Category Archives: Genetics

Genetics

The ‘gene deserts’ unravelling the mysteries of disease – BBC.com

Mutations in these regions of so-called "junk" DNA are increasingly being linked to a range of diseases, from Crohn's to cancer.

Ever since the Human Genome Project was declared complete in 2003, scientists have sought to pinpoint new regions among the three billion letters of our genetic code which may play a critical role in disease.

With the help of technologies which can analyse whole genome samples faster and more cheaply than ever before, vast numbers of genome-wide association studies dubbed GWAS have been published, identifying genetic variants linked to different chronic illnesses.

Frustratingly for many geneticists, this has turned out to be the easy bit. The much harder part is understanding how they are relevant. For example, while GWAS have identified segments of DNA associated with inflammatory bowel disease at 215 different chromosomal sites , scientists have only been able to pinpoint the exact mechanisms involved for four of them.

One of the biggest challenges is that many of these pieces of DNA lie in so-called gene deserts, swathes of the genome that initially appeared to contain nothing of relevance genetic "junk" that could be disregarded. After all, less than 2% percent of the human genome is dedicated to coding for genes which produce proteins, while much of the remaining 98% has no obvious meaning or purpose.

"You'll go, 'Oh here's a really important association and it increases your risk of many different diseases'," says James Lee, a clinician-scientist who runs a research group at the Francis Crick Institute in London. "But when you actually go and look at that bit of DNA, there's just nothing there."

For many years, gene deserts have been one of the most perplexing areas of medical science, but scientists are slowly managing to accrue information about their apparent purpose and why they exist.

Recently, Lee and colleagues at the Crick Institute published a new investigation into a particular gene desert known as chr21q22. Geneticists have known about this gene desert for more than a decade, because it is associated with at least five different inflammatory diseases from inflammatory bowel disease (IBD) to a form of spinal arthritis known as ankylosing spondylitis. Yet deciphering its function has always proven elusive.

However, for the first time, the Crick scientists were able to show that chr21q22 contains an enhancer, a segment of DNA which can regulate nearby or distant genes, capable of cranking up the amount of proteins they make. Lee refers to this behaviour as "a volume dial". Delving deeper, they found that this enhancer is only active in white blood cells called macrophages where it can ramp up the activity of a previously little-known gene called ETS2.

While macrophages play a vital role in clearing dead cells or fighting off harmful micro-organisms, when the body produces too many they can wreak havoc in inflammatory or autoimmune diseases, flooding into affected tissues and secreting damaging chemicals which attack them. The new study demonstrated that when ETS2 is boosted in macrophages, it heightens virtually all their inflammatory functions.

Lee describes it as "the central orchestrator of inflammation". "We've known for a while that there must be something at the top of the pyramid that is telling the macrophages to behave like this," he says. "But we've never known what it was. The most exciting bit of this, is if we can target it in some way, we might have a new way to treat these diseases."

But if gene deserts are capable of causing us so much harm, why are they in our DNA?

Tracing back in time, Lee's colleagues at the Crick's Ancient Genomics Laboratory were able to show that the disease-causing mutation in chr21q22 first entered the human genome somewhere between 500,000 and one million years ago. This particular DNA change is so ancient that it was even present in the genomes of Neanderthals as well as some ancestors of Homo sapiens.

It turns out that its original purpose was to help the body fight off foreign pathogens. After all, before antibiotics were invented, being able to rapidly switch on a heightened inflammatory response through ETS2 was extremely useful. "Within the first couple of hours of seeing bacteria, it ramps up your macrophage responses," says Lee.

As a result, blocking ETS2 completely could leave IBD patients vulnerable to future infections. However, Lee says when its activity is turned down by between 25 to 50%, it seems to be capable of eliciting a profound anti-inflammatory effect, without risking making the patient too immunosuppressed. While this theory has yet to be tested in clinical trials, the researchers showed that MEK inhibitors a class of cancer drugs which can dampen ETS2 signalling were capable of reducing inflammation not just in macrophages but in gut samples taken from people with IBD.

This appears to represent a new pathway to a completely novel class of treatments for IBD patients. "Some of these MEK inhibitor drugs do have side effects, and what we're trying to do now is to make them more targeted and safer, so that for lifelong diseases like IBD, we would actually be able to offer patients a drug that could switch off the inflammatory process and actually make them a lot better," says Lee.

Now the Crick's researchers are turning their attention to the other four diseases which have been linked to the chr21q22 gene desert, to see whether altering ETS2 activity can also help alleviate the excess inflammation which seems to be driving the condition.

"One of the most significant ones is an inflammatory liver disease called primary sclerosing cholangitis," says Lee. "It's a particularly nasty disease because it can cause liver failure leaving people needing transplants. It can also have a much higher risk of causing liver cancers, and this can happen in young people. And at the moment, there's not a single drug that has been shown to work, there's very little to offer patients," he says.

Scientists also predict that studying gene deserts will yield vital information which will help to improve our understanding of the variouspathways involved in tumour development.

As an example, cancer researchers havepinpointed a gene desert called 8q24.21 which is known to contribute to cervical cancer as the human papilloma virus, the main cause of the disease, embeds itself in this part of the genome. In doing so, the virus enhances a gene called Myc which is a well-known driver of cancer. Studies are suggesting that the connection between 8q24.21 and Myc may also play a role in a number of ovarian, breast, prostate and colorectal cancers.

RichardHoulston, of the Institute of Cancer Research in London, says that various genetic variants which have been identified as contributing to the heritable risk of many common cancers have been found in gene deserts. Knowledge of these target genes will provide opportunities for drug discovery as well as for cancer prevention.

HoweverHoulstonpoints out it is harder to translate this knowledge into new therapeutics for cancer compared to IBD, because tumours are not static targets, but continuously evolve over time. "This is the challenge, whereas with something like Crohn's disease and other bowel conditions, it's not evolving," he says.

Lee is optimistic that the Crick's work on IBD will provide a template for how researchers can find new ways of understanding the pathways involved in all kinds of autoimmune and inflammatory diseases. The institute's scientists are now investigating other gene deserts which have been associated with conditions such as lupus, a disease in which the immune system damages the body's tissues, leading to symptoms such as skin rashes and tiredness.

Other research centres around the world such as the University of Basel in Switzerland are also examining how single inherited mutations in gene deserts could lead to some rare genetic diseases. Three years ago, Basel scientists discovered how one of these mutations could lead to babies being born with limb malformation due to its regulatory effects on a nearby gene.

Lee predicts that understanding the roles of gene deserts will ultimately help improve the notoriously inefficient drug development process. "Making new drugs for these diseases is terribly unsuccessful," he says. "Only about 10% of the drugs going into clinical studies are ever approved at the end, so 90% of them fail because they don't make people better. But if you know that your drug going into development is actually targeting a pathway supported by genetics, the chances of that drug actually being approved is at least somewhere between three- and five-fold higher."

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The 'gene deserts' unravelling the mysteries of disease - BBC.com

Genetics

UGA plant geneticists are tackling the climate crisis – Longview News-Journal

Plant genetics research at the University of Georgia spans schools, departments, disciplines, and centers. From the College of Agricultural and Environmental Sciences (CAES) to Franklin College of Arts and Sciences, the Plant Center to the Institute of Plant Breeding, Genetics & Genomics and more, UGA faculty with genetics expertise are seeking plant-based solutions to societal challenges. (Photo by Andrew Davis Tucker)

ATHENS -- With record-breaking temperatures and extreme weather escalating, the threats posed by climate change are intensifying. But the plants of tomorrow small and humble though they might be could help us meet the massive challenges of our warming planet.

Plant genetics research at the University of Georgia spans schools, departments, disciplines, and centers. From the College of Agricultural and Environmental Sciences to Franklin College of Arts and Sciences; from the Plant Center to the Institute of Plant Breeding, Genetics & Genomics and more, UGA faculty with genetics expertise are seeking plant-based solutions to societal challenges.

Some of these faculty are conducting studies at the cellular level, while others investigate plants as whole organisms. Still others are exploring how epigenetics shape entire ecosystems. And while a number of UGA geneticists prioritize fundamental discovery, others are partnering with breeders or with industry to bring new crops and plant-based products to market.

Were spread out all over campus, Bob Schmitz, UGA Foundation Professor of Plant Sciences and the Lars G. Ljungdahl Distinguished Investigator of Genetics, said. But we all speak the same language."

Growing up in Minnesota, Distinguished Research Professor John Burke took an interest in the outdoors, collecting snakes, salamanders, and turtles with his two older brothers. Years later, he earned his Ph.D. in genetics from UGA and returned as a faculty member in 2006. Among his many studies, he has put particular focus on sunflowers.

Schmitz likes to tell people that hell work on any plant that has DNA which is all of them, of course. Our questions are broader than any particular plant, he said.

A member of the Department of Genetics in the Franklin College of Arts and Sciences, Schmitz studies the mechanisms of epigenetic inheritance in plants, or how a plants environment influences the way its genes operate.

Members of the Schmitz Lab, working in partnership with international researchers, discovered that rare changes to DNA methylation can spuriously occur over generations of plants. They then found that they could use those multigenerational changes, which tick at a constant rate, to determine plant divergence time.

The information provided by this epigenetic clock, Schmidtz says, includes data relevant to the timing of invasive species introduction and the impact of human activity on native environments. These insights could prove useful for understanding how plant populations migrate, expand, or contract due to a changing climate.

Passing along fundamental genetic discoveries to research partners along the basic-to-applied continuum is something UGA does well, John Burke, a distinguished research professor and head of the Department of Plant Biology in the Franklin College of Arts and Sciences, said. He notes that the broad intersectionality of plant research has become a signature strength of the university.

There are intentional mechanisms in place to help bridge gaps between units, Burke said. We have ways to work together here. Thats critically important.

While some UGA plant geneticists pursue fundamental discovery, others are bridging the gap between basic and applied research. From Crop & Soil Sciences to Plant Pathology and Horticulture within the College of Agricultural and Environmental Sciences, these faculty members are helping transform crop plants, native species, and the future of bioenergy for a changing global climate.

As the Georgia Research Alliance Eminent Scholar Chair in Crop Genomics, Robin Buell uses comparative genomics, bioinformatics, and computational biology to investigate the genome biology of plants and plant pathogens. While her subjects have ranged from rice and potatoes to maize, switchgrass, and medicinal plants, she currently studies poplar. Buell is the principal investigator on a $15.8 million Department of Energy grant to genetically engineer poplar trees (Populus sp. and hybrids) for biofuel production and other uses.

Poplar has strong potential to provide an alternative to petroleum-based products, Buell explains.

Its so fast-growing, its almost a weed," she said. "You can grow it almost everywhere. You dont have to grow it on prime land. Weve been able to do genetic engineering for the last 20 years, active breeding for even longer. But those developments have been incremental, not substantial.

This project has a more audacious goal.

Lets reinvent this tree, she said. Lets take Humpty Dumpty, lets break him, and lets put him back together again, but in a more intelligent way and faster.

The redesigned poplars will be fabricated through an intensive process that begins with measuring mRNA transcripts and includes mapping gene function throughout the tree. The end result could provide an alternative fuel for jet engines, among other sustainable products.

Wayne Parrott, distinguished research professor of crop and soil sciences, calls his area of investigation Biotechnology 2.0. An internationally renowned geneticist, Parrott has spent more than 35 years at UGA leveraging tools to help new soybean varieties and investigating the environmental and human safety of genetically modified crops.

My lab focuses on the development and use of biotechnology applications to help out with conventional plant breeding and plant improvement, he said. But theres a lag between what people want to do and what people are able to do.

His team is closing that gap by developing biotechnology applications to help strengthen conventional crop plant breeding and improvement.

Parrott directs the Institute for Plant Breeding, Genetics & Genomics, where researchers from multiple disciplines develop new crop varieties and conduct studies to understand the genetic traits of plants important to agriculture and humankind. He credits the institute with helping bring together plant genetics experts from all positions along the research pipeline.

Esther van der Knaap is a distinguished research professor of horticulture in the College of Agricultural and Environmental Sciences. She describes Integrated Plant Sciences as a central access point for prospective students to plant and fungal research across UGA. The curriculum allows students to undertake rotations in their first year to determine the best fit for their research interests, whether bioinformatics, ecology, genetics, breeding, biochemistry or some combination.

This type of program is something I dreamed about at my previous institution, but it wouldnt have been possible, van der Knaap said. At UGA, it was possible.

Van der Knaaps own research involves tomato foodshed. At the Center for Applied Genetic Technologies, which supports the development, application, and commercialization of new technologies to genetically improve crops, the van der Knaap lab studies variations in tomato fruit quality, from shape and size to taste. The latter trait is closely connected to aroma and especially important for fresh market tomatoes.

Van der Knaaps team is collaborating with food scientists, breeders, and biochemists at UGA and at the University of Florida to identify genes that cause variations in the flavor profile of tomato as they became domesticated over time, from fully wild to what we buy in grocery stores today. The resulting information about genes that improve flavor can be used by breeders to develop tastier tomatoes for the market.

Our focus is on capturing the genes that control fruit quality traits in tomato, she said. We also investigate the genetic diversity of these genes that, collectively, offer knowledge to breeders in both public and private sectors.

A new frontier in plant genetics research is high-throughput phenotyping, a type of genetic screening that uses cutting-edge technologies to generate data about large plant populations such as a crop field or forest. Guoyu Lu, an assistant professor in the School of Electrical and Computer Engineering and a specialist in high-throughput phenotyping, says that these new technologies could help researchers, breeders, farmers, and forestry officials make decisions in real time to support and protect the plants they oversee.

Lu comes to this work with a track record of engineering innovation. Before joining the UGA faculty in 2022, his career included positions as a research scientist on autonomous driving at Ford and a computer vision engineer at the Disney ESPN Advanced Technology Group. His projects have attracted the interest and investment of Ford, GM, Qualcomm, Tencent, Mackinac and more.

I work on the AI side, Lu said. Im an AI scientist, but Im developing algorithms for plant scientists.

Using computer vision and robotics, including unmanned aerial vehicles, Lu and his team are capturing and generating data on specific genetic traits within large plant populations. The information they gather includes root structure, height, disease state, and more all collected without harming the plants themselves.

Currently, Lu is working to build an AI algorithm that is one-size-fits-all a multipurpose tool suitable for gathering genetic data on many different plants across multiple populations. He wants that tool to be accessible to anyone who needs it in the field, especially as extreme weather patterns intensify.

My work uses UAV to estimate the 3D structure models of both crops and forests, he said. The 3D structures can provide height, coverage, and other information. This data can be used to estimate growth, carbon dioxide absorption, impact on the environment, and more.

Plant genetics at UGA begins and ends with partnerships. Researchers have forged ties across disciplines and schools, with strong collaboration from field sites and with sustained support from leaders and partners across Georgia and beyond.

We have some of the top researchers in the world right here at UGA, Burke said. And the work is going on across the spectrum.

The race to adapt to a changing climate is on and these scientists are leading the way, with bold inquiry and deep appreciation for the plants they have dedicated their professional lives to understanding and championing.

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UGA plant geneticists are tackling the climate crisis - Longview News-Journal

Genetics

Genetic Tests for Predicting Clopidogrel Response Gain Traction: AHA – TCTMD

Its time for genetic testing of clopidogrel response to move into the mainstream, suggests a new scientific statement from the American Heart Association (AHA) that outlines the supporting evidence but also acknowledges the obstacles that still stand in the way of wider adoption.

Clopidogrel, the mainstay oral P2Y12 inhibitor, is a prodrug thats metabolized by the enzyme CYP2C19 before becoming biologically active. But a substantial part of the populationthe prevalence varies by race/ethnicityhas a loss-of-function variation in the CYP2C19 gene. For decades, its been known that patients with this allele have more platelet aggregation and ischemic events than noncarriers while on clopidogrel therapy.

Still, US and European guidelines addressing antiplatelet therapy in CAD havent gone so far as to recommend routine genetic testing, though a few of these documents did give a nod to selective use in situations like dual antiplatelet therapy (DAPT) de-escalation after PCI for ACS.

Writing group chair Naveen L. Pereira, MD (Mayo Clinic, Rochester, MN), told TCTMD that one driver of their new AHA statement is the fact that the guidelines havent yet addressed the latest published clinical trials (POPular Genetics, TAILOR-PCI, PHARMCLO, and IAC-PCI), observational studies, and meta-analyses.

We felt that incorporating data from these studies and providing some guidance to clinicians by interpreting the data, which can be pretty complicated sometimes, would be helpful, said Pereira, who served as a co-principal investigator for the TAILOR-PCI trial.

Beyond this, the authors also collected information on the pharmacology and pharmacokinetics of P2Y12 inhibitors, both genetic and nongenetic determinants of patients response to the drugs, as well as practicalities like reimbursement and how to choose among assays.

Our conclusion was that the evidence to date supports genetic testing, Pereira noted. But in an AHA statement, we cannot directly say, You should do genetic testing. That's up to the guidelines.

As the document points out, many clinicians have positive perceptions about pharmacogenetic testing and its clinical implications, [but fewer than] 10% adopt pharmacogenetic testing in their routine clinical practice, primarily because of a lack of clinical guidelines and pharmacogenetic education.

Indeed, only a very small fraction of practices preemptively genotype, said Pereira. For patients who go on clopidogrel only to fare poorly and experience an event, genetic testing is moot by that point, he explained, since the answer would be to simply give an alternative antiplatelet drug.

Why Clopidogrel Shouldnt Be Skipped

Increasingly, the oral P2Y12 inhibitor of choice isnt clopidogrel but ticagrelor or prasugrelneither of which are dependent on CYP2C19. Some clinicians wonder, why not just avoid the problem of clopidogrel response entirely?

There are physicians who say, I know that having a loss-of-function genotype is a problem when I give clopidogrel, but if I give ticagrelor or prasugrel to all my patients, I don't have to worry about genetic testing, Pereira commented. The problem with this blanket approach is that these drugs are more potent antiplatelets, so on the whole there will be an increase in bleeding incidence. If you want to balance the ischemic and bleeding event risk, it appears that genetic-guided therapy [from the outset] would be an optimal strategy, he added.

Pereira pointed out that multiple studies have shown the cost-effectiveness of using genetic testing to guide antiplatelet therapy. Both clopidogrel and prasugrel are now generic, but not ticagrelor (Brilinta; AstraZeneca), which is considerably more expensive. Medicare considers genetic testing for CYP2C19 loss-of-function alleles to be medically necessary in certain situations, such as when an ACS patient is undergoing PCI, and thus covers its cost. Some commercial payers also offer reimbursement for the testing.

With the availability of point-of-care assays, the logistical hurdles to widespread adoption are also less high. Previously, it could take 2 or 3 days to get results after sending a blood sample for analysis, he noted, but now the testing can be done at bedside with a buccal swab, producing results within an hour.

Naturally, the field loves to see data, Pereira said. While it would be ideal to have a clinical trial comparing genetic-guided therapy versus no testing, with that design, there would be a lot of overlap, since perhaps 70% of patients in the testing arm and 100% of those in the control arm would be taking clopidogrelwith any difference driven by the 30% in the testing arm on another P2Y12 inhibitor. You're going to need tens of thousands of patients to show a difference, so I think doing a trial like that is very difficult at this point, he said. Its easier to see the impact of testing when, as he pointed out was done in a prespecified analysis of TAILOR-PCI, only patients found to have a loss-of-function variant are compared: those given clopidogrel versus those given ticagrelor or prasugrel.

In an AHA statement, we cannot directly say, You should do genetic testing. That's up to the guidelines. Naveen L. Pereira

Overall, Pereira urged, I think it's important to pay attention to evidence in a holistic way. . . . All the data, even though there's not that one big trial showing a difference, really points to [the need] to be careful giving loss-of-function patients clopidogrel. This is especially true when talking about the monotherapy thats happening with newer stents after DAPT de-escalation.

What hed like to see next, said Pereira, is for guidelines to give specific advice on how to use CYP2C19 testing. Clinicians in the meantime should consider looking at [point-of-care] platforms and see how they can incorporate that in their practices so it becomes easy and intuitive. Implementation, the statement adds, depends on the ease not only of performing the tests but also of interpreting their results, as well as knowledge about how to adjust therapy accordingly and the ability to integrate each patients genetic status into the electronic health record for care teams to access.

But What About Platelet Function?

In a commentary published on the AHAs Professional Heart Daily website, Mark B. Effron, MD (John Ochsner Heart and Vascular Institute, New Orleans, LA), highlights the fact that platelet function testing (PFT) is another option for predicting who will benefit from a more-potent antiplatelet agent versus clopidogrel, or from de-escalation of therapy.

In most institutions in the United States, it is easier to obtain results of a platelet aggregation test using VerifyNow than it is to obtain genomics on the patient, he writes. Until . . . there are studies evaluating the benefit of an all-comers genomic strategy versus a directed PFT, there will still be controversy as to which is more appropriate in the management of patients receiving P2Y12 inhibitor therapy.

In their statement, Pereira and colleagues point out that platelet function testing and genetic testing each has advantages and disadvantages.

The key advantage of PFT lies in directly defining the intermediate phenotype of interest (ie, levels of on-treatment platelet reactivity) for which studies have shown an association with clinical outcomes (ie, increased thrombotic and bleeding risks with high and low platelet reactivity, respectively), they say. Nevertheless, its clinical implementation has been challenging given the need for multiple repeated assessments due to potential of variability of results over time and the need for a patient to be on treatment for a certain length of time with a given antiplatelet agent (eg, for at least 12 weeks with clopidogrel) to be able to assess antiplatelet effects and define responsiveness adequately.

Effron agrees that a tailored approach is the way forward, though the exact strategy is still being debated. Whether directed P2Y12 therapy is accomplished through genotype-guided antiplatelet therapy or through PFT, he says, it is becoming clear that patient profiling is needed to determine the best therapy for the patient.

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Genetic Tests for Predicting Clopidogrel Response Gain Traction: AHA - TCTMD

Genetics

Bringing Gene Therapy to the Brain – The Scientist

This webinar will be hosted live and available on-demand

Thursday, August 8, 2024 2:30 - 4:00 PMET

The blood-brain barrier (BBB) is a semi-permeable membrane between the blood and the interstitium of the brain that regulates molecule and ion movement between the circulation and the brain. This barrier poses an obstacle to gene therapy delivery, as strategies that work for other organs may not necessarily be able to cross the BBB. In this webinar brought to you by The Scientist, Douglas Marchuk and Viviana Gradinaru will explain the obstacles posed by the BBB, as well as how overcoming the BBB allows them to investigate new approaches for combatting neurological disease.

Topics to be covered

Douglas A. Marchuk, PhD James B. Duke Distinguished Professor Department of Molecular Genetics and Microbiology Duke University School of Medicine

Viviana Gradinaru, PhD Lois and Victor Troendle Professor of Neuroscience and Biological Engineering Director, Molecular and Cellular Neuroscience Center of the Tianqiao and Chrissy Chen Institute for Neuroscience Director and Allen V.C. and Lenabelle Davis Leadership Chair Merkin Institute for Translational Research California Institute of Technology

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Bringing Gene Therapy to the Brain - The Scientist

Genetics

UW initiative aims to bring together social sciences and genetics – Wisbusiness.com

Integrating the fields of genetics and social science is putting us on the right track for understanding the world better, a UW-Madison expert says.

The universitys La Follette School of Public Affairs yesterday held a panel discussion on its Initiative in Social Genomics, which aims to bring together these disciplines to explore how genetics are connected to behavior, socio-economic outcomes and other factors.

Jason Fletcher, a professor of public affairs with the school, underlined the complexity involved with combining two nuanced areas of study into one discipline. Still, conducting research focused on just one while excluding the other fails to recognize that both genetics and social factors interact with one another, he said.

By focusing on your one domain, youre not including all of the relevant factors, he said, noting that only in the past two decades or so has information from both fields been combined into the same data structures.

He said the university is making major investments into training more people to wrangle this firehose of data to conduct meaningful social genomics research.

Because it is so complicated, the solutions so far have not been obvious, theyve required a lot of work, he said. And were not there. We dont have the solutions yet, but I think thats the enterprise here, is that we need collaborations to build this bridge where both sides are building at the same time, and coming together.

Lauren Schmitz, an assistant professor of public affairs with the school, said that ever since the human genome was first fully mapped in 2003, we have many more questions than answers about what makes us tick. She noted rapid advancements in computing and genome sequencing have led to a flood of new genetic data that scientists are still working to understand.

In part, sequencing the human genome wasnt the silver bullet humanity hoped for, because we realized that we cant study the human genome in isolation, she said yesterday. If we want to gain a better understanding of how genetic diversity shapes who we are, we need to understand and get outside the lab, to study genetic diversity and our genes in the wild.

Conditions of work, environmental factors and even economic trends also powerfully shape our life outcomes, she noted.

Her own research, focused on aging and longevity, explores how social conditions and disadvantages affect biological age. She said scientists can now calculate biological age quite accurately based on analysis of epigenetics, or how various factors affect gene expression. With just a blood sample, they can calculate how life circumstances are accelerating or slowing down the aging process.

This scientific explosion of data is really allowing us to see the impacts of public policy on the cellular level, she said.

In a 2022 study focused on the Great Depression, Schmitz sought to understand how this period of economic hardship affected biological aging.

What we found is that individuals who were in utero, who were in the womb during the Great Depression, were aging faster decades later, she said. And so here we see this really important connection between early life conditions and late-life aging.

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UW initiative aims to bring together social sciences and genetics - Wisbusiness.com

Genetics

Women have a higher genetic risk for PTSD, according to study by VCU and Swedish researchers – VCU News

By Olivia Trani

Women are twice as likely as men to develop post-traumatic stress disorder, but the factors contributing to this disparity have largely remained unsettled. A research team led by Virginia Commonwealth University and Lund University in Sweden conducted the largest twin-sibling study of PTSD to date to shed light on how genetics may play a role. Their results, published Tuesday in theAmerican Journal of Psychiatry, are the first to demonstrate that women have a higher genetic risk for the disorder compared with men.

By analyzing health data from over 16,000 twin pairs and 376,000 sibling pairs, the research team discovered that heritability for PTSD was 7 percentage points higher in women (35.4%) than in men (28.6%). They also found evidence that the genes that make up the heritable risk for PTSD vary between the two sexes.

The researchers say their findings could inform strategies for PTSD prevention and intervention following a traumatic event, as well as help address stigmas related to womens mental health.

Women are at higher risk for developing PTSD than men, even when controlling for the type of trauma, income level, social support and other environmental factors. Some of the theories as to why that is have frankly been unkind to women, such as attributing the sex difference to a weakness or lack of ability to cope, saidAnanda B. Amstadter, Ph.D., a professor in theVCU School of Medicinesdepartments ofPsychiatryandHuman and Molecular Geneticsand lead author of the study. I think this study can help move the narrative that people can have an inherited biological risk for PTSD, and that this genetic risk is greater in women.

Nearly 70% of the global population are exposed to at least one traumatic event in their lifetime, such as physical or sexual assault, a motor vehicle accident, exposure to combat or a natural disaster. About 6% of those who are exposed to trauma develop PTSD.Amstadters research focuses on understanding the conditions that might increase or decrease a persons risk of experiencing PTSD, particularly how a persons genes impact their risk.

If you think of risk for PTSD like a pie chart, were trying to better understand what factors make up the pieces of this pie, she said. Some of the risk is influenced by a persons environment, such as the experiences they have while growing up. On the other hand, some of the risk will be influenced by the genes they inherit from their parents.

Previous research has looked into how genes influence the likelihood of developing PTSD, but the study conducted by Amstadter and her colleagues is the first of its kind to investigate how genetic risk varies by sex.

For this project, the research team examined anonymized clinical data from Swedish population-based registries. Their analysis consisted of more than 400,000 pairs of twins or siblings born up to two years apart in Sweden between 1955 and 1980. Studies on twins and siblings, because of their genetic similarities, can help researchers determine how a persons genes influence their risk for mental illnesses.

Every time a person within this age group interacts with Swedens health care system, whether thats visiting their primary care doctor, filling a prescription or going to the hospital, that information is recorded in their national registries. This kind of data is a really powerful tool for addressing questions related to genetic risk for medical conditions, Amstadter said. Prior PTSD studies involving twins and siblings have typically only included a few thousand individuals. Because our sample size was so large in comparison, we were able to make calculations with a higher degree of certainty.

Through statistical modeling, the researchers calculated how much a persons genetic makeup influenced their likelihood of developing PTSD following a traumatic event. In finding that PTSD was 35.4% heritable in women but only 28.6% heritable in men, they demonstrated that women have a higher biological risk for PTSD.

Their models also revealed that the genes associated with PTSD were highly correlated (0.81) but not entirely the same between men and women. This suggests that the genetic underpinnings of sex hormones, like testosterone, estrogen and progesterone, may be involved in the development of PTSD. The research team is collaborating with the Psychiatric Genomics Consortium to identify the molecular genetic variants that may contribute to sex-specific pathways of risk.

Amstadter conducted the research at theVirginia Institute for Psychiatric and Behavioral Geneticsat VCU alongside co-authors Shannon Cusack, Ph.D., a postdoctoral scholar; and Kenneth Kendler, M.D., the institutes director, professor of psychiatry and eminent scholar. They collaborated with Lund University co-authors Sara Lnn, Ph.D.; Jan Sundquist, M.D., Ph.D.; and Kristina Sundquist, M.D., Ph.D.

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Women have a higher genetic risk for PTSD, according to study by VCU and Swedish researchers - VCU News

Genetics

Genetics study points to potential treatments for restless leg syndrome – University of Cambridge news

Restless leg syndrome can cause an unpleasant crawling sensation in the legs and an overwhelming urge to move them. Some people experience the symptoms only occasionally, while others get symptoms every day. Symptoms are usually worse in the evening or at night-time and can severely impair sleep.

Despite the condition being relatively common up to one in 10 older adults experience symptoms, while 2-3% are severely affected and seek medical help little is known about its causes. People with restless leg syndrome often have other conditions, such as depression or anxiety, cardiovascular disorders, hypertension, and diabetes, but the reason why is not known.

Previous studies had identified 22 genetic risk loci that is, regions of our genome that contain changes associated with increased risk of developing the condition. But there are still no known biomarkers such as genetic signatures that could be used to objectively diagnose the condition.

To explore the condition further, an international team led by researchers at the Helmholtz Munich Institute of Neurogenomics, Institute of Human Genetics of the Technical University of Munich (TUM) and the University of Cambridge pooled and analysed data from three genome-wide association studies. These studies compared the DNA of patients and healthy controls to look for differences more commonly found in those with restless leg syndrome. By combining the data, the team was able to create a powerful dataset with more than 100,000 patients and over 1.5 million unaffected controls.

The results of the study are published today in Nature Genetics.

Co-author Dr Steven Bell from the University of Cambridge said: This study is the largest of its kind into this common but poorly understood condition. By understanding the genetic basis of restless leg syndrome, we hope to find better ways to manage and treat it, potentially improving the lives of many millions of people affected worldwide.

The team identified over 140 new genetic risk loci, increasing the number known eight-fold to 164, including three on the X chromosome. The researchers found no strong genetic differences between men and women, despite the condition being twice as common in women as it is men this suggests that a complex interaction of genetics and the environment (including hormones) may explain the gender differences we observe in real life.

Two of the genetic differences identified by the team involve genes known as glutamate receptors 1 and 4 respectively, which are important for nerve and brain function. These could potentially be targeted by existing drugs, such as anticonvulsants like perampanel and lamotrigine, or used to develop new drugs. Early trials have already shown positive responses to these drugs in patients with restless leg syndrome.

The researchers say it would be possible to use basic information like age, sex, and genetic markers to accurately rank who is more likely to have severe restless leg syndrome in nine cases out of ten.

To understand how restless leg syndrome might affect overall health, the researchers used a technique called Mendelian randomisation. This uses genetic information to examine cause-and-effect relationships. It revealed that the syndrome increases the risk of developing diabetes.

Although low levels of iron in the blood are thought to trigger restless leg syndrome because they can lead to a fall in the neurotransmitter dopamine the researchers did not find strong genetic links to iron metabolism. However, they say they cannot completely rule it out as a risk factor.

Professor Juliane Winkelmann from TUM, one of senior authors of the study, said: For the first time, we have achieved the ability to predict restless leg syndrome risk. It has been a long journey, but now we are empowered to not only treat but even prevent the onset of this condition in our patients.

Professor Emanuele Di Angelantonio, a co-author of the study and Director of the NIHR and NHS Blood and Transplant-funded Research Unit in Blood Donor Health and Behaviour, added: "Given that low iron levels are thought to trigger restless leg syndrome, we were surprised to find no strong genetic links to iron metabolism in our study.It may be that the relationship is more complex than we initially thought, and further work is required."

The dataset included the INTERVAL study of Englands blood donors in collaboration with NHS Blood and Transplant.

A full list of funders can be found in the study paper.

Reference Schormair et al. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology, and risk prediction. Nature Genetics; 5 June 2024; DOI: 10.1038/s41588-024-01763-1

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Genetics study points to potential treatments for restless leg syndrome - University of Cambridge news