Category Archives: Genetics

Genetics

Restless legs syndrome tied to 140 ‘hotspots’ in the genome – Livescience.com

Researchers have uncovered more than 140 sections of the human genome tied to restless legs syndrome (RLS), a neurological condition that affects up to 10% of the U.S. population.

These stretches of DNA in the genome are known as genetic risk loci, and prior to the new study, only 22 were known to be tied to RLS. The new research, published Wednesday (June 5) in the journal Nature Genetics, increases that number to 164.

Three of the newfound risk loci are located on the X chromosome, which females typically carry two of in each cell while males carry only one. RLS is more common among women than men, but based on their new results, the researchers don't think this difference is explained by the trio of risk loci on the X chromosome.

"This study is the largest of its kind into this common but poorly understood condition," Steven Bell, co-senior study author and an epidemiologist at the University of Cambridge, said in a statement. "By understanding the genetic basis of restless legs syndrome, we hope to find better ways to manage and treat it, potentially improving the lives of many millions of people affected worldwide."

Related: 10 unexpected ways Neanderthal DNA affects our health

This discovery could also be used to help predict a person's risk of developing RLS, the study authors wrote in their paper.

RLS, also called Willis-Ekbom disease, causes people to experience an unpleasant crawling or creeping sensation in their legs, as well as the irresistible urge to move them. These sensations are often more intense in the evening or at night, while people are resting. The condition is thought to be underdiagnosed, and when it is diagnosed, its exact cause is often unknown. RLS can arise due to another condition, such as iron deficiency, kidney disease or Parkinson's, and it's likely tied to dysfunction in part of the brain that uses dopamine to control movement.

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There is currently no cure for RLS, but certain treatments, such as anti-seizure drugs, can help ease a person's symptoms.

In the new study, the researchers pooled the data from several, enormous genome-wide association studies, which compare the DNA of people with a given disease to that of people without it. In all, the new research included data from more than 116,000 people who had RSL with more than 1.5 million people without the condition.

Notably, all those included were of European ancestry, which may limit the relevance of the findings in other demographics.

The researchers found no strong differences in genetic risk factors between the sexes, even though RLS is more common in women. They think this suggests that RLS is governed by a combination of genetic, environmental and hormonal factors, so the genetic risk loci don't dictate a person's risk in isolation.

Among the newfound risk loci, the team hunted for genes that might already be targeted by existing approved drugs the goal was to find treatments that potentially be given to patients in the near future.

They found 13 risk loci targeted by existing drugs, including two genes that code for so-called glutamate receptors. These receptors are proteins found on nerve cells that play a vital role in the transmission of signals throughout the nervous system. Preliminary clinical trials suggest that targeting these two receptor genes with anti-epileptic drugs namely, perampanel and lamotrigine can benefit some patients with RLS.

In addition to identifying potential drugs, the team ran a statistical analysis to see if RLS raises the risk of any other conditions. This suggested that RLS may be a risk factor for developing type 2 diabetes, although past studies on the potential link have found mixed results. As such, "these results should not be overinterpreted," the researchers cautioned they need to be confirmed in future research.

Despite their limitations, the findings may bring doctors one step closer to being able to predict someone's risk of developing RLS and understanding the wider impacts the condition has on people's health, the team said.

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Restless legs syndrome tied to 140 'hotspots' in the genome - Livescience.com

Genetics

Paired tumor-germline testing can enhance patient carewith guidance from genetics specialists – The Cancer Letter

Data from the IMROZ phase III trial demonstrated Sarclisa (isatuximab) in combination with standard-of-care bortezomib, lenalidomide and dexamethasone followed by Sarclisa-Rd (the IMROZ regimen) significantly reduced the risk of disease progression or death by 40%, compared to VRd followed by Rd in patients with newly diagnosed multiple myeloma not eligible for transplant.

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Paired tumor-germline testing can enhance patient carewith guidance from genetics specialists - The Cancer Letter

Genetics

Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets – Nature.com

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Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets - Nature.com

Genetics

Genetic Risk Score Revolutionizes TNBC Prediction in Black Women – Targeted Oncology

Black women in the U.S. often face a higher risk of developing aggressive breast cancer, particularly triple-negative breast cancer (TNBC), which can occur before routine screening is recommended. To address this disparity, accurate risk prediction methods are crucial. A multiple-ancestry polygenic risk score (MA-PRS), developed from genetic data of diverse populations, has shown promise in predicting overall breast cancer risk. In this study, researchers assessed the effectiveness of MA-PRS in predicting TNBC and early-onset TNBC in a large cohort of self-reported Black women.

Analyzing data from over 14,000 eligible participants, predominantly under 50 years old, the study found that MA-PRS significantly improved TNBC risk prediction beyond clinical factors alone. Specifically, women in the top 5% of MA-PRS distribution had roughly twice the risk of TNBC compared to the general population. Importantly, MA-PRS demonstrated comparable impact to mammographic density, a well-established risk factor for breast cancer.

The findings suggest that incorporating MA-PRS into breast cancer risk assessment could enhance early detection and potentially improve survival rates for TNBC among Black women. By accurately identifying those at elevated risk, interventions and screening strategies can be tailored more effectively, addressing a critical need in breast cancer management for this demographic.

Here, Holly Pederson, MD, breast medical oncologist at Cleveland Clinic, and Elisha Hughes, PhD, director of biostatistics at Myriad Genetics, discuss the findings and implications from this study presented at ASCO 2024.

Transcription:

0:05 | The polygenic score was really powerful risk stratifier, or it really explains a lot of the genetic susceptibility that many women have for, you know, overall breast cancer and specifically triple-negative disease. About as powerful as everything else combined with the exception of maybe mammographic density, and the polygenic score and mammographic density are both, I would say equally powerful risk stratifiers.

0:30 | This may change, help to change, screening recommendations even, because it shouldn't just be based on age, but also on ancestry and genetics. I mean, it only makes sense. The other, you know, the other main implication is that we are looking to evaluate young women and identify those families that seem as if they may have a heritable disorder to prevent future cancers. But we'd also love to identify the woman who might be at risk. And and it's, it's about 6% of women who really fall into that high-risk category. But that's an important 6%. So we'd like to make a difference there.

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Genetic Risk Score Revolutionizes TNBC Prediction in Black Women - Targeted Oncology

Genetics

Gene variants and breast cancer risk in Black women – National Institutes of Health (NIH) (.gov)

June 4, 2024

Breast cancer is the most often diagnosed cancer in many parts of the world, including the U.S. More than 310,000 new cases are expected nationwide this year.

Black women tend to develop breast cancer at a younger age than White women. Black women are also more likely than Whites to die from the disease, and they are twice as likely to develop an aggressive subtype called triple-negative breast cancer. But despite the increased risks faced by women of African descent, most large-scale genetic studies of breast cancer to date have focused on women of European ancestry.

To better understand their unique genetic risks, a research team led by Dr. Wei Zheng of Vanderbilt University analyzed genetic data from over 40,000 females of African descent. About 18,000 had been diagnosed with breast cancer. The data were gathered as part of the NIH-funded African Ancestry Breast Cancer Genetic consortium, which combined data from 26 studies. Most participants (85%) were African Americans. The rest were from Barbados or Africa.

The researchers conducted a genome-wide association study (GWAS) to look for genetic variants that are found more often in participants with breast cancer than in those without. This is believed to be the largest GWAS study to date of breast cancer in this population. Results were reported in Nature Genetics on May 13, 2024.

The analysis pinpointed 12 genetic regions, or loci, associated with breast cancer. Three of these loci were linked to the aggressive triple-negative cancer. About 8% of the women carried two genetic copies of risk variants in all three of these loci. Such women, the researchers found, were 4.2 times more likely to be diagnosed with triple-negative breast cancer than women who hadonly one or no copies of the variants.

Because this type of cancer lacks specific cell receptors often seen with breast cancer (like estrogen or HER2 receptors), there are fewer targeted options for treatment. These findings may help researchers identify new treatment targets.

The researchers also confirmed many breast cancer risk variants that were found earlier in other populations.And they identified an uncommon risk variant in the gene ARHGEF38, which had been previously linked to aggressive prostate and lung cancers.

The scientists used their findings to create polygenic risk scores (PRS) for breast cancer risk in females of African descent. PRS use genomic data to gauge the chance that a person will develop a certain medical condition. PRS created previously, using results from other populations, tend to perform poorly at predicting breast cancer risk for Black women. The new PRS, based on genomic data from African descendants, outperformed previous PRS at predicting breast cancer risk in this population.

The findings and data could lead to improved detection of breast cancer in this at-risk population and provide clues for potential treatment targets. Studies with even larger, more diverse populations will be needed to further improve the prediction of breast cancer risk.

We have worked with researchers from more than 15 institutions in the U.S. and Africa to establish this large genetic consortium, Zheng says. Data put together in this consortium have been and will continue to be used by researchers around the world.

by Vicki Contie

References:Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction. Jia G, Ping J, Guo X, Yang Y, Tao R, Li B, Ambs S, Barnard ME, Chen Y, Garcia-Closas M, Gu J, Hu JJ, Huo D, John EM, Li CI, Li JL, Nathanson KL, Nemesure B, Olopade OI, Pal T, Press MF, Sanderson M, Sandler DP, Shu XO, Troester MA, Yao S, Adejumo PO, Ahearn T, Brewster AM, Hennis AJM, Makumbi T, Ndom P, O'Brien KM, Olshan AF, Oluwasanu MM, Reid S, Butler EN, Huang M, Ntekim A, Qian H, Zhang H, Ambrosone CB, Cai Q, Long J, Palmer JR, Haiman CA,Zheng W. Nat Genet. 2024 May;56(5):819-826. doi: 10.1038/s41588-024-01736-4. Epub 2024 May 13. PMID:38741014.

Funding:NIHs National Cancer Institute (NCI).

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Gene variants and breast cancer risk in Black women - National Institutes of Health (NIH) (.gov)

Genetics

GSA-MiXeR: A powerful tool to improve our understanding of heritable traits and diseases – News-Medical.Net

Researchers from the University of Oslo have developed an innovative tool that promises to improve our understanding of heritable human traits and diseases. Published in Nature Genetics, the analytical tool is designed to make sense of genetic data by focusing on the role of individual genes, and how groups of genes contribute to the risk of developing a disease. With GSA-MiXeR, researchers now have a powerful new way to translate genetic research into practical insights that could lead to better treatments for a range of complex diseases.

More than 970 million people worldwide are living with a mental illness, according to WHO. The global burden of these diseases is considerable. While researchers have been successful in identifying genetic factors associated with conditions like schizophrenia through genome-wide association studies (GWAS), figuring out what these discoveries mean for our health is still a big challenge.

GWAS, which are often produced by large international consortia, analyze the genomes of many individuals to find genetic variations associated with specific diseases. Our tool, called GSA-MiXeR, is designed to analyze the genetic data collected from these large-scale studies, aiming to identify how groups of genes contribute to the risk of developing a disease."

Oleksandr Frei, Researcher, Center for Precision Psychiatry, University of Oslo

Complex polygenic traits, which are influenced by many genetic factors, have been particularly difficult to interpret. "GSA-MiXeR addresses this by providing a clearer picture of how different genes work together", he explains.

When applied to a variety of complex traits and diseases, including schizophrenia, GSA-MiXeR has been able to highlight specific gene groups that are more closely related to the disease than traditional methods have been able to. One example is how GSA-MiXeR identified that genes involved in controlling calcium channels in our cells and those involved in dopamine signaling, play a significant role in schizophrenia. "These findings are not just important for understanding the diseasethey also may point to potential targets for developing new treatments", Frei says.

Better understanding of complex traits and disorders can lead to precision medicine, where treatments are tailored to the genetic makeup of individual patients. This approach can improve the effectiveness of treatments and reduce side effects. By translating genetic research into practical insights, GSA-MiXeR can contribute to more personalized and effective healthcare, ultimately leading to better health outcomes for patients, Frei says.

With GSA-MiXeR, scientists now have a powerful new way to translate genetic research into practical insights that could lead to better treatments for a range of complex diseases.

This research is done in a collaboration with the group of Professor Anders M. Dale at the Center for Multimodal Imaging and Genetics, the University of California in San Diego, USA.

Source:

Journal reference:

Frei, O., et al. (2024). Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets.Nature Genetics. doi.org/10.1038/s41588-024-01771-1.

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GSA-MiXeR: A powerful tool to improve our understanding of heritable traits and diseases - News-Medical.Net

Genetics

Understanding the effect genetics have on Alzheimer’s – Buffalo News

Alzheimer's disease is a neurological condition that worsens with time and mainly affects the elderly. It causes changes in personality, memory loss, and cognitive impairment. It is the most frequent form of dementia, a collection of brain abnormalities that impair social and intellectual abilities to the point that they become too great to be useful for day-to-day living. The buildup of tau tangles and amyloid plaques in the brain, which impair neuronal transmission and cause cell death, is the hallmark of the illness.

Alzheimer's disease comes in two primary forms: early-onset and late-onset. While the symptoms of both kinds are similar, there are notable differences between them in terms of the age at which symptoms initially manifest and their underlying genetic makeup. So, this leads to the question:is Alzheimer's genetic?

Late-onset is the most prevalent kind of Alzheimer's disease, which usually first appears after age 65. This kind affects a large population; around 10% of Americans 65 years of age and older have a diagnosis. With age comes a huge rise in danger. There are both hereditary and non-hereditary variables that lead to late-onset Alzheimer's disease.

An important genetic component of Alzheimer's disease with a late start is the e4 variation of the APOE gene. Apolipoprotein E, a protein involved in the body's metabolism of fats, is encoded by the APOE gene. This gene has three common variations, e2, e3, and e4. Alzheimer's disease risk is increased in those with the e4 variation. A single copy of the e4 allele increases risk by three times, whereas two copies raise risk by eight to twelve times. It is crucial to remember that not everyone who carries the e4 variation will have Alzheimer's; some people may still have the illness. This implies that there may be other genetic, environmental, and behavioral variables involved.

Less than 1% of instances of Alzheimer's disease are early-onset, making it a far more uncommon condition. Typically, people in their 30s, 40s, or 50s have symptoms. The genetics of this kind of Alzheimer's frequently play a significant role. Early-onset Alzheimer's disease is mostly linked to three genes: APP, PSEN1, and PSEN2. Amyloid plaques can build up in the brain as a result of aberrant proteins produced by mutations in these genes.

Families with a history of Alzheimer's disease that developed slowly frequently show signs of autosomal dominant inheritance. This indicates that there is a 50% possibility that an offspring will inherit a mutant gene and might acquire the disease if one parent possesses the mutation.

Non-genetic variables increase an individual's risk of Alzheimer's disease, even if hereditary factors account for a large portion of the illness's development. The biggest risk factor is becoming older, especially if you have late-onset Alzheimer's. Lifestyle, general brain health, and cardiovascular health are additional risk factors. Alzheimer's disease risk can also be raised by cardiovascular health conditions such asdiabetes, hypertension, and high cholesterol. Lifestyle elements like nutrition, physical activity, and intellectual pursuits are also crucial. Research indicates that participating in cognitively stimulating activities, maintaining a nutritious diet, and getting regular exercise can lower the risk of cognitive decline.

The answer to the question, "Is Alzheimer's genetic?" is not simple. The likelihood of developing the illness is influenced by both hereditary and non-genetic variables. Although some genetic variations, such as APOE e4, greatly raise risk, they do not control outcome. Important roles are also played by lifestyle and environmental variables. Having a thorough understanding of these variables can aid in the development of management and preventative plans. Our understanding of the interaction between genetics and other risk factors is changing as research advances, which gives us hope for improved treatments and preventive actions in the future.

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Understanding the effect genetics have on Alzheimer's - Buffalo News

Genetics

‘Fossil viruses’ embedded in the human genome linked to psychiatric disorders – Livescience.com

Ancient viral DNA embedded in the human genome may boost people's susceptibility to neuropsychiatric disorders, such as depression, bipolar disorder and schizophrenia.

A study published in May in the journal Nature Communications zoomed in on human endogenous retroviruses (HERVs) snippets of DNA that form approximately 8% of the modern human genome.

Psychiatric disorders tend to run in families, and studies of twins have also hinted that genetics plays a role in whether people develop them. Estimates suggest that schizophrenia and bipolar disorder may have a heritability as high as 80%, meaning most of the variability seen in these disorders comes down to differences in people's genetics.

Specific versions of genes, or gene variants, have been tied to these disorders, but not much is known about the influence of HERVs.

Related: Common cold virus may predate modern humans, ancient DNA hints

"We were fascinated by the concept that [HERVs] existed in the human genome and so much was not known about them," study co-author Timothy Powell, a neuroscientist and molecular geneticist at King's College London, told Live Science.

HERVs are bits of viruses that have been woven into the human genome over evolutionary time, with the oldest examples introduced to our ancestors over 1.2 million years ago. Some HERVs are known to be switched on in cancer cells, and they may contribute to the disease; others are active in healthy tissues or play important roles in early development, so they're not necessarily all bad. Some HERVs are even active in the brain, but it's not yet clear what they're up to.

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Previously, scientists have studied the role of HERVs in psychiatric disorders by comparing the genetic material of individuals without such disorders with that of people affected by a given disorder. A drawback of this method, however, is that it doesn't account for the influence of environmental factors or other conditions a person may have. This makes it difficult to say with certainty that a given stretch of DNA, in isolation, is strongly associated with the disorder.

The new study used a different approach to weigh the effects of thousands of HERVs. The researchers accessed genetic data from previous studies that involved tens of thousands of people, as well as from postmortem brain tissue samples collected from nearly 800 patients with and without psychiatric disorders. They then studied which gene variants different individuals carried, noting whether they seemed to affect nearby HERVs.

They found that specific gene variants were associated with a higher risk of three psychiatric disorders schizophrenia, depression and bipolar disorder. These variants also affected whether HERVs in the brain were "switched on" and to what degree.

"This [association] gives us much more certainty that the genetic differences we're seeing between cases and controls are more likely to be a true reflection of the biology of the disorder," Rodrigo Duarte, a research fellow at King's College London, told Live Science.

The team is the first to identify five new HERVs strongly tied to psychiatric disorders. Two were associated with schizophrenia, one was common to schizophrenia and bipolar disorder, and one was specific to major depressive disorder. These five HERVs are distinct from any previously linked with each of the conditions.

"It is a major advancement," said Dr. Avindra Nath, clinical director at the National Institute of Neurological Disorders and Stroke who was not involved in the study. "The way that we've been studying all these other neurological diseases, we need to look at them again using their technique," Nath told Live Science.

The study suggests that these HERVs enhance the chances of developing the disorders, but at this point, not much can be said for how much these genetic snippets boost an individual person's risk. Carrying one of the HERVs doesn't necessarily guarantee a person will be affected by the linked disorder.

Going forward, the group plans to manipulate HERV activity in brain cells in lab dishes to see whether they affect the way the neurons grow and form connections.

"From a genetic standpoint, it's an advancement of the field," Nath said. "But from a pathogenesis standpoint, much remains to be answered" about how the HERVs actually contribute to disease.

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Genetics

Genes Link Sleep Patterns to Autism and Bipolar Disorder – Neuroscience News

Summary: Researchers found genetic associations between sleep patterns and neuropsychiatric conditions like autism, ADHD, and bipolar disorder. Polygenic risk score analysis revealed that autism and schizophrenia link to evening chronotype, while ADHD, schizophrenia, and bipolar disorder link to insomnia. These insights may lead to new therapies for sleep disturbances in these patients.

Key Facts:

Source: European Society of Human Genetics

Disturbed sleep is very common in almost all neuropsychiatric and neurodevelopmental conditions (NDPCs), such as autism, attention deficit and hyperactivity disorder, schizophrenia, and bipolar disorder.

While it is understandable that the symptoms of such conditions would lead to sleep disruption and also that sleep disruption would worsen symptoms in these conditions, Irish researchers have now found new genetic associations between some of these conditions and chronotype, the behavioural manifestations of an individuals circadian rhythm (night owl or early bird).

These findings may point the way to the development of new therapies for patients.

Presenting the results of the study to the annual conference of the European Society of Human Genetics today (Tuesday), Dr Laura Fahey, a postdoctoral researcher in the Family Genomics Research Group, Maynooth University, Republic of Ireland, will say that sleep disturbances are known to predate the onset of major depressive disorder and bipolar disorder, and that polygenic score analysis can identity whether these conditions and sleep traits share genetic variation.

The researchers therefore used polygenic risk score analysis on large-scale genetic studies of NDPCs to test their ability to predict chronotype and insomnia in over 409,000 participants in the UK Biobank.

Their findings strengthen known genetic correlation results in that they show that polygenic scores for autism and schizophrenia are associated with an evening chronotype, while polygenic scores for attention-deficit/hyperactivity disorder, schizophrenia, and bipolar disorder are associated with insomnia.

We also identified novel associations between bipolar disorder and chronotype, as well as insomnia and autism, says Dr Fahey.

These are interesting insights into the genetic basis of sleep disruption, and may open new research avenues for the treatment of sleep and circadian rhythm disturbances in these patients.

The finding that shared genetic variation between bipolar disorder and chronotype was enriched (overrepresented) in a pathway* called NRF2-KEAP1 was interesting to us, as the NRF2 pathway was previously linked to the pathology of bipolar disorder and schizophrenia.

Additionally, NRF2 has previously been shown to be rhythmically regulated by circadian clock genes.

However, it was surprising that there was no enrichment of shared genetic variation in any biological pathway for the other sleep-NDPC phenotype pairs investigated. This was particularly surprising for ADHD and insomnia, as we found these two phenotypes to have the strongest genome-wide correlation.

A reason for this could be that the shared genetic variation is highly polygenic, affecting all biological pathways somewhat equally. It could also be that this shared genetic variation is enriched in cell- or tissue-specific pathways, which we did not explore, Dr Fahey says.

The researchers also intend to test polygenic scores from more diverse populations, the UK Biobank data used in their study being on individuals of white British ancestry.

We need to know whether this work can be applied to other population groups, says Dr Fahey, since we hope that our work may contribute to the development of predictive and preventive interventions in the future..

Further research could also investigate the impact of the genetic variation found in the biological pathways identified by the scientists as influencing circadian rhythm; for example, whether there are specific subsets of patients with these changes where it would be useful to look for differences in gene expression.

However, the next stage of my research project will take a broader perspective and aim to better understand the genetic architecture using different methods and investigating both rare and common genetic variations underlying sleep and circadian rhythm disturbances in NDPCs, Dr Fahey says.

Professor Alexandre Reymond, from the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, and chair of the conference, said: It is interesting to see that perturbations of the same molecular pathways are associated with distinct phenotypes (bipolar disorder/schizophrenia and chronotype), a phenomenon called pleiotropy.

It is tantalising to think that, if we are in presence of direct pleiotropy where one trait influences the other trait, we may have some hints about possible treatments.

Note:

* Gene-regulation pathways turn genes on and off. Such action is vital because genes provide the recipe by which cells produce proteins, which are the key components needed to carry out nearly every task in the body.

Author: Mary Rice Source: European Society of Human Genetics Contact: Mary Rice European Society of Human Genetics Image: The image is credited to Neuroscience News

Original Research: The findings will be presented at the European Society of Human Genetics annual conference

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Genes Link Sleep Patterns to Autism and Bipolar Disorder - Neuroscience News