June 6-9, 2020, Virtual Meeting
The winner of this year’s Leena Peltonen prize, to be awarded at the ESHG annual meeting being held entirely on line, is Dr Gosia Trynka, from the Wellcome Sanger Institute, Hinxton, Cambridge, UK. The prize is awarded to an outstanding young researcher in the field of human genetics, and honours the memory of Dr. Leena Peltonen, a world-renowned human geneticist from Finland who died in 2010 and who contributed greatly to the identification of disease genes for human diseases.
After an MSc in Biotechnology from Jagiellonian University, Krakow, Poland, Gosia Trynka obtained a PhD cum laude from the University of Groningen, The Netherlands. In 2012 she moved to the US to take up a Postdoctoral fellowship at Brigham and Women's Hospital, Harvard Medical School and the Broad Institute. She has led the Immune Genomics Group at the Wellcome Sanger Institute since 2014 and this year she took on an additional responsibility as the Experimental Science Director at Open Targets, a public/private partnership that uses genomics data to improve drug target identification and prioritisation.
Her group at the Sanger Institute combines immunology and genomic assays with statistical approaches to study how human genetic variation impacts the immune system and predisposes to the development of autoimmune diseases. "As a head of Human Genetics at the Sanger Institute, Leena Peltonen recruited a cadre of young faculty. She was seen as a champion and an inspiration to the younger generation of scientists. As a junior faculty whose independent research career was enabled by the Sanger environment that Leena has championed I feel honoured to be recognised with this prize," she says.
Professor Nicole Soranzo, Senior Group Leader of the Human Complex Traits Group at the Wellcome Sanger Institute, and a member of the award’s nominating committee, said: “I am delighted that Dr Gosia Trynka has been bestowed this important recognition for her contribution to the understanding of the genetic and molecular causes of devastating human immune diseases. Gosia is a hugely talented, original and courageous scientist, who continues to break new ground through her highly innovative statistical, experimental and translational approaches. A passionate educator and mentor, she has already established herself as a role model and champion for the next generation of human genetics scientists.”
The clinical presentation of Covid-19 varies from patient to patient and understanding individual genetic susceptibility to the disease is therefore vital to prognosis, prevention, and the development of new treatments. For the first time, Italian scientists have been able to identify the genetic and molecular basis of this susceptibility to infection as well as to the possibility of contracting a more severe form of the disease. The research will be presented to the 53rd annual conference of the European Society of Human Genetics, being held entirely on-line due to the Covid-19 pandemic, today [Saturday].
Professor Alessandra Renieri, Director of the Medical Genetics Unit at the University Hospital of Siena, Italy, will describe her team’s GEN-COVID project to collect genomic samples from Covid patients across the whole of Italy in order to try to identify the genetic bases of the high level of clinical variability they showed. Using whole exome sequencing (WES)1 to study the first data from 130 Covid patients from Siena and other Tuscan institutions, they were able to uncover a number of common susceptibility genes that were linked to a favourable or unfavourable outcome of infection. “We believe that variations in these genes may determine disease progression,” says Prof Renieri. “To our knowledge, this is the first report on the results of WES in Covid-19.”
Searching for common genes in affected patients against a control group did not give statistically significant results with the exception of a few genes. So the researchers decided to treat each patient as an independent case, following the example of autism spectrum disorder. “In this way we were able to identify for each patient an average of three pathogenic (disease-causing) mutations involved in susceptibility to Covid infection,” says Prof Renieri. “This result was not unexpected, since we already knew from studies of twins that Covid-19 has a strong genetic basis.”
Although presentation of Covid is different in each individual, this does not rule out the possibility of the same treatment being effective in many cases. “The model we are proposing includes common genes and our results point to some of them. For example, ACE2 remains one of the major targets. All our Covid patients have an intact ACE2 protein, and the biological pathway involving this gene remains a major focus for drug development,” says Prof Renieri. ACE2 is an enzyme attached to the outer surface of several organs, including the lungs, that lowers blood pressure. It serves as an entry point for some coronaviruses, including Covid-19.
These results will have significant implications for health and healthcare policy. Understanding the genetic profile of patients may allow the repurposing of existing medicines for specific therapeutic approaches against Covid-19 as well as speeding the development of new antiviral drugs. Being able to identify patients susceptible to severe pneumonia and their responsiveness to specific drugs will allow rapid public health treatment interventions. And future research will be aided, too, by the development of a Covid Biobank accessible to academic and industry partners.
The researchers will now analyze a further 2000 samples from other Italian regions, specifically from 35 Italian Hospitals belonging to the GEN-COVID project.2 . “Our data, although preliminary, are promising, and now we plan to validate them in a wider population,” says Prof Renieri. “Going beyond our specific results, the outcome of our study underlines the need for a new method to fully assess the basis of one of the more complex genetic traits, with an environmental causation (the virus), but a high rate of heritability. We need to develop new mathematical models using artificial intelligence in order to be able to understand the complexity of this trait, which is derived from a combination of common and rare genetic factors.
“We have developed this approach in collaboration with the Siena Artificial Intelligence Lab, and now intend to compare it with classical genome-wide association studies3 in the context of the Covid-19 Host Genetics Initiative, which brings together the human genetics community to generate, share, and analyse data to learn the genetic determinants of COVID-19 susceptibility, severity, and outcomes. As a research community, we need to do everything we can to help public health interventions move forward at this time.”
Chair of the ESHG conference, Professor Joris Veltman, Dean of the Biosciences Institute at Newcastle University, Newcastle upon Tyne, UK, said: “We are very excited to have this work on the genetics of COVID19 susceptibility presented as one of our late-breaking abstract talks at the ESHG. Our Italian colleagues present the first insight into the role of genetic susceptibility influencing the severity of the response to a COVID19 infection. It needs to be expanded to encompass much larger populations, but it is impressive to see the speed at which research on this virus has proceeded in just a few months’ time.”
1.Whole exome sequencing involves sequencing all the protein-coding regions of genes in a genome. It can identify genetic variants that alter protein sequences at a much lower cost than whole genome sequencing.
3. A genome-wide association study is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait.
Abstract no: C25.6 WES profiling of COVID-19
The increasing popularity of direct to consumer (DTC) genetic testing is having an impact on clinical genetics services, according to Australian researchers who will present their work to the 53rd annual conference of the European Society of Human Genetics, being held entirely on-line due to the Covid-19 pandemic, today [Saturday]. Many consumers are unsure about what to do with the results they receive, and many general practitioners are ill-equipped to advise them, meaning that they turn to clinical genetics services for help.
Ms Jane Tiller, Ethical, Legal and Social Adviser in Public Health Genomics, Monash University , Victoria, Australia, and colleagues analysed how often clinical genetics services were receiving referrals related to DTC testing, and what actions were taken by the clinic after receiving the referral. Until now, this subject has received little attention. «We knew that clinical genetics services had limited resources and long waiting lists. We wanted to explore the impact of DTC-related referrals in order to be able to forecast effects on the delivery of clinical genetics services and inform policymakers so that they could adjust resource needs accordingly,» she says.
The researchers surveyed eleven publicly-funded Australian clinical genetics services, asking questions related to the DTC-generated referrals they had received over the past ten years. They found that 83% of such referrals were made by general practitioners, in order to aid interpretation of results, and that over 30% of referrals were related to imputed disease risk estimates, where an online tool interprets raw genetic data to obtain a health risk profile. The services reported that DTCGT results were often unreliable; fewer than 10% of the results tested were validated.
Currently the national regulator, the Therapeutic Goods Administration (TGA) is considering the issue of DTC genetic testing. Because the sale of health-related DTC testing is prohibited in Australia, some Australians obtain this testing through overseas companies or use data from ancestry sites to obtain imputed health data.
"If the TGA relaxes these restrictions on DTC genetic testing, this could increase yet further the need for clinical genetics services by consumers of DTC tests,» says Ms Tiller. «Our study raises many issues. There are tensions between the desire to allow consumers access to their genetic information and subsequently managing and funding the healthcare follow-up that they need, either to interpret their results, or to determine an individual risk management plan. Commercial companies who gain from selling these tests often neither consider nor contribute to the cost in downstream health management."
In addition to the need for sufficient resources and funding for public genetics services, measures that could be taken to improve the situation include increasing the genomic knowledge of general practitioners. «GP knowledge ranges from the extremely genomically literate to the extremely genomically illiterate. There is no way of guaranteeing that all GPs have a sufficient degree of genomic literacy to interpret potentially inaccurate DTC results. Improving genomic literacy across GPs would certainly assist with this aim, and is critical as genomic testing becomes more common,» she says.
Another problem that needs addressing is the lack of a consistent policy for referral management across Australia. Some services provide an appointment to all DTC-related referrals, some provide none, and some assess referrals on a case-by-case basis, leading to considerable inequalities in access. «A uniform national policy regarding the treatment of DTCGT-related referrals should be developed to reduce inequality and ensure consistent decision-making by publicly-funded genetics services in this area.
"Now we need to look in further detail at year on year rates of referral, rates of validation and specific disease risk. As DTC genetic testing continues to grow, we expect its impact on health services will increase. Although our study was carried out in Australia, our findings are relevant for other countries with publicly-funded or single-payer clinical genetics. Policymakers need to take note and act now in order to facilitate efficient operation of clinical genetics and to provide the maximum benefit to the population," Ms Tiller will conclude.
Chair of the ESHG conference, Professor Joris Veltman, Dean of the Biosciences Institute at Newcastle University, Newcastle upon Tyne, UK, said: “Direct to consumer (DTC) genetics tests are becoming more widely available in society and this study asks the question whether this increases the workload for clinical genetics services in Australia. Overall, my impression is that the number of referrals related to these DTC tests is rather low, but it does make clear that most GPs do not know what to do with these and that shows a need for more education in this area.”
Abstract no: C07.3 Measuring the burden of direct-to-consumer genetic testing on clinical genetics services
Genome-wide association studies (GWAS) analyse a genome-wide set of genetic variants in different individuals to see if any are associated with a trait or disease. Such studies are getting larger and larger and, in some cases, millions of participants are involved. This means that researchers can see smaller and smaller effects increasing the number of genes they can link to a disease or trait.
"It is good for us, because it allows us to understand much more about genetics influences our make-up, behaviour, and disease status, " says Dr Andrea Ganna, from the Institute for Molecular Medicine Finland, Helsinki, Finland, who will present his team’s research to the 53rd annual conference of the European Society of Human Genetics, being held entirely on-line due to the Covid-19 pandemic, today [Monday]. " But this good news comes with a downside. These large numbers mean that biases can creep in and affect our results. The most difficult of these to control is participation bias – when people who participate in a study are not from a random set but have something in common that is linked to their participation."
"To give an extreme example, if we were to use the participants in a professional basketball team to understand how tall or fit people are, the results would not be at all representative of the general population. But even low- level participation bias can skew results,» says Dr Ganna.
Recent studies looking at people who have participated more than once in a genetic study have shown a correlation with their level of educational attainment, for example. The researchers set out to characterise better what the consequences of this type of bias were. To do so, they needed a trait that they were certain was not determined genetically on the non-sexual chromosomes and about which they could be sure in advance that no association with those genes existed.
"The only area where we felt certain that genetics outside the sexual chromosomes was not involved was the genetic differences between males and females,” commented co-author Dr Nicola Pirastu, from the University of Edinburgh, Edinburgh, United Kingdom. «Therefore our analyses should have come out completely negative."
The team carried out an association study of data from over three million individuals1 looking at which genetic variants showed differences in study participation frequencies between males and females. «To our surprise, we found over 150 loci with such differences. For example, we saw more body mass index-raising alleles2 among men than women, suggesting that genetically higher-weight women were less likely to participate in population studies than men. This can only have been related to differences in the characteristics that drive men and women to participate. And we saw a similar effect in different cohorts, which confirmed our hypothesis," said Dr Pirastu.
These findings emphasise the importance of scientists’ awareness of the necessity of careful study design and the meticulous choices of cases and controls when conducting genetic studies. In order to draw useful conclusions, the risk of participation bias should be minimised. If these kinds of bias exist in a study involving men and women, it will be far more difficult to distinguish between true results and those arising from biases when looking at disease. "For example, in the recent pandemic we know that those people who have been tested for Covid-19 were not chosen at random and share common characteristics, so making the right choice of controls to be used to understand if there are any genetic determinants involved is very important. I think our study shows what the risks are if this is not done," says Dr Ganna.
At the moment, all the evidence is that participation biases are mild enough not to be a major problem. But it is important to take them into account when planning the collection of data from large cohorts and when data from participants is collected at multiple time points. Genotyping a random set of the population, for example, from the blood spots collected at birth, would be a good way of further verifying if these biases exist. "We have shown that it would allow us to correct the statistical analyses. In addition, it would cost very little in comparison of what it has cost to date to create these studies. We really need to do this if we are to be able to draw the right conclusions from our analyses," Dr Ganna will conclude.
Chair of the ESHG conference, Professor Joris Veltman, Dean of the Biosciences Institute at Newcastle University, Newcastle upon Tyne, UK, said: “This fascinating study shows us how important it is to be aware of unexpected biases in participation in genetic association studies as well as other large scale ‘population’ studies, as this can significantly impact results if not properly corrected for.”
1. Data from the UK BioBank, 23andMe, iPSYCH FinnGen, and Biobank Japan.
2. An allele is a variant form of a gene.
Abstract no: C21.1 A genome-wide association study of sex at birth in 3 million individuals reveals widespread sex-differential participation bias with potential implications for GWAS interpretation
Osteoporosis affects more than 200 million people worldwide and demographic change means that these numbers are continuing to increase. Osteoporosis- related fractures have a significant effect on the quality of life of older people and also on the cost of healthcare provision. Now, a group of genetic researchers from The Netherlands, the US, and Norway, have shown the way to predicting not only which patients are likely to have fractures but also make an approximation of when. This could make an important contribution to improving the health of older people, they say.
Dr Carolina Medina-Gomez, from the Laboratory of Human Genetics, Erasmus MC, Rotterdam, The Netherlands, will present the team’s work to the 53rd annual conference of the European Society of Human Genetics, being held entirely on-line due to the Covid-19 pandemic, today [Tuesday 9 June]. "Using a genome-wide association study, we were able to develop a genetic risk score to help identify individuals who are likely to fracture early. Some of these individuals can have normal bone mass density, so would not be deemed as osteoporotic by the usual scans. It is important to be able to identify such patients so that we can offer them the right treatment at an early stage," she says.
The researchers studied the fracture history of 11,351 participants in the Rotterdam Study with up to 20 years of follow up. The aim of the Rotterdam study, which started in 1990, is to investigate factors that determine the occurrence of disease in elderly people.
The genetic risk score (GRS) was derived from the largest genome-wide association study (GWAS) on BMD to date, carried out in data from the UK BioBank. A GWAS analyses a genome-wide set of genetic variants in different individuals to see if any of the variants is associated with a trait or disease.
Physical activity during the course of a life has an impact on the onset of osteoporosis and campaigns promoting exercise at all ages are important for preventing its early onset. But people with a genetic predisposition to early fracture could benefit from targeted interventions, not only to increase bone mass density in adulthood but also to prevent falls, for example by improving balance and muscle power. So being able to identify these patients at an early stage could lead to a better outcome for these individuals.
Widening the research to include non-European populations will be an important step forward. Until now genetic risk scores have been generated from GWAS containing mainly European populations, and do not always yield the same results in people from different backgrounds. Even though the prevalence of osteoporosis is much higher in Europeans, the study of how well the GRS can predict time to fracture in other populations is crucial, say the researchers.
"The current method of classifying patients based on bone density scans is effective, but we are trying to help those individuals with apparently normal bone mass density who suffer fractures, and it is these people the bone research community is trying to identify so that we can offer them the right intervention and treatment,» says Dr Medina-Gomez. "We will still need to be able to fine tune which PRS weighting system will allow us a more precise identification of these people, and to assess the added value of using a PRS as compared to a Fracture Risk Assessment Tool (FRAX)* assessment as used at present by clinicians. If the PRS can help clinicians identify the group of individuals who would benefit from medication, for example, it would be an extraordinary achievement."
Chair of the ESHG conference, Professor Joris Veltman, Dean of the Biosciences Institute at Newcastle University, Newcastle upon Tyne, UK, said: “Genetic information often tells us whether a person is at increased risk to develop a disorder or not. Unfortunately, it mostly does not tell us when these disorders will develop, and that minimises the use of genetics for practical medical decision-making. In this study, the authors have pioneered the use of a genetic risk score to identify people at risk of developing bone fractures early in life. If replicated and fine-tuned, this would provide relevant information to a group of people and their health care providers.”
*A FRAX assessment involves a computer questionnaire to calculate the risk of fracture over the next ten years. It includes details of age, sex, height and weight, certain related conditions and steroid use, and smoking and drinking habits and, if available, bone mineral density.
Abstract no: C30.4 Genetic assessment of age-associated fracture risk
The research was funded by the Netherlands Organization for Health Research and Development (ZonMw VIDI 016.136.367).