In a world first, researchers have developed a genetic risk score (GRS) test able to identify patients at high-risk of developing alcohol-related cirrhosis.
Cirrhosis results in approximately 300 000 deaths each year world-wide. In their study, the researchers found that a high GRS from the test of excessive alcohol consumers resulted in a three-fold increase in cirrhosis risk. Having diabetes together with a high GRS increased the cirrhosis risk among drinkers more than 10-fold.
Joint senior author of the study, Clinical Associate Professor Devanshi Seth, said that only a minority of high-risk drinkers – approximately 10 to 15%– actually end up developing alcohol-induced cirrhosis. To date, however, there had been no way to identify those at-risk individuals.
“Our GRS test lets us identify at-risk individuals at an early stage enabling the application of focused interventions. Evidence suggests that even just informing excessive drinkers that they have an increased cirrhosis risk may motivate them to reduce their alcohol intake, helping prevent serious disease,” said Clinical Associate Professor Seth.
The lead author of the study, Dr John Whitfield from QIMR Berghofer Medical Research Institute, said that the test had been developed by examining samples from patients with and without alcohol-related cirrhosis, but who all had a history of heavy alcohol consumption.
“This was classified as men consuming more than 80 grams (8 standard drinks) of alcohol daily and women more than 50 grams daily, both for a time period of ten or more years.”
“Risk scores were computed by the analysis of up to eight gene variations and three clinical risk factors (including type 2 diabetes) associated with alcohol-related cirrhosis,” Dr Whitfield said.
“We’ve shown that a GRS based on only three genetic risk variants plus diabetes status can be extremely meaningful in determining overall cirrhosis risk. Our test will allow for early and personalised management of high-risk patients,” said Clinical Associate Professor Seth.
People who have a higher genetic risk of clinical depression are more likely to experience physical symptoms such as chronic pain, fatigue and migraine, researchers have found.
Depression is a serious disorder with lifetime risks of poor health, according to Dr Enda Byrne from UQ’s Institute for Molecular Bioscience.
“A large proportion of people with clinically-diagnosed depression present initially to doctors with physical symptoms that cause distress and can severely impact on people’s quality of life,” Dr Byrne said.
“Our research aimed to better understand the biological basis of depression and found that assessing a broad range of symptoms was important.
“Ultimately, our research aimed to better understand the genetic risks and generate more accurate risk scores for use in research and healthcare.”
Despite recent breakthroughs, Dr Byrne said it was difficult to find more genetic risk factors because of the range of patient ages, their symptoms, responses to treatment and additional mental and physical disorders.
“Previous genetic studies have included participants who report having seen a doctor for worries or tension – but who may not meet the ‘official’ criteria for a diagnosis of depression,” Dr Byrne said
Published in JAMA Psychiatry, the study analysed data from more than 15 000 volunteers who provided details of their mental health history, depression symptoms and a DNA sample using a saliva kit.
“We wanted to see how genetic risk factors based on clinical definitions of depression differed – from those based on a single question to those based on a doctor’s consultation about mental health problems,” Dr Byrne said.
The study found that participants with higher genetic risk for clinical depression are more likely to experience physical symptoms such as chronic pain, fatigue and migraine.
“It is also linked to higher rates of somatic symptoms – that is, physical symptoms that cause distress and can severely impact on people’s quality of life,” Dr Byrne said.
“Our results highlight the need for larger studies investigating the broad range of symptoms experienced by people with depression.”
Researchers have reported finding a link between allergic diseases and mental health conditions, but one which was likely not causal.
The analysis of data from the UK Biobank was published in Clinical and Experimental Allergy. The researchers used a genetic instrument derived from associated variants for a broad allergic disease phenotype to test for causal relationships with various mental health outcomes. They also investigated whether these relationships were specific to atopic dermatitis (AD), asthma or hayfever.
The researchers found that people with asthma, atopic dermatitis, and hay fever also had a higher likelihood of having depression, anxiety, bipolar disorder, or neuroticism. However neither category appeared to play a role in causing the other. Nevertheless, future studies should investigate whether interventions that aim to improve allergic diseases might also have an effect on mental health (and vice versa).
“Our research does not rule out a potential causal effect upon the progression of disease, which is yet to be investigated and could help uncover novel treatment strategies for allergic disease or mental health traits,” said lead author Ashley Budu-Aggrey, PhD, of the University of Bristol.
Senior author Hannah Sallis, MSc, PhD, added that the research used a combination of approaches and data from several studies. “This helps to strengthen our confidence in the findings,” she said. “Establishing whether allergic disease causes mental health problems, or vice versa, is important to ensure that resources and treatment strategies are targeted appropriately.”
Researchers have found that human cells and tissues cells tolerate many more mutations than previously thought, without impacting their function or showing the features associated with ageing.
To understand the impact of defective DNA replication on cancer risk and features associated with ageing, researchers compared DNA taken from individuals with inherited mutations in genes involved in DNA replication with DNA from individuals with normal versions of these genes. The results, published in Nature Genetics, suggest that build-up of mutations in normal cells is unlikely to be the only factor in the development of age-related disease, adding to the ongoing debate about the causes of ageing.
One model of ageing suggests that accumulation of mutations in the DNA of healthy cells results in the changes that we see as the body grows older. This model is based on the observation that mutations accumulate in normal cells throughout life, theorising that the older people having more mutations compared to younger people results in impaired function of genes and disturbs cell function, ultimately leading to diseases of old age and the visible features typically associated with ageing.
However, this new research shows that human cells and tissues can function apparently normally with many more mutations than are usually present, suggesting that ageing may not solely be due to buildup of such mutations.
DNA replication is required to duplicate the DNA in a cell ready for cell division. It involves creating an entire error-free copy of the human genome from the existing strand, and is undertaken with very high accuracy in normal healthy cells by proteins called DNA polymerases. When the DNA polymerases have a mutation, causing them to be faulty, it leads to more DNA errors, or small mutations, accumulating with each and every cell replication.
In this study, researchers applied new techniques to sequence the DNA of normal cells and tissues from patients who have inherited mutated versions of the DNA polymerase genes, POLE and POLD1.
By comparing tissue samples with unaffected individuals, they found that normal tissues from those who had a faulty DNA polymerase had elevated mutation rates. These study participants did not, however, show features of early onset ageing or age-related diseases despite having accumulated numbers of mutations that would have made them hundreds of years old in terms of their ‘mutational age’. Therefore, other than an increased risk of certain cancers, the research shows that cells can accumulate many mutations and not show features associated with ageing, challenging the current model.
Further research is therefore needed to understand the biological processes underlying ageing.
Colon cancer cells. Source: National Cancer Institute on Unsplash
A new study has found that having second- or third-degree relatives with colorectal cancer increases a person’s risk of developing the disease.
Early colonoscopy screening is often recommended for first-degree relatives of someone diagnosed with early-onset (before age 50) colorectal cancer, cases of which have been increasing significantly over the past few decades. But the study suggests that early screening may be beneficial for second- and third-degree relatives as well.
The study reviewed more than 1500 early-onset colon cancer cases in the Utah Cancer Registry,found that first-degree relatives of someone diagnosed with early-onset colorectal cancer are 6 times more likely to be diagnosed with colorectal cancer before age 50, while second-degree relatives (aunts, grandparents etc) are 3 times likelier and third-degree relatives (first cousins etc) 1.56 times likelier.
“Our study provides new insight into the magnitude of risk for more distant relatives of colorectal cancer cases, and in particular, for relatives of cases who were diagnosed before age 50,” said first author Heather Ochs-Balcom, associate professor of epidemiology and environmental health, UB School of Public Health and Health Professions. “This work is important given the rising rates of early-onset colorectal cancer.”
There was also 2.6-fold higher risk of colorectal cancer at any age if they have a first-degree relative with early-onset colon cancer. The risk is 1.96 and 1.3 times greater for second- and third-degree relatives, respectively. In addition, the risk for all degrees of relatives for early-onset colon cancer is higher than the risk for colon cancer at any age.
The findings, published in Cancer Epidemiology, suggest that early colonoscopy screening may be beneficial for second-degree relatives and possibly third-degree relatives, in addition to first-degree relatives of individuals diagnosed with colorectal cancer before age 50.
The researchers also point out that relatives may benefit from being more aware of their extended family history and sharing this information with their physician when making cancer-screening decisions.
Ball-and-stick model of the testosterone molecule, C19H28O2, as found in the crystal structure of testosterone monohydrate. Credit: Ben Mills, Wikimedia Commons.
With the Olympics underway, testosterone is again in the spotlight over its role in enhancing physical performance, with rules about its natural level being once again debated. It has also been popularly thought to be involved in success in other endeavours – but its importance in this regard may be overrated.
New research has found little evidence that testosterone exerts a meaningful influence on successes in life for men or women. The study in fact suggests that testosterone’s importance outside of physical endeavours could be even less important than previously believed.
In men, it is known that testosterone is linked to socioeconomic position, such as income or educational qualifications. Researchers from the University of Bristol’s Population Health Sciences (PHS) and MRC Integrated Epidemiology Unit (IEU) set out to determine whether this is because testosterone has an influence on socioeconomic position, as opposed to socioeconomic circumstances affecting testosterone levels, or if it was a case of health affecting both. The findings are published in Science Advances.
To isolate effects of testosterone itself, the investigators used Mendelian randomisation in a sample of 306,248 UK adults from UK Biobank. They explored testosterone’s influence on socioeconomic position, including income, employment status, neighborhood-level deprivation, and educational qualifications; on health, including self-rated health and BMI, and on risk-taking behaviour.
Dr Amanda Hughes, Senior Research Associate in Epidemiology in Bristol Medical School: Population Health Sciences (PHS), said: “There’s a widespread belief that a person’s testosterone can affect where they end up in life. Our results suggest that, despite a lot of mythology surrounding testosterone, its social implications may have been over-stated.”
First, the team identified genetic variants linked to higher testosterone levels, and explored their links to outcomes. Since genetic variations are essentially fixed throughout a lifetime, it is highly unlikely that they are affected by socioeconomic circumstances, health, or other environmental factors.
In common with prior studies, multivariate analysis showed men with higher testosterone had higher household income, lived in less deprived areas, and were more likely to have a university degree and a skilled job. Higher testosterone in women was linked to lower socioeconomic position, including lower household income, living in a more deprived area, and lower chance of having a university degree. Consistent with previous evidence, higher testosterone was associated with better health for men and poorer health for women, and greater risk-taking behaviour for men.
In contrast, the Mendelian randomisation method showed there was little evidence that the testosterone-linked genetic variants were associated with any outcome for men or women. The research team concluded that there is little evidence that testosterone meaningfully affected socioeconomic position, health, or risk-taking in men or women. The study suggests that – despite the mythology surrounding testosterone – its importance is much less than previously held.
Since the results for women were less precise than the men’s, the influence of testosterone in women could be further explored with larger sample sizes.
Dr Hughes added: “Higher testosterone in men has previously been linked to various kinds of social success. A study of male executives found that testosterone was higher for those who had more subordinates. A study of male financial traders found that higher testosterone correlated with greater daily profits. Other studies have reported that testosterone is higher for more highly educated men, and among self-employed men, suggesting a link with entrepreneurship.
“Such research has supported the widespread idea that testosterone can influence success by affecting behaviour. There is evidence from experiments that testosterone can make a person more assertive or more likely to take risks – traits which can be rewarded in the labor market, for instance during wage negotiations. But there are other explanations. For example, a link between higher testosterone and success might simply reflect an influence of good health on both. Alternatively, socioeconomic circumstances could affect testosterone levels. A person’s perception of their own success could influence testosterone: in studies of sports matches, testosterone has been found to rise in the winner compared to the loser.”
Journal information: Testosterone and socioeconomic position: Mendelian Randomization in 306,248 men and women in UK Biobank’, Science Advances (2021).
Researchers from St Jude Children’s Research Hospital have demonstrated the feasibility of comprehensive genomic sequencing for all paediatric cancer patients, which maximises the lifesaving potential of precision medicine.
All 309 patients who enrolled in the study were offered whole genome and whole exome sequencing of germline DNA. For the 253 patients for whom adequate tumour samples were available, whole genome, whole exome and RNA sequencing of tumour DNA was carried out.
Overall, 86% of patients had at least one clinically significant variation in tumour or germline DNA. Those included variants related to diagnosis, prognosis, therapy or cancer predisposition. An estimated 1 in 5 patients had clinically relevant mutations that would not have been picked up with standard sequencing methods.
“Some of the most clinically relevant findings were only possible because the study combined whole genome sequencing with whole exome and RNA sequencing,” said Jinghui Zhang, PhD, St Jude Department of Computational Biology chair and co-corresponding author of the study.
While such comprehensive clinical sequencing is not widely available, as the technology becomes less expensive and accessible to more patients, comprehensive sequencing will become an important addition to paediatric cancer care.
“We want to change the thinking in the field,” said David Wheeler, PhD, St Jude Precision Genomics team director and a co-author of the study. “We showed the potential to use genomic data at the patient level. Even in common pediatric cancers, every tumor is unique, every patient is unique.
“This study showed the feasibility of identifying tumour vulnerabilities and learning to exploit them to improve patient care,” he said.
Tumour sequencing resulted in a change in treatment for 12 of the 78 study patients for whom standard of care was unsuccessful. In four of the 12 patients, the treatment changes stabilised disease and extended patient lives. Another patient, one with acute myeloid leukaemia, went into remission and was cured by blood stem cell transplantation.
“Through the comprehensive genomic testing in this study, we were able to clearly identify tumor variations that could be treated with targeted agents, opening doors for how oncologists manage their patients,” said co-corresponding author Kim Nichols, MD, St Jude Cancer Predisposition Division director.
The results of the study were published online in the journal Cancer Discovery.
Journal information: Newman, S., et al (2021) Genomes for Kids: The scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discovery. doi.org/10.1158/2159-8290.CD-20-1631.
Findings from a new study into ‘junk DNA’ have brought scientists one step closer to solving the mysteries of ageing and cancer.
Jiyue Zhu, a professor in the College of Pharmacy and Pharmaceutical Sciences, led a team which recently identified a DNA region known as VNTR2-1 which seems to drive activity of the telomerase gene, which has been shown to prevent ageing in certain types of cells. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).
The telomerase gene controls the activity of the telomerase enzyme, which helps produce telomeres, the caps at the end of each strand of DNA that protect the chromosomes within our cells and which shorten over time until cells are no longer able to divide.
However, in certain cell types, such as reproductive cells and cancer cells, the telomerase gene’s activity ensures that telomeres are reset to the same length when DNA is copied. This is essentially what restarts the aging clock in new offspring but is also the reason why cancer cells can continue to multiply and form tumors.
Understanding how the telomerase gene is regulated and activated and why it is only active in certain types of cells could someday be the key to understanding how humans age, as well as how to stop the spread of cancer. That is why Prof Zhu has focused the past 20 years of his career as a scientist solely on the study of this gene.
Zhu said that VNTR2-1’s discovery is especially noteworthy due to the type of DNA sequence it represents.
“Almost 50% of our genome consists of repetitive DNA that does not code for protein,” noted Prof Zhu. “These DNA sequences tend to be considered as ‘junk DNA’ or dark matter in our genome, and they are difficult to study. Our study describes that one of those units actually has a function in that it enhances the activity of the telomerase gene.”
In previous work, deleting the DNA sequence from human and mouse cancer cells caused telomeres to shorten, cells to age, and tumours to stop growing. They conducted a subsequent study measuring the length of the sequence in DNA samples taken from Caucasian and African American centenarians and control participants in the Georgia Centenarian Study, a study that followed a group of people aged 100 or above between 1988 and 2008. The researchers found that the length of the sequence ranged from as short as 53 repeats of the DNA to as long as 160 repeats.
“It varies a lot, and our study actually shows that the telomerase gene is more active in people with a longer sequence,” Prof Zhu said.
Since very short sequences were found only in African American participants, they looked more closely at that group and found that there were relatively few centenarians with a short VNTR2-1 sequence as compared to control participants. However, Prof Zhu said that a shorter sequence does not necessarily translate to a shorter lifespan, since the telomerase gene is less active with possibly a shorter telomere length which could reduce cancer risk.
“Our findings are telling us that this VNTR2-1 sequence contributes to the genetic diversity of how we age and how we get cancer,” Prof Zhu said. “We know that oncogenes–or cancer genes–and tumor suppressor genes don’t account for all the reasons why we get cancer. Our research shows that the picture is a lot more complicated than a mutation of an oncogene and makes a strong case for expanding our research to look more closely at this so-called junk DNA.”
Prof Zhu observed that many African Americans in the United States for generations have Caucasian ancestry, which could have added this sequence. So he and his team hope to next be able to study the sequence in an African population.
Journal information: Xu, T., et al. (2021) Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene. PNAS. doi.org/10.1073/pnas.2019043118.
The frequency of misattributed paternity, where the assumed father is not the biological father, is low and decreasing in Sweden, according to an analysis of nearly 2 million family units with children born mainly between 1950 and 1990.
The rates of misattributed paternity are estimated to range from 0.8% to 30% across different countries and studies. Taking information from genetic and behavioural studies, the article characterised that individuals at higher risk being those who conceive younger, live in deprived circumstances, are in long term relationships (rather than marriages), or in certain cultural groups.
In the study published in the Journal of Internal Medicine, the overall rate of misattributed paternity was 1.7%, with rates closer to 1% in more recent decades.
The researchers used nationwide ABO blood group data and a nationwide register of familial relationships in Sweden. These data were analysed using both a frequentist Poisson model and the Bayesian Gibbs model. The study, which drew on 1.95 million mother-father-offspring family units estimated that the frequency of misattributed paternity was 1.7% in both models. Misattributed paternity was more common among parents with low educational levels, and has decreased over time to a current 1%.
The researchers noted that beyond its general scientific and societal relevance, the frequency of misattributed paternity has an effect on studies on hereditary conditions. Fortunately, the study’s findings indicate that misattributed paternity is unlikely to have large effects on such studies. “Using simple but elegant methods, together with large-scale register data, we present population-based estimates of a peculiar question. These findings should once and for all put an end to the common misconception of overinflated occurrences of misattributed paternity in the general population,” said lead author Torsten Dahlén, of the Karolinska Institutet, in Sweden.
A new study has developed a new model for examining the genetic risk for nicotine dependence.
Tobacco smoking carries undeniable health risks, and being unable to quit or moderate smoking draws out the problem. While some people may be casual smokers and can easily quit, others become heavy smokers who struggle to quit. This risk for nicotine dependence comes from a complex mix of environmental, behavioural, and genetic factors.
Twins studies indicate that 40 to 70 percent of the risk factors are heritable. Until recently, however, studies have only explained about 1 percent of the observed variation in liability to nicotine dependence, using a genetic score based on how many cigarettes a person smokes per day.
The new study led by psychologists at Emory University leveraged genome-wide association studies for a range of different traits and disorders correlated with nicotine dependence and explained 3.6 percent of the variation in nicotine dependence. The findings were reported in the journal Nicotine & Tobacco Research.
Higher polygenetic scores for a risk for schizophrenia, depression, neuroticism, self-reported risk-taking, a high body mass index, alcohol use disorder, along with more cigarettes smoked a day were all indicators of a higher risk for nicotine dependence, the researchers found. Meanwhile, the results showed that polygenetic scores associated with higher education attainment lowered the risk for nicotine dependence.
Senior author Rohan Palmer, assistant professor, Behavioral Genetics of Addiction Laboratory, Emory University explained: “If you look at the joint effect of all of these characteristics, our model accounts for nearly 4 percent of the variation in nicotine dependence, or nearly four times as much as what we learn when relying solely on a genetic index for the number of cigarettes someone smokes daily,”
“What we’re finding,” Prof Palmer added, “is that to better leverage genetic information, we need to go beyond individual human traits and disorders and think about how risk for different behaviors and traits are interrelated. This broader approach can give us a much better measure for whether someone is at risk for a mental disorder, such as nicotine dependence.”
“All of the traits and diseases we looked at are polygenic, involving multiple genes,” added first author Victoria Risner, who did the work as an Emory undergraduate majoring in neuroscience and behavioural biology. “That means that millions of genetic variants likely go into a complete picture for all of the heritable risks for nicotine dependence.”
The researchers hope that others will build on their multi-trait, polygenetic model and continue to boost the understanding of the risk for such complex disorders. “The more we learn, the closer we can get to one day having a genetic test that clinicians can use to inform their assessment of someone’s risk for nicotine dependence,” Prof Palmer said.
Though smoking hazards are well known, about 14 percent of Americans use tobacco daily. Around half a million people die each year in the US from smoking or exposure to smoke, and another 16 million have serious illnesses caused by tobacco use, including cancer, cardiovascular disease, and pulmonary disease. While chemicals produced during smoking and vaping cause the health impacts, nicotine hooks people on these habits.
Risner worked on this paper for her Honours thesis. “Nicotine dependence was interesting to me because the vaping scene was just arriving while I was an undergraduate,” she says. “I saw some of my own friends who were into vaping quickly becoming dependent on it, while some others who were using the same products didn’t. I was curious about the genetic underpinnings of this difference.” Risner is now in medical school at University of North Carolina.
The work made use of genome-wide association studies for a range of traits and disorders. The researchers then sought matching variants in genetic data from a nationally representative sample of Americans with nicotine dependence. Polygenetic scores for the different traits and disorders either raised or lowered the risk for that dependence. The strongest predictors were number of cigarettes smoked per day, self-perceived risk-taking, and educational attainment.
The multi-variant, polygenetic model offers a path forward. For instance, a clearer picture of heritability for nicotine dependence, may be gained by adding more risk associations to the model (such as nicotine metabolism) and clusters of polygenic traits (such as anxiety along with neuroticism).
“As we continue to zero in on who is most at risk for becoming nicotine dependent, and what inter-related factors, whether genetic or environmental, may raise their risk, that could help determine what intervention might work best for an individual,” Prof Palmer said.
“Just a few decades ago, it was not well understood that nicotine dependence could have a genetic component,” Risner said. “Genetic studies may help reduce some of the stigma society has against substance use disorders, while also making treatment more accessible.”
Journal information: Risner, V A., et al. (2021) Multi-Polygenic Analysis of Nicotine Dependence in Individuals of European Ancestry. Nicotine & Tobacco Research. doi.org/10.1093/ntr/ntab105.
