Association of MAP2 gene polymorphisms and altered expression with schizophrenia risk in a Chinese Han population

BackgroundSchizophrenia (SCZ) is a highly heritable primary psychotic disorder. The microtubule-associated protein 2 (MAP2) gene is essential for dendritic integrity and synaptic plasticity, positioning it as a key candidate for bridging genetic risk and neuropathology. Nevertheless, the role of common genetic variations within MAP2 in SCZ susceptibility remains to be elucidated.MethodsWe conducted a candidate gene association study of MAP2 in a Han Chinese cohort comprising 418 SCZ patients and 418 matched healthy controls. Targeted sequencing was used to genotype single nucleotide polymorphisms (SNPs). MAP2 mRNA levels were quantified by RT-qPCR and correlated with genotypes and clinical symptoms. Bioinformatic tools (such as GTEx, BrainSeq, 3DSNP, HaploReg, RegulomeDB and SNP2TFBS database) were employed for functional annotation of risk loci.ResultsWe identified multiple MAP2 SNPs associated with SCZ risk in a Han Chinese cohort. Specifically, the AA genotype of rs288057 and the GG genotype of rs288087 were significantly associated with increased disease risk (OR = 2.393 and 2.258, respectively). Expression analysis revealed a marked reduction in peripheral MAP2 mRNA levels in patients compared to controls. This downregulation was genotype-dependent: the risk AA at rs288057 and GG at rs288087 were correlated with lower mRNA levels, a finding supported by its significant eQTL effect in the GTEx and BrainSeq database. In silico annotation suggested rs288087 resides within a putative enhancer region, while rs288057 may affect a promoter-proximal regulatory site. Clinically, MAP2 expression showed a significant positive correlation with the severity of negative symptoms (SANS score). Furthermore, ROC analysis indicated that MAP2 expression levels distinguished patients from controls with an AUC of 0.728.ConclusionThis study identifies MAP2 as a schizophrenia risk gene, wherein non-coding variants likely reduce its expression via distinct regulatory mechanisms, linking this downregulation to core negative symptoms. These findings highlight MAP2’s pathophysiological and translational relevance.

Heat waves mess with your brain. Scientists are trying to figure out why.

It’s been hot in London this week. Really hot. A dangerous heat wave has hit Western Europe. Yesterday, the UK recorded its highest ever June temperature at 36.1 °C (about 97 °F). But as the weather app on my phone confirmed, it felt like 39 °C.

It’s frightening that we are seeing such temperatures in the UK in June. According to the Met Office, the country’s national weather and climate service, June temperatures peaked at an average 19 °C (66 °F) in England between 1991 and 2020. Across Europe, the heat wave is likely to cause thousands of deaths. There will be other awful consequences for agriculture, infrastructure, and the health system.

But this week I want to look at what the heat does to our minds and brains. Personally, I’ve found it almost impossible to think straight. The heat is distracting and my mind is foggy. I dread to think about the conditions of people who work outdoors, in even hotter regions.

It’s not just exhaustion and confusion. The effects of heat on the brain can be deadly. And researchers are still trying to figure out why.

Studies have confirmed that as temperatures rise, people seem to get more irritable and more violent. Most of these studies are based on associations, though. It’s difficult to directly study how a heat wave might affect our thinking, says Catherine Thompson, a cognitive psychologist at Liverpool Hope University. 

She has been studying the effects of extreme heat on firefighters instead. It’s easier to measure people’s cognitive skills before and after they undergo scheduled training that involves entering a burning building.  

It’s early days, but the team found that firefighters found it harder to focus and control their attention immediately after heat exposure—something people in heat waves can empathize with, I’m sure. 

The firefighters’ skills returned to normal after 20 minutes or so of cooling down. But they’d experienced just 15 minutes of intense heat exposure. Thompson doesn’t know what the effects of living through a days-long heat wave might be—or how long they’ll last. Figuring that out might involve shipping cognitive test kits to thousands of people during the few days’ notice of an impending heat wave. “My guess [is] that no one’s done it because it’s just so difficult to do,” says Thompson. 

Still, researchers can learn about some of the impacts of heat waves through studies after the fact. And those studies suggest that the heat seems to have more disastrous outcomes for people with mental-health disorders. 

Those outcomes become apparent when temperatures rise above what is considered typical for a given region. “There seems to be a correlation where the hotter it gets, especially during the hottest times of the year, the worse the mental-health outcomes,” says Joshua Wortzel, who directs the Heat-Mind Lab at Hartford HealthCare in Connecticut.

In a study published in 2023, Emma Lawrence at the University of Oxford, who studies the effect of climate change on mental health, and her colleagues reviewed the evidence linking mental-health outcomes to ambient outdoor temperatures. They found that during heat waves, there was a 9.7% increase in the rate of hospital admissions for people with such conditions. 

“People who live with mental-health conditions are among the most susceptible to the physical impacts of heat,” says Lawrence. People with schizophrenia were found to have been three times more likely to die during the record-breaking heat wave that affected Canada in 2021, for example.

In order to protect people, we need a better understanding of the mechanisms underlying these effects. After all, a lot of things change when it’s very, very hot. Some people may end up stuck indoors, avoiding outdoor play and exercise, and it can be difficult to get a good night of sleep, for example. Sleep, socializing, and exercise are all really important for our mental health. 

But whether unusual heat does something specific to our brains is, as Wortzel puts it, “the million-dollar question.”

Research in lab animals suggests that excessive heat can alter the way chemical signals work in our brain. The levels of neurotransmitters like serotonin, for example, seem to increase when rats and mice are exposed to high temperatures, according to multiple studies. The heat may also interfere with the way networks in our brains communicate with each other. It might affect the way oxygen reaches our brain cells.

“There are so many biological reasons why brains may be negatively affected by heat,” says Wortzel.

Emerging research suggests that for whatever reason, children and young people are among the most vulnerable. In research published earlier this week, Wortzel and his colleagues saw a 2.97% increase in the suicide rate among people in the US aged 15 to 24 for every 1 °C increase in average monthly temperature. That’s more than double the increase seen in people over the age of 24 (which is concerning in its own right).

Other work hints that heat exposure might have long-term consequences for children’s brain development. Babies who were exposed to either extreme heat or cold appeared to have altered white matter by the time they were nine to 12 years old—although it’s not clear how these impacts might affect an individual child.

“It seems that extreme temperature exposure for very young children may affect their brain development,” says Lawrence, who spoke to me from Oxford. She was meant to be in London for Climate Action Week, but her event, which focused on extreme heat, ended up being canceled … owing to the extreme heat.

We are living through the effects of climate change. And that brings a new urgency to the question of how heat affects our brains. Children born in 2020 are predicted to experience around seven times the number of heat waves their grandparents did, says Lawrance. “[We] need to be serious about adapting to a warming world.”

This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.

Mental Illness Shows Context-Specific Genetic Effects

Many DNA variants linked with neuropsychiatric disorders (NPD) that do not code for proteins depend on neuronal activation, a study suggests.

The findings, in Science, highlight the power of cell stimulation to reveal context-specific “hidden” genetic effects in conditions such as schizophrenia.

They suggest that genetic regulation is not fully revealed by measuring gene expression alone.

Instead, gene activity—at least in the brain—may depend on context and the physiological state of neurons.

“Liang et al. demonstrate that the genetic processes that underlie neuropsychiatric disease are heavily determined by a dynamic physiological environment rather than by fixed cellular conditions,” said Biao Zheng, PhD, and Panos Roussos, PhD, from Icahn School of Medicine at Mount Sinai in New York, in a Perspective article accompanying the study.

They added: “To understand disease genetics, we might need to study the genome in motion and not at rest.”

Genome-wide association studies have revealed hundreds of genetic loci associated with mental illness, with more than 280 identified for schizophrenia alone.

But many of these DNA regions do not encode proteins and their impact is often subtle and difficult to detect.

To investigate further, Lifan Liang, PhD, from the University of Chicago, and co-workers studied gene expression and chromatin accessibility in single neurons derived from induced pluripotent stem cells collected from a hundred human donors.

The single-cell multi-omics study involved assessing transcriptional and epigenomic profiles before and after neurons were activated through potassium-induced depolarization.

The team found that much of the activity in regulatory DNA regions only became apparent with neuronal stimulation.

Both the number of detectable expression quantitative trait loci (eQTLs)—genetic variants associated with differences in gene expression—and chromatin accessibility QTLs (caQTLs)—DNA variants associated with differences in chromatin accessibility—rose after neuronal stimulation.

Shared and cell type-specific transcription factors worked together, possibly through regulatory cascades, to drive cell type-specific neuronal responses to stimuli.

eQTLs after stimulation had substantially weaker overlap with brain eQTL catalogs derived from postmortem tissue compared with eQTLs before stimulation.

This suggested that many relationships between regulatory DNA activity and gene expression become detectable only during neuronal activation and could be missed by traditional tissue-based studies.

A higher number of caQTLs were associated with neuropsychiatric disease compared with eQTLs, suggesting that disease-associated genetic variants could have detectable effects on regulatory DNA even when downstream changes in gene expression were not obvious.

Supporting this, chromatin accessibility and transcriptional responses to neuronal activation often occurred at different times.

Regulatory regions associated with genes that respond rapidly to neuronal stimulation often remained accessible after transcription subsided. By contrast, some late response genes exhibited accessible chromatin before their expression was induced.

When taken together, these observations implied that chromatin accessibility can be an indication of both prior and future transcriptional potential.

“We identified thousands of cell type–specific and activity-dependent quantitative trait loci for gene expression (eQTLs) and chromatin accessibility (caQTLs), helping prioritize NPD risk variants and genes that manifested functional effects only upon neuronal stimulation,” the researchers asserted.

They added: “Our work provides mechanistic insights on neuron subtype–specific activity-dependent gene regulation, substantially expanding the repertoire of context-specific causal variants and genes for NPD and other brain traits.”

The post Mental Illness Shows Context-Specific Genetic Effects appeared first on Inside Precision Medicine.

<![CDATA[Estrogen shapes schizophrenia in women: onset peaks, dosing shifts, and relapse risk from periods to pregnancy, postpartum, and menopause.]]>

The Download: Europe’s heat wave hits the grid, and IBM’s chip targets Moore’s Law

This is today’s edition of The Download, our weekday newsletter that provides a daily dose of what’s going on in the world of technology.

Europe’s extreme heat is shutting down power plants

Europe is in the middle of a record-breaking heat wave, and the grid is being pushed to its limits as people turn to fans and air-conditioning to try to stay cool. But some power plants won’t be online to help handle the load.

The main source of stress is increased demand, largely driven by cooling. And the challenges are only expected to worsen as climate change brings more frequent and intense heat waves.

Find out how rising temperatures are stretching power supplies—and how utilities can adapt.

—Casey Crownhart

What Europe’s heat wave means for the power grid

Grid planning in the age of climate change generally means that we need a lot more supply, and quickly. But one interesting facet to this challenge is that in some places, seasonal patterns are shifting, compounding the difficulty of meeting demand. 

Europe has historically seen its grid peak in the winter when electric heating is widespread. So some planned outages happen in the spring and into the summer, which is affecting the supply right now. But a growing need for air-conditioning will alter the balance.

Read the full story on how climate change is reshaping electricity demand.

—Casey Crownhart

This story is from The Spark, our weekly newsletter giving you the inside track on all things climate. Sign up to receive it in your inbox every Wednesday.

IBM unveils chip technology that could help extend Moore’s Law another decade

IBM has built a new prototype chip with around 100 billion transistors on an area the size of a fingernail. That’s twice the density of the company’s previous state-of-the-art technology announced in 2021. And the design could pave the way for faster and more energy-efficient computers for years to come.

In the last fifteen years, transistors have been shrunk close to their limits. They can’t get smaller without their function deteriorating. IBM’s new chip resolves this with an approach familiar to urban planners: building up.

Here’s how the strategy is bringing new hope to the technology industry

—Sophia Chen

The must-reads

I’ve combed the internet to find you today’s most fun/important/scary/fascinating stories about technology.

1 Anthropic says Alibaba “illicitly” extracted Claude’s capabilities 
It claims the Chinese firm ran a “brazen” campaign to access the model. (BBC)
+ It says it’s the “largest known distillation attack” on the company. (CNBC)
+ The technique trains a weaker model on a stronger one’s outputs. (FT $)
+ Anthropic previously accused other Chinese rivals of using it. (CNN)
+ But it’s still feuding with the White House. (MIT Technology Review)

2 NASA has detected possible chemical signatures of ancient life on Mars
The Perseverance rover spotted complex carbon on rocks. (New Scientist $)
+ The molecules are typically associated with dead organisms. (Guardian)
+ The US has lost its lead in the hunt for alien life. (MIT Technology Review)

3 The EU has joined a US pact to stop relying on Chinese AI
Much of the rest of the world seems to still be a battleground for control. (FT $)
+ China is expanding its AI push in the Global South to counter the US. (The Wire China)
+ Chinese AI experts are freaking out about the AI arms race. (Wired $)

4 OpenAI and Broadcom have unveiled their first jointly designed AI chip
Jalapeño is built to power large-scale AI systems like ChatGPT. (NYT $)
+ It’s part of OpenAI’s push to “build the full stack.” (CNBC)

5 A new report shows ICE has built a vast hi-tech surveillance system
It includes facial recognition, drones, and data scraping.(Guardian)
+ Is the Pentagon allowed to surveil citizens with AI? (MIT Technology Review)

6 Electronics can now be printed onto living tissue
Which could enable smart implants and ingestible diagnostics. (The Economist $)

7 The data center boom is sparking a third wave of inflation 
Demand for memory chips is pushing prices higher.(WSJ $)

8 Companies are scrambling to curb spending on AI token “chewing”
Accenture data shows non-technical staff are draining budgets. (404 Media)

9 Claude Design is creating a bland wave of website uniformity
The AI tool is homogenizing the internet’s aesthetic. (The New Yorker $)

10 Elon Musk has lost his trillionaire status
Thanks to SpaceX stock coming back to Earth. (Business Insider)

Quote of the day

“Tom Brown is not being a weirdo like Dario and can actually engage.” 

—A person directly familiar with calls between the Trump administration and Anthropic tells Wired that they’ve improved since cofounder Tom Brown replaced CEO Dario Amodei in the talks.

One More Thing

TONY LUONG


The quest to learn if our brain’s mutations affect mental health

For years, scientists searching for the roots of conditions like schizophrenia, autism, and Alzheimer’s have focused on single genes. But the real source may lie in a more complex genetic puzzle inside the brain.

Mike McConnell has spent decades exploring the idea that neurons do not all share identical DNA, and that these differences could help explain psychiatric disease. His work has contributed to evidence that brain cells can form a “genetic mosaic,” with mutations that vary across the brain.

Discover how this could reshape our understanding of mental illness.

—Roxanne Khamsi

We can still have nice things

A place for comfort, fun, and distraction to brighten up your day. (Got any ideas? Drop me a line.)

+ This classical reimagining of the Super Mario soundtrack is exquisite.
+ At long last, we can calculate the fuel efficiency of launching our enemies into the Sun.
+ Before CGI, explosions were an art form. This compilation of classic practical effects is pure action-movie nostalgia.
+ Cambridge botanists lovingly recreated a 336-year-old garden to honor the “father of natural history.” (Big thanks to reader Peter Ryan for the find!) 

Adjunctive berberine for schizophrenia with metabolic syndrome: a systematic review and meta-analysis

BackgroundAntipsychotic-induced metabolic syndrome complicates the clinical management of schizophrenia. This investigation seeks to examine berberine’s efficacy and safety as adjunctive therapy in schizophrenia patients with metabolic syndrome.MethodsA thorough literature search was executed across international (PubMed, Cochrane Library, EMBASE) and Chinese (China National Knowledge Infrastructure, WanFang Data) databases to retrieve randomized controlled trials (RCTs) examining adjunctive berberine for schizophrenia with metabolic syndrome. Data extraction and synthesis were conducted by three independent reviewers employing RevMan 5.3 software.ResultsThree eligible RCTs (n = 233) were incorporated. Adjunctive berberine demonstrated superior efficacy over controls in reducing body weight (standardized mean difference (SMD) = −0.56, I² = 0%; P = 0.0003), body mass index (SMD = −0.51, I² = 0%; P = 0.0001), waist circumference (SMD = −0.31, I² = 20%; P = 0.04), total cholesterol (mean difference (MD) = −0.43, I² = 63%; P = 0.004), triglycerides (MD = −0.31, I² = 0%; P < 0.0001), and fasting plasma glucose (MD = −0.30, I² = 0%; P = 0.005). No significant differences existed in low density lipoprotein cholesterol (MD = -0.27, I² = 75%; P = 0.1), high density lipoprotein cholesterol (MD = -0.02, I² = 31%; P = 0.56), glycated hemoglobin (MD = -0.22, I² = 67%; P = 0.21), systolic blood pressure (MD = -1.62, I² = 0%; P = 0.17), or diastolic blood pressure (MD = -1.68, I² = 39%; P = 0.15).ConclusionThis systematic review provides preliminary evidence supporting adjunctive berberine as a promising intervention for improving certain metabolic parameters in schizophrenia patients with metabolic syndrome. Larger, high-quality RCTs are needed to confirm these observations.
<![CDATA[Clinicians empower schizophrenia patients with shared decisions and flexible treatment options—oral, long-acting injectable, or transdermal—to improve adherence, trust, and remission potential.]]>
<![CDATA[Explore how the asenapine transdermal patch helps schizophrenia care with steadier dosing, fewer side effects, and new options beyond sublingual pills.]]>

Gender-specific symptom outcomes on cariprazine treatment: a 12-month naturalistic longitudinal follow-up study in schizophrenia

IntroductionA growing body of literature is focusing on third-generation antipsychotics and their unique characteristics, but few studies have examined gender as a crucial factor in response profiles. The present study aims to address this gap by analyzing the outcomes of 12-month naturalistic treatment with cariprazine to elucidate changes in specific psychopathological domains between men and women.MethodsThe present 12-month longitudinal naturalistic study involved a sample of individuals diagnosed with schizophrenia according to the DSM-5-TR treated with cariprazine at the outpatients’ psychiatric services of a major university and community hospitals in Italy. The assessments conducted included sociodemographic data, the Structured Clinical Interview for the DSM-5 (SCID-5), and the Positive and Negative Symptom Scale (PANSS) Total and Subscale scores, as well as the PANSS-derived Marder factors. The PANSS was administered at three time points: before starting the treatment with cariprazine (T0), after 6 months (T1), and after 12 months (T2).ResultsFifteen male and 17 female subjects were assessed at the three time points. The mean dose of cariprazine was 4.2 ± 1.3 mg for men and 4.0 ± 1.5 mg for women. Both genders exhibited improvements in all PANSS subscale symptoms after 6 and 12 months of cariprazine treatment compared to the baseline, with the only exception of the Uncontrolled hostility/excitement Marder factor among men. Progressive improvements through time points in symptom subscales were found in both sexes, reaching numerical differences in every PANSS subscale in both sexes at T2. Gender specifc response profiles emerged after 6 and 12 months of treatment in the PANSS subscales and items in men and women.DiscussionCariprazine exhibited significant efficacy in both sexes, with no significant differences between men and women despite a gender specific response profile emerged. Additional studies are needed to further investigate the efficacy profile and long-term outcome of cariprazine treatment by gender.