth it!
And you can find your way back!
Remember, OCD may try to use your faith as a weapon, your faith is not the problem—the disorder is. OCD is a health condition that seeks certainty where faith invites trust.
If you find yourself in a cycle of “loud” thoughts and repetitive compulsions—like over-praying, seeking constant reassurance, or fearing you’ve lost your connection to the divine—know that healing is possible.
To help more individuals like Marie navigate these challenges, the International OCD Foundation has released a comprehensive new brochure specifically for people of faith.
Download the “OCD is Not What You Think It Is” Brochure here or visit the Faith & OCD Resource Page to find more specialized support and information.
The post When OCD Is Loud, Trust Your Higher Power appeared first on International OCD Foundation.