Category Archives: Genetics

Seeing the Forest Through the Trees: Dr. Wendy Chung on Genetics and Cancer – Columbia University

On June 13, 2013, the U.S. Supreme Court unanimously ruled that human genes cannot be patented, in a case against Myriad Genetics brought on behalf of the ACLU and a group of interested parties, including Columbia University geneticist Dr. Wendy Chung. Dr. Chung saw the negative impact exclusive testing with a single lab had on patients, sometimes barring them access to genetic testing that could arm them with decision-making information about their diagnosis, treatment and care. Myriad held the exclusive licenses to the patents on the BRCA1 and BRCA2 genes, the most commonly affected genes in hereditary breast and ovarian cancer.

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At the time of the ruling, Dr. Chung said, This decision means we are not going to be impeded in giving full information to our patients about all of their genes. Reflecting on past progress and what is to come, Dr. Chung discusses the ever-evolving field of genetic testing and research, zeroing in on cancer.

Over the course of my career, the changes weve seen are profound, because when we started doing this, we didn't know about any cancer susceptibility genes, like BRCA1 or BRCA2. We knew that they must exist because we'd see families that seemed to have very strong family histories of cancer, and usually these were particular types of cancers, such as breast cancer running in the family or colon cancer, but we didnt know the exact genes or genetic variants. In my lifetime, I've seen first, the identification of those genes, and then second, the clinical implementation of genetic testing.

Most people are familiar with BRCA1 and BRCA2 genes, whether it's because they've heard of the Angelina Jolie story or they themselves know of someone with an increased cancer risk due to these genes. They were somewhat of a misnomer at the beginning, because they were named BRCA1 and BRCA2 for breast cancer 1 and 2, but they truly are breast and ovarian cancer genes. A lot of the infrastructure that was built around clinical implementation was built around those two genes, because those were the genes we knew about first and it was clear from a clinical standpoint what to do with that information. There were women who thought about having surgeries to reduce their cancer risk, whether that was a mastectomy [the surgical removal of one or both breasts] or oophorectomy [the removal of one or both ovaries]. Weve since developed programs to help those women make important decisions based on knowledge of their cancer risk profile. This ability really can be life-changing and lifesaving.

But those with mutated BRCA1 or BRCA2 genes arent in fact the majority of people who either get breast cancer or who are at risk for breast cancer. They're the peak of risk; having one of these genes puts you at the highest risk. We've since identified other genes that instead of increasing cancer risk by ten-fold, they might increase risk by two-fold. There's quite a different decision that patients make when you're at a two-fold increased risk rather than ten-fold. We've started building tailored care models, ways of educating people and thinking about different treatment and care management options based on a persons individual risk.

Yes, the second big wave in the clinical implementation of genetic testing was thinking about how you start to then integrate that information into clinical care, into routinization in terms of being able to provide a comprehensive genomic assessment for each patient diagnosed with cancer or at risk for cancer to tailor their treatment and care. For me, this second wave has really been for two different clinical use cases. One is people diagnosed with cancer and trying to think about their cancer management specifically. The other clinical use cases are people who don't yet have cancer, and hopefully, never will have cancer, but where we use this information in risk stratification to think about how to either reduce risk or screen for cancer and tailor that plan based on the individual and specific factors, everything from gender to stage in life to genetic and non-genetic risk factors and putting that all together.

For instance, within the Jewish community, we know that 1 in 40 people has a mutation in either the BRCA1 or BRCA2 genes. We have a very accurate understanding of the cancer risk profiles for this population. We even have curves to know over the life course when that risk starts becoming higher. So, this first wave of progress has been powerful, where we identified the BRCA1 and BRCA2 genes, knowing the cancers associated with them, knowing that in particular, Jewish communities were at higher risk. The same storyline has happened for colon cancer. Realizing that there are genes for colon cancer, weve routinized screening to identify which individuals with colon cancer may have genes that increase their risk of other types of gastrointestinal cancer, or uterine or ovarian cancer for the women. Were able to really understand the full cancer risk for them and their families.

We're just starting to get into a brand-new era, where historically we've done genetic testing for genes, like BRCA1 and BRCA2, that have a remarkably high penetrance, or in other words, very high likelihood that someone will get cancer. Were now getting to the point where we can use genetic and non-genetic information to come up with better cancer risk stratification for a larger number of people. That's a new concept in terms of thinking about not just individual genes or variants, but looking at something like 500 different genes or variants, and in a mathematical way, being able to look at the combination of those in an individual. We can take all of that data and apply algorithms to understand the cancer risk of that individual based on all those unique genetic contributions. We can now see not just one tree, but the entire forest.

Yes, this is precision prevention. Its information about your individual risk profile in sufficient detail so you can come up with a strategy to mitigate your risk and/or detect cancer at an early treatable stage. We can model the effect of various interventions including exercise, diet, smoking, and show someone how they can bend their personal curve to reduce their cancer risk.

One of my core beliefs is that people should be empowered to get information they need and to be able to make rational decisions about their health. The problem is that some of the direct-to-consumer products may not be clear in what they're providing. You might think you're getting something about your breast cancer risk stratification, but there's little scientific or medical information content in there. I worry about people who think they might have clean genes after taking a home-based genetics test and think they dont have to worry about going for their annual mammogram or having a colonoscopy. If you want to find your long-lost relatives or if youre adopted and you don't know your familys origin, then some of these consumer DNA products might be a good way to do that. Using these products to trace your ancestry and your roots can be useful, but dont depend on them for medical guidance.

The Human Genome Project. Im smiling because we just had a virtual session with President Clinton, [former NIH directors] Francis Collins and Harold Varmus, and Donna Shalala [former U.S. Secretary of Health and Human Services]. We had a whole session, thinking back to the Clinton era and reflecting on this major accomplishment. Bill Clinton was a strong advocate for the Human Genome Project, and it was during his administration that the first draft was completed.

The Human Genome Project fueled everything that I've talked about being able to find genes, identify genes, and being able to do better cancer risk stratification. That was one of the best investments we made as a scientific community and has been hugely impactful.

Weve taken a few baby steps, but I want to emphasize that right now my field is not fair and is not equitable. What I mean by that is we serve a wonderfully rich and diverse community here at the Herbert Irving Comprehensive Cancer Center and with the genetic testing that we do I cannot give equally useful information to all the patients who come to see me. If you happen to be of European ancestry, I can give you much better information than if you come to me and your roots are from Nigeria. The fundamental problem is that we don't have equal representation in the genetic data that we have to interpret what the DNA means. Right now, 80% of the genetic data we have on average people comes from individuals that represent 20% of the world's population. We should have 80% from 80%. Anyone other than individuals of European ancestry are underrepresented. To me, that is fundamentally not fair and not equitable. We have a lot of work to do there.

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Seeing the Forest Through the Trees: Dr. Wendy Chung on Genetics and Cancer - Columbia University

Study of Cancer Genetics to Help with Targeted Treatment – VOA Learning English

Scientists have studied the full genetic information of more than 18,000 cancer samples. They found new information about the patterns of mutations, or changes, that could help doctors provide better treatment.

Their study, which appeared recently in the publication Science, is not the first to do such a complete genetic study of cancer samples. But no one has ever used such a large sample size.

Serena Nik-Zainal of the University of Cambridge was part of the team that did the research. She said this was the largest cohort in the world. It is extraordinary."

Over 12,000 samples in the study came from patients recruited by Britains National Health Service. They were part of a project to study whole genomes from people with common cancers and rare diseases. The rest of the data came from existing cancer data sets.

Researchers were able to study such a large number because of the same improvements in technology that recently permitted scientists to complete the map of the entire human genome.

Andrew Futreal, a genomic expert at MD Anderson Cancer Center in Houston, was not involved in the study. He said the study gives scientists some knowledge of the destructive forces that cause cancer.

Cancer is a disease of the genome or full set of instructions for running cells. It happens when changes in a persons DNA cause cells to grow and divide uncontrollably. DNA is a substance that carries the genetic information in the cells of living things, like a human. In 2020, there were about 19 million new cancer cases worldwide.

For the study, researchers looked at 19 different kinds of cancer in the human body. It identified 58 new mutational signatures, or pieces of evidence leading to the causes of cancer. Nik-Zainal said researchers also confirmed 51 of more than 70 previously reported mutation patterns. Some arise because of problems within a persons cells; others are caused by ultraviolet radiation, tobacco smoke, or chemicals.

Knowing more of them helps us to understand each persons cancer more precisely, which can help guide treatment, Nik-Zainal said.

Genetic sequencing, the process used to study the makeup of a cell, is already being included in cancer care. It is part of the growing move toward personalized medicine, or care based on a patients genes and specific disease. Now doctors will have much more information to draw from when they look at individual cancers.

To help doctors use this information, researchers developed a computer program that will let them find common mutation patterns and seek out rare ones. Nik-Zainal said doctors could suggest a treatment based on a special pattern.

Futreal said the data can also show doctors what tends to happen over time when a patient develops a cancer with a certain mutation pattern. This will help doctors give earlier treatment and hopefully stop the developing disease.

Im John Russell.

Laura Ungar reported on this story for the Associated Press. John Russell adapted it for VOA Learning English.

____________________________________________________________________

sample n. a group of people or things that are taken from a larger group and studied, tested, or questioned to get information

pattern n. the regular and repeated way in which something happens

mutation n. a change in hereditary material

cohort n. a group of individuals having something (usually a statistical factor) in common in a study

genome n. the complete set of genes in a cell or organism

DNA n. a substance that carries genetic information in the cells of plants and animals

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Study of Cancer Genetics to Help with Targeted Treatment - VOA Learning English

Heart Warriors: ‘Genetics is the future of medicine’ according to U of A researcher, who uses it to help with muscular dystrophy – The Gateway Online

A University of Alberta researcher researching muscular dystrophy was one of five researchers at the institution to receive a grant from the Heart & Stroke Foundation of Canada.

Toshi Yokota, a professor in the department of medical genetics and current The Friends of Garrett Cumming Research Chair, was a recipient of the 2021-2022 Grant-In-Aid program. This provides funding for important, pertinent, and novel research in the area of heart disease and stroke over three years.

The project funded by the Heart & Stroke Foundation of Canada involves using peptides, short chains of amino acids, to deliver antisense oligonucleotides-shorts, DNA-like molecules, to help with heart failure in patients suffering with muscular dystrophy.

Duchenne muscular dystrophy (DMD), the most common type of muscular dystrophy, is most commonly seen in males, with one in 3,500 males born worldwide suffering from this condition. A person with muscular dystrophy would see progressive weakening of their muscles, such as in their arms and legs and eventually their torso as well.

These patients often do not die from issues with the muscles of their limbs since they can still survive without them; what causes many patients to die in their 20s and 30s is heart failure. Previous methods which have been developed are unable to enter the heart to help with heart failure. Yokota and their team are studying a new molecule which may help with this.

We started this project a couple of years ago and in collaboration with Dr. Hong Moulton, at the Oregon State University, Yokota said. She discovered a new peptide called the DG-9 [and] I found that it works very well in the heart; it penetrates the membrane and we can deliver antisense oligos to the heart muscle.

Yokotas love of research started back when they were a child.

From my elementary school or secondary school I always liked science and I read lots of books about science and I like, for example, watching stars and insects or animals, they said. It sounded quite natural to me. I like science and I like research.

Yokota began diving more into genetics during their undergraduate degree at the University of Tokyo. In graduate school, one of their professors, Dr. Shinichi Takeda, had just started a new lab researching muscular dystrophy and was looking for new students.

I thought genetics was the future of medicine and thats very fascinating I think its quite natural to me to join his lab, they said.

Something that Yokota wants students to remember is to focus on what you can do and what interests you, not what you cannot do.

When I was a high school student I was more interested in astrophysics and read many books written by Stephen Hawking and other scientists, they said. But it turned out I am better at biology and I changed my focus to biology at my university, which worked out very well.

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Heart Warriors: 'Genetics is the future of medicine' according to U of A researcher, who uses it to help with muscular dystrophy - The Gateway Online

Is osteoarthritis hereditary? Genetics, causes, and more – Medical News Today

Osteoarthritis (OA) is a degenerative joint disease that causes pain and stiffness and decreases mobility. While OA is not always hereditary, experts believe that there may be a genetic component that increases the risk of developing this condition.

Around 32.5 million adults in the United States have OA. Various factors contribute to individuals developing OA, including increasing age, obesity, joint injuries, and a persons sex.

While genetics play a role in increasing the risk of someone developing OA, this condition is not hereditary.

This article explores how genetics contribute to OA and discusses other risk factors.

There are over 100 different types of arthritis, and OA is one of the most common. OA is a degenerative joint disease that worsens over time. Currently, there is no cure for this condition.

When a person has OA, their cartilage breaks down. Cartilage is a protective, fibrous connective tissue that cushions the ends of bones and allows them to move easily over each other.

When cartilage begins to break down, the bones rub against one another. In addition, bony spurs, or osteophytes, might form as the bone attempts to heal itself.

People with OA may experience pain, stiffness, and swelling in the joints.

Autoimmune forms of arthritis, such as rheumatoid arthritis, result from the immune system attacking the bodys healthy tissue.

However, doctors usually consider OA a wear and tear disease, as it is more common in people over the age of 50 and is more likely to affect weight-bearing joints, such as the knees and hips. Injuries or genetic predisposition can also increase the risk of OA.

While OA is not always heredity, in some cases, a person can inherit an increased risk of developing this condition. Experts do not currently know how the predisposition of an increased risk of developing OA passes between family members.

Experts estimate that around 4070% of OA cases have a genetic component, with a stronger link for the hip, hand, and spine. The hereditary forms of OA arise from mutations in genes that help form and maintain bone and cartilage. This type of OA may appear at a young age and rapidly progress.

There is not a single specific gene that increases the risk of developing OA. Multiple genes and other risk factors, such as obesity, injuries, and joint anatomy, also contribute to OA.

Research suggests that several groups of genes may increase the risk of developing OA, including:

While scientists have identified different gene variations that may contribute to OA, they do not yet know precisely what part genetics play in developing this condition.

Additionally, people with certain genetic traits or inheritable conditions, such as Ehlers-Danlos syndrome (EDS), may have an increase in the risk of developing OA.

People with EDS have low collagen levels, which can reduce their ability to support muscles and joints. This can lead to unstable and hypermobile joints that may contribute to OA.

More research is necessary to understand the complex interplay between genetic factors and OA.

The cause of OA is wear and tear at the joints.

A range of factors can contribute to individuals developing OA:

Typically, OA risk increases with age and appears most often in individuals over the age of 50. However, it can appear in younger individuals, particularly after a bone fracture or a cartilage or ligament tear.

OA usually worsens over time and can develop in several joints. It often begins in a single large joint, such as a hip or knee, but it may also involve a smaller joint, such as an ankle.

Some people may have OA in a single joint, but it may progress to involve other joints, such as the spine, neck, and wrists.

While doctors do not fully understand why this happens, it is possible that the pain from OA causes the individual to move differently, which then forces the joints out of alignment.

OA is a degenerative condition with no cure. This condition worsens over time and can cause significant difficulty in mobility.

If a person has individuals in their family with OA, it does not mean they will also develop the condition. Experts estimate that the heritability of OA is around:

Researchers do not fully understand the link between OA and life expectancy. In some cases, OA of the knee or hip may negatively affect an individuals life expectancy, but this is potentially due to pain, difficulty in mobility, and other health conditions.

Other types of OA, such as OA of the hand, do not appear to have an effect on life expectancy.

OA is a degenerative joint disease that worsens over time, causing difficulty in mobility and pain. Age is the primary factor that increases OA risk, but other causes include injury, obesity, sex, and genetics.

The heritability of OA is around 4070%. However, having family members with OA does not mean that a person will develop the condition.

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Is osteoarthritis hereditary? Genetics, causes, and more - Medical News Today

Novel genetic mapping study traces links between DNA variations and blood proteins – News-Medical.Net

A new genetic mapping study led by researchers at the Johns Hopkins Bloomberg School of Public Health traces links between DNA variations and thousands of blood proteins in two large and distinct populations. The results should help researchers better understand the molecular causes of diseases and identify proteins that could be targeted to treat these diseases.

The study included more than 9,000 Americans of European or African ancestry, and generated maps of DNA-to-protein links for both groups. The study is thought to be the first of its kind to include two large and ancestrally distinct population cohorts. Proteins play a critical role in cellular function, and changes in protein mechanisms-;often regulated by DNA variations-;can lead to disease. DNA-to-protein mapping could help explain differences in the rates of some diseases in the two groups and help researchers understand some health disparities.

The study appears May 2 in Nature Genetics.

Researchers have been mapping the molecular roots of human diseases for decades through so-called genetic mapping studies. The best known is the genome-wide association study (GWAS). A GWAS typically links variations in DNA to disease risk by analyzing the DNA of subjects-;often tens or hundreds of thousands of individuals at a time-;along with their history of a given disease. This uncovers statistical associations linking the disease to specific DNA variations.

Missing from the GWAS picture: Most of the disease-linked DNA variants identified by GWAS analysis do not lie within protein-coding genes. Researchers therefore assumed that many-;even most-;disease-linked DNA variants affect proteins indirectly, by regulating one or more steps in the gene-to-protein production process, thereby altering protein levels. Linking diseases directly to proteins, researchers can better understand the roots of disease-;and also identify protein targets for disease prevention and treatments.

This relatively new kind of mapping study provides a wealth of information that will allow researchers to test for potential links of proteins on various types of health outcomes-; risk of cancers, heart disease, severe COVID-; and help to develop or repurpose therapeutic drugs."

Nilanjan Chatterjee, PhD, Study Senior Author and Bloomberg Distinguished Professor, Biostatistics, Johns Hopkins Bloomberg School of Public Health

To demonstrate the DNA-protein mapping's application, the researchers used it to identify an existing rheumatoid arthritis drug as a plausible new treatment for the common joint-pain disorder known as gout.

The study was a collaboration between Chatterjee's team and the research group of Josef Coresh, MD, George W. Comstock Professor in the Bloomberg School's Department of Epidemiology and one of the paper's co-authors, and colleagues at several institutions.

The analysis covered 7,213 Americans of European ancestry and 1,871 African Americans in the long-running Atherosclerosis Risk in Communities (ARIC) study, headed by Coresh; and 467 African Americans from the African American Study of Kidney Disease and Hypertension (AASK). In both of these studies, the research teams had sequenced the genomes of the participants and recorded bloodstream levels of thousands of distinct proteins.

For their mapping study, Chatterjee's team analyzed the ARIC and AASK genomic data to identify more than two thousand common DNA variations that lie close to the genes encoding many of these proteins and correlate with the proteins' bloodstream levels.

"The value of knowing about these DNA variants that predict certain protein levels is that we can then examine much larger GWAS datasets to see if those same DNA variants are linked to disease risks," Chatterjee says.

Using a European-American dataset, they found that it predicted several proteins whose levels would influence the risk of gout or bloodstream levels of the gout-related chemical urate. These proteins included the interleukin 1 receptor antagonist (IL1RN) protein, which appears to lower gout risk-;a finding that suggests the existing rheumatoid arthritis drug anakinra, which mimics IL1RN, as a plausible new therapy for gout.

Having data from both white and Black Americans allowed the researchers to map protein-linked DNA variants more finely than if they had been restricted to one or the other. The African-ancestry models generated in the study will allow future analyses of how different populations' genetic backgrounds might contribute to differences in disease rates.

"We know that prostate cancer risk, for example, is higher in African American men, so in principle, one could combine prostate cancer GWAS data on African Americans with our protein data to identify proteins that contribute to elevated prostate cancer risk in that population," Chatterjee says.

The team has made its datasets and protein prediction models publicly available online so researchers can use the resource. Chatterjee's team and collaborators anticipate doing further studies in the ARIC and AASK cohorts, as well as in other diverse cohorts, to gather information on proteins and other factors that influence the DNA-to-disease chain of causality.

"Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies" was co-authored by first authors Jingning Zhang and Diptavo Dutta, and by Anna Kttgen, Adrienne Tin, Pascal Schlosser, Morgan Grams, Benjamin Harvey, CKDGen Consortium, Bing Yu, Eric Boerwinkle, Josef Coresh, and Nilanjan Chatterjee.

The analysis of this project was supported by a RO1 grant from the National Human Genome Research Institute at the National Institutes of Health (1 R01 HG010480-01). Additional NIH grants supporting this research include R01 HL134320, R01 AR073178, R01 DK124399, and HL148218. The Atherosclerosis Risk in Communities study has been funded in whole or in part by the National Heart, Lung, and Blood Institute; National Institutes of Health; Department of Health and Human Services (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I).

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Journal reference:

Zhang, J., et al. (2022) Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies. Nature Genetics. doi.org/10.1038/s41588-022-01051-w.

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Novel genetic mapping study traces links between DNA variations and blood proteins - News-Medical.Net

Genetic Links Revealed Between Severe COVID-19 and Other Medical Conditions – SciTechDaily

A recent study of data from the Veterans Affairs Million Veteran Program discovered genetic correlations between COVID-19 severity and a variety of medical problems that are established risk factors for severe COVID-19.

A new analysis of data from the Veterans Affairs Million Veteran Program has uncovered genetic links between COVID-19 severity and various medical conditions that are known risk factors for severe COVID-19. Anurag Verma of the Corporal Michael Crescenz VA Medical Center in Philadelphia, Pennsylvania, US, and colleagues published these findings on April 28th, 2022, in the open-access journal PLOS Genetics.

Some patients with COVID-19 have a more severe case of the disease than others. Previous research has found certain variants in specific human genes that are linked with a person experiencing more severe COVID-19. Some of these variations may also be associated with other medical conditions that may already be well understood; discovering these shared variants could increase understanding of COVID-19 and reveal potential new paths for treatment.

While genes linked to severe COVID-19 were associated with established risk factors and adverse outcomes, including deep vein thrombosis, a significant subset of these genes had opposite associations with reduced risk of immune-mediated disorders such as psoriasis, lupus, and rheumatoid arthritis. Credit: Anurag Verma, Katherine Liao, and Scott Damrauer (CC-BY 4.0)

To identify shared variants, Verma and colleagues used an unprecedented dataset of genotypic information linked to electronic health record data (EHR) for more than 650,000 U.S. veterans. They conducted a type of analysis known as a phenome-wide association study (PheWAS) to examine links between variants often found in Veterans who experienced severe COVID-19 and variants associated with a broad selection of medical conditions.

The analysis revealed that certain variants associated with COVID-19 are also associated with known risk factors for COVID-19. Particularly strong links were found for variants associated with venous embolism and thrombosis, as well as type 2 diabetes and ischemic heart diseasetwo known COVID-19 risk factors.

The analysis also found genetic links between severe COVID-19 and neutropenia for Veterans of African and Hispanic ancestry; these links did not appear for those of European ancestry.

Among respiratory conditions, idiopathic pulmonary fibrosis and chronic alveolar lung disease shared genetic links with severe COVID-19, but other respiratory infections and chronic obstructive pulmonary disease (COPD) did not. Some variants associated with severe COVID-19 were also associated with reduced risk of autoimmune conditions, such as psoriasis and lupus. These findings highlight the need to carefully weigh various aspects of the immune system when developing new treatments.

Despite some limitations of the PheWAS method, these findings could help deepen understanding of COVID-19 and guide development of new treatments.

Verma concludes, The study demonstrates the value and impact of large biobanks linking genetic variations with EHR data in public health response to the current and future pandemics. MVP is one of the most diverse cohorts in the US. We had a unique opportunity to scan thousands of conditions documented before the COVID-19 pandemic. We gained insights into the genetic architecture of COVID-19 risk factors and disease complication.

One thing that stood out to us was the high number of immune-mediated conditions that shared genetic architecture with severe manifestations of COVID-19, coauthor Katherine Liao adds.The nature of the associations brought to light how the SARS-CoV2 virus pushes on a pressure point in the human immune system and its constant balancing act of fighting infection while maintaining enough control so that it does not also become an autoimmune process, attacking self.

Reference: A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program by Anurag Verma, Noah L. Tsao, Lauren O. Thomann, Yuk-Lam Ho, Sudha K. Iyengar, Shiuh-Wen Luoh, Rotonya Carr, Dana C. Crawford, Jimmy T. Efird, Jennifer E. Huffman, Adriana Hung, Kerry L. Ivey, Michael G. Levin, Julie Lynch, Pradeep Natarajan, Saiju Pyarajan, Alexander G. Bick, Lauren Costa, Giulio Genovese, Richard Hauger, Ravi Madduri, Gita A. Pathak, Renato Polimanti, Benjamin Voight, Marijana Vujkovic, Seyedeh Maryam Zekavat, Hongyu Zhao, Marylyn D. Ritchie, VA Million Veteran Program COVID-19 Science Initiative, Kyong-Mi Chang, Kelly Cho, Juan P. Casas, Philip S. Tsao, J. Michael Gaziano, Christopher ODonnell, Scott M. Damrauer and Katherine P. Liao, 28 April 2022, PLOS Genetics.DOI: 10.1371/journal.pgen.1010113

Funding: This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award MVP035. S.M.D. is supported by US Department of Veterans Affairs (IK2-CX001780). R.C. is supported by NIH grants R01 AA026302 and P30 DK0503060. K.P.L. is supported by NIH P30 AR072577, and the Harold and Duval Bowen Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Genetic Links Revealed Between Severe COVID-19 and Other Medical Conditions - SciTechDaily

The 5% solution: Researchers crack wheat’s genetic code, open door to higher yields – Herald and News

DAVIS, Calif. Researcher Jorge Dubcovsky and his team have identified one of the genes in wheat that increases yield the holy grail for farmers.

Yield the amount of wheat grown per acre is how wheat farmers pay the bills.

We always joke in wheat breeding that the first three top priorities are yield, yield and yield, Dubcovsky, a University of California-Davis wheat breeder, told the Capital Press. There are premiums and discounts for protein, but the grower is paid by the yield. Thats the only thing that the grower gets.

The gene Dubcovsky and his team discovered controls the maximum number of grains the plant produces. They estimate the discovery could eventually increase yields by as much as 5%.

Breeders devote most of their efforts to pursuing yield, Dubcovsky said.

You only advance varieties that will yield better than the previous one, Dubcovsky said. If not, nobody will buy it.

But, he said, yield has been a very difficult trait to crack.

The reason is many variables impact wheat yields.

One year, the varieties that dont shatter in the wind will yield more. The next year, there could be a disease. Another year, too much heat.

Its difficult to pinpoint whether a varietys overall performance is due to genes or other factors, Dubcovsky said.

Dubcovsky leads the research for WheatCAP, a consortium of 41 breeders and researchers at 22 institutions in 20 states.

Researchers have identified most of the genes that contribute to a good bread, including protein, loaf volume and uniformity, and use molecular markers to select for those traits.

Has he finally cracked the trait?

I think we have cracked the easier part of this difficult problem, he said with a chuckle.

How it works

In the future, farmers holding a new variety of wheat in their hands wont see any difference from todays wheat, Dubcovsky said.

But if you look at the end of the spike, you have one more spikelet at the end, he said.

The plants genes determine when to stop producing those spikelets, which hold the grain, he explained. Researchers want to enable the plant to produce spikelets a little bit longer.

The newly discovered gene, designated WAPO1, controls the maximum number of grains in a wheat spike. Breeding it into plants could make room for more grains to grow in each spike by delaying formation of the terminal spikelet.

The only thing you will notice is that a spike will be a little bit longer and have more of those spikelets on the side, he said.

Step by step

At its core, yield is measured by the number of wheat spikes per square foot of land, multiplied by the number of grains each spike has, multiplied by the weight of each grain, Dubcovsky said.

One of those components, the number of grains, is a little bit easier to do genetics with, he said.

Researchers have identified several genes that control the weight of grains, he said.

But a plant with more grains has to produce enough starch to fill them, or else farmers will end up with more but smaller grains, and a plant producing the same yield.

Now, researchers are working on the more difficult part of the question, Dubcovsky said: making a more robust plant, with more biomass, that can mobilize more starch to the extra grains to increase yield.

We have made a step forward, he said. We have half of the equation solved.

The gene already existed in half of the modern wheat varieties in the world, he said. Identifying it may benefit those varieties that didnt already have it. WAPO1 is frequently found in wheat varieties used to make bread flour but not in pasta wheats such as durum.

We know now in which varieties its present and which its not present, he said. We didnt know that before. We were blind.

But it will be years before higher-yielding wheat varieties appear in farmers fields. New varieties take 5 to 10 years to develop, Dubcovsky said.

The reality in breeding is that we go step by step, he said. In plants that have a good biomass, you can push yield 5%.

That might not sound like much of an improvement at first.

But given that the worlds wheat farmers raise 750 million metric tons each year, and wheat produces 20% of calories and protein consumed by the human population, and the need to soon feed 3 billion more people on the same amount of land, that 5% starts taking a different perspective, he said.

Two farmers

Gary Bailey and Andy Juris raise wheat about 200 miles apart in Washington state. For both farmers, yield is a major consideration when deciding which varieties to plant.

Their farms receive different amounts of rain.

Bailey farms in St. John and represents Whitman County farmers on the Washington Grain Commission board. His land can receive 14 to 17 inches of rain per year a lot for this part of the state.

For him, a typical winter wheat yield is about 80 bushels per acre.

Juris farms in Bickleton and is vice president of the Washington Association of Wheat Growers. His farm normally receives 8 to 10 inches of rain each year although last year during the drought it got 3 inches.

In a fallow rotation, in which he rests his soil some years, his average yield is 35 to 40 bushels per acre.

Where he does annual cropping in shallow soils that cant hold precipitation, he averages 25 bushels per acre.

Dubcovskys 5% increase would mean a bushel or two more per acre, Juris said.

Were kind of clinging on sometimes by our fingernails to the margins of what is considered decent, farmable ground, he said. Were always looking for that next percentage.

Time will tell

Breeders in the Pacific Northwest say Dubcovskys discovery will put another tool in their toolbox.

Identifying the gene wont directly affect general breeding efforts in the near future, but could help breeding for specific production systems long term, Washington State University spring wheat breeder Mike Pumphrey said.

If the genes already present in Oregon State Universitys germplasm, molecular markers can be used for marker-assisted selection, said OSU breeder Bob Zemetra.

If not, it could be bred into elite germplasm and evaluated to determine the impact on yield, he said.

Everyone agrees on one point: Quality must not be sacrificed.

Yield pays the bills, but if a grower is discounted for low quality, that can change how much theyre paid in a hurry, said Mary Palmer Sullivan, vice president of the Washington Grain Commission.

Pumphrey recommends growers watch reliable, replicated, multi-year, multi-location regional yield performance data, while considering other traits of importance.

As part of the WheatCAP consortiums $15 million grant from the USDA National Institute of Food and Agriculture, researchers are evaluating the effect of the genes in combination with other traits for increased yield, said Arron Carter, winter wheat breeder at WSU.

Researchers need to take a holistic approach with all components of production, Carter said, adding that top yield is dictated by genetics, climate, inputs, cropping system and soil health.

I dont think we have reached our limits yet, he said. I think genetics can continue to push yield higher.

GMO quandary

Years ago, corn and soybean yields skyrocketed with the advent of genetically modified organisms, or GMOs, in which genetic traits such as pest resistance are inserted into the varieties.

The global wheat market, however, has not embraced the technology. As yet, there are no commercialized varieties of wheat available in the market developed through biotechnology.

It is unfortunate that we cannot use GMOs in wheat, because we can do a lot more, Dubcovsky said. Basically, you are asking us to give you more food in the same space, and you tied our hands at our backs. But since those are the rules, we continue to do breeding with our hands tied at our backs.

Breeding will continue to improve without GMOs, he said. But GMOs would allow solutions to a lot of problems, including nutrition and the economic value of wheat.

I understand, people always fear what they dont know, and we need to respect peoples fear, he said. From a scientific point of view, theres no rationale on the limitations they are putting upon me (with) GMO. But I respect the people if people do not want to eat them, I will not produce it.

Investing in food

Dubcovsky, 65, said its also time to find a younger researcher to overlap with him at UC-Davis to eventually take up the mantel.

In the meantime, I will continue doing it, I enjoy doing it, he said.

Even when a new person arrives, hed happily keep helping out.

This is my passion, so I will proudly continue working on it, he said.

Sullivan, of the grain commission, notes that Dubcovsky identified the gene through federal research funding.

While each state that has a checkoff for wheat contributes towards research, we cant do it alone, she said. These are the types of grants and opportunities that we wouldnt otherwise have. The more information, and the more tools they have in their toolbox, the better off were going to be. Its a really good investment in taxpayer dollars.

Dubcovsky echoed the need to support agricultural research.

Food is not something thats sold in the supermarket, he said. Food is something you need to fight for and you need to invest for, if you want to have food on the table tomorrow. Producing food takes work of a lot of people.

Dubcovsky left research on yield for the end of his career because he knew it would be difficult.

Making a more productive plant requires a plant that grows faster, a little taller, with a stronger stem to support more grain.

It can be done, he said, pointing to triticale, a cross between durum wheat and rye, which has some of those traits.

We know that its possible, he said. Now we just need to figure out how to get there.

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The 5% solution: Researchers crack wheat's genetic code, open door to higher yields - Herald and News

Children’s Research Institute Seminar Series: Genetics and Functional Mechanisms of the SPTBN1 Syndrome – UNC Research – UNC Research

Presented by:Damaris Lorenzo, PhDAssistant Professor of Cell Biology and Physiology

Dr. Lorenzos lab investigates the contribution of the cytoskeleton to key physiological processes and the mechanistic basis of cytoskeleton-associated disorders. Their goal is to understand the roles of cytoskeletal proteins in the regulation of cellular dynamics and bioenergetics in metabolically active tissues as well as their involvement in brain development and connectivity.Read more >>

Please contactchildrensresearch@med.unc.edufor Zoom details.

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Children's Research Institute Seminar Series: Genetics and Functional Mechanisms of the SPTBN1 Syndrome - UNC Research - UNC Research

Treating, preventing cancer beyond genetics: U of A researcher – Edmonton Journal

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If we understand the causes of cancer, then we can start highlighting the known causes, the lifestyle issues that introduce or increase our risk

Environmental and metabolic factors not just genetics are growing considerations in the fight against cancer, concludes a research review by a leading expert at the University of Alberta.

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Cancer as a genetic disease, focusing on the set of genetic instructions every person is born with; it is also an environmental disease, focusing on the exposome, which includes everything a persons body has been exposed to; and cancer is a metabolic disease, focusing on the metabolome, or all the chemical byproducts of the process of metabolism, explains David Wishart, professor in the departments of biological sciences and computing science, in a Thursday news release.

But that metabolic perspective hasnt had much research until now, as more scientists begin to understand the metabolomes role in cancer.

Heritable cancers account for just five to 10 per cent of all cancers, Wishart said, with the other 90 to 95 per cent initiated by factors in the exposome, which in turn trigger genetic mutations.

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Thats an important thing to consider, because it says that cancer isnt inevitable.

As cancer develops and spreads in the body, it creates its own environment and introduces certain metabolites, becoming a self-fuelled disease. And thats where cancer as a metabolic disorder becomes really important.

Considering the genome, exposome and metabolome together when thinking about cancer shows more promise for finding treatments.

Researchers who focus only on the genetic perspective are looking to address particular mutations but there are around 1,000 genes that can become cancerous when mutated, and it typically takes two different mutations within these cells for cancer to grow, notes Wishart, meaning there are a million potential mutation pairs. Then it can become hopeless to narrow down possibilities when seeking new treatments.

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But considering cancer from the metabolic perspective, there are just four major metabolic types, said Wishart, so determining the patients cancer type can immediately guide doctors on the best treatment for their specific cancer.

It really doesnt make a difference where the cancer is its something youve got to get rid of. Its how it thrives or grows that matters, said Wishart. It becomes a question of, Whats the fuel that powers this engine?

Wishart cautions that health-care providers still need a mix of therapeutics for cancer, and a deeper understanding of the metabolome and its role in the cancer feedback loop is also critical to preventing cancer.

If we understand the causes of cancer, then we can start highlighting the known causes, the lifestyle issues that introduce or increase our risk, he said.

From the prevention side, changing our metabolism through lifestyle adjustments will make a huge difference in the incidence of cancer.

The research review was funded by Genome Canada, the Canadian Institutes of Health Research and the Canada Foundation for Innovation.

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Treating, preventing cancer beyond genetics: U of A researcher - Edmonton Journal

Discovering Genetic Variants that Significantly Predispose People to Critical COVID-19 – News-Medical.Net

Please can you introduce yourself, tell us about your background in medical informatics, and what inspired your latest research into identifying independent variants that significantly predispose to critical COVID-19?

My name is Erola Pairo-Castineira, and I am a postdoctoral researcher specializing in statistical genetics in Professor Baillie's lab at the University of Edinburgh.

I'm interested in the differences in DNA sequence between people and how this affects how sick you get when infected with SARS-CoV-2. Most people are asymptomatic or have mild symptoms when infected, while some people need hospitalization and a few need to be admitted into ICU to receive mechanical ventilation. Although certain factors like age and sex affect your predisposition to critical COVID-19, there are differences even in people with similar age, sex, and other variables affecting COVID-19 severity.

Our research aims to find the genetic factors that may predisposeto critical COVID-19 and learn how COVID-19 affects cells in the body. The main objective of the project is to find which biological pathways influence critical COVID-19 to be able to find druggable targets that may benefit everyone.

People suffering from critical COVID-19 have been admitted into an intensive care unit. They will have all the classic symptoms of COVID-19, such as a cough and fever, but also very low blood oxygen. The mechanism causing it is inflammation in the lung, where the virus is replicating.

Image Credit: plo/Shutterstock.com

In our first study, we found five genetic signals related to critical COVID-19 related to host antiviral defense mechanisms and mediators of inflammatory organ damage. Other studies since then have found signals related to susceptibility to infection with SARS-CoV-2 and hospitalization and critical illness with COVID-19.

Microarray genotyping reads a set of variants in the genome, and from them, and using information about genomes of known populations, we infer the rest of the genome. This is very difficult to do for rare variants, which will have low accuracy in the inference, and it is also affected by the quality of the reference panel used. Even in the best cases, not all variants can be retrieved with high accuracy, and some of them have to be filtered. Whole-genome sequencing reads every base in our genome, providing high accuracy for all variants.

To carry out the analysis, we compared the genome of people who had critical COVID-19, focusing on people in intensive care units in UK hospitals, with individuals that had only mild symptoms during SARS-CoV-2 infection, and with the general population. The comparison highlights variants of the genome that affect your probability of becoming critically ill with COVID-19.

In this study, we found 16 new regions associated with critical COVID-19. We were also able to identify some of these variants as variants that affect the function of some proteins (for example, a protein called IFNA10). In other cases, we could show that changes in gene expression would affect the probability of having severe COVID-19.

Interferons are a large family of proteins with roles in antiviral defense. They are produced when the cell recognizes a viral intruder, and they propagate defensive and offensive signals to help destroy the virus and protect nearby cells. Interferons can induce inflammation by activating the transcription of a number of different genes, and if they are not tightly controlled during an immune reaction, they may cause hyper-inflammation.

There are different types of interferon, called Interferon Type-I, Interferon Type-II, and Interferon Type-III. The genes we have found are mainly associated with Type-I Interferon signaling. Interestingly, one of these genes (TYK2) has a protein product that a widely available drug, baricitinib, can inhibit. It was recently shown in the RECOVERY trial (a large-scale randomized control trial for many potential COVID-19 treatments in the UK) that administration of baricitinib can lower mortality in COVID-19.

Image Credit: Thanapipat Kulmuangdoan/Shutterstock.com

In the case of baricitinib, it was lucky that it was already available for rheumatoid arthritis, so it had been proven safe and effective. Usually, the process is much longer when a potential gene target is identified. The most important first step is confirming the associations we see in the DNA data in cells and tissues - in vitro experiments will be required to ensure the target is worth pursuing. An appropriate drug must be identified, tested, and shown to be safe. It can be a long process; however, our analysis can narrow down the most likely drug targets, which is a major step forward.

The study's main limitation is that we recruited cases in the middle of a pandemic, so we didn't have genotypes for mild cases to use as controls. Instead of mild COVID-19 cases, we used controls from different studies of the general population. This was technically challenging since the genotyping or whole-genome sequencing tools used differed, and we had to account for these differences. We now have genotypes from mild COVID-19 cases generated using the same pipelines as our critical COVID-19 cases.

Collaboration is vital to this research. People with very different expertise are needed to do an analysis like this. To carry out this analysis, we needed people to work in many different roles. Administrative staff organized paperwork and established sites, doctors and nurses recruited patients, research technicians sequenced DNA, then informaticians processed this DNA information in a computer and analyzed it to find the DNA regions related to COVID-19. Finally, it's rarely true that the results immediately make sense, so there were a number of groups of researchers working closely together to interpret the biological meaning of the results.

We're still working on critical COVID-19. We have recruited more individuals and will soon start a new analysis with 15,000 critical cases and 15,000 mild controls (people who had mild or asymptomatic COVID-19). We also have gene expression data from hospitalized patients that we can link to our analysis outputs which will likely help us address some of the limitations mentioned above.

My name is Erola Pairo-Castineira I am currently a postdoctoral researcher at the Roslin Institute at the University of Edinburgh. Over the last two years, I have been working on host genetic studies of COVID-19. I have conducted several analyses that have led to the discovery of new genetic associations of COVID-19 critical illness. Before my current position, I was a postdoctoral researcher in the MRC-HGU, working on the integration of omics and genotype data to identify causal genes and pathways underlying pigmentation traits.

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Discovering Genetic Variants that Significantly Predispose People to Critical COVID-19 - News-Medical.Net