The Wellcome Trust Case Control Consortium, the largest ever study of the genetics behind common diseases such as diabetes, rheumatoid arthritis and coronary heart disease, today publishes its results in the journals Nature and Nature Genetics.
The £9 million study is one of the UK's largest and most successful academic collaborations to date. It has examined DNA samples from 17 000 people across the UK, bringing together 50 leading research groups and 200 scientists in the field of human genetics from dozens of UK institutions. Over two years, they have analysed almost 10 billion pieces of genetic information.
"Many of the most common diseases are very complex, part 'nature' and 'nurture', with genes interacting with our environment and lifestyles," says Professor Peter Donnelly, Chair of the Consortium, who is based at the University of Oxford. "By identifying the genes underlying these conditions, our study should enable scientists to understand better how disease occurs, which people are most at risk and, in time, to produce more effective, more personalised treatments."
The study has substantially increased the number of genes known to play a role in the development of some of our most common diseases. Many of these genes that have been found are in areas of the genome not previously thought to have been related to the diseases.
"Just a few years ago it would have been thought wildly optimistic that it would be possible in the near future to study a thousand genetic variants in each of a thousand people," says Dr Mark Walport, Director of the Wellcome Trust, the UK's largest medical research charity, which funded the study. "What has been achieved in this research is the analysis of half a million genetic variants in each of 17 000 individuals, with the discovery of more than ten genes that predispose to common diseases.
"This research shows that it is possible to analyse human variation in health and disease on an enormous scale. It shows the importance of studies such as UK Biobank, which is seeking half a million volunteers aged between 40 and 69, with the aim of understanding the links between health, the environment and genetic variation. New preventive strategies and new treatments depend on a detailed understanding of the genetic, behavioural and environmental factors that conspire to cause disease."
Among the most significant new findings are four chromosome regions containing genes that can predispose to type 1 diabetes and three new genes for Crohn's disease (a type of inflammatory bowel disease). For the first time, the researchers have found a gene linking these two autoimmune diseases, known as PTPN2.
The study has also confirmed the importance of a process known as autophagy in the development of Crohn's disease. Autophagy, or 'self-eating', is responsible for clearing unwanted material, such as bacteria, from within cells. This may be key to the interaction of gut bacteria in health and in inflammatory bowel disease, and could have clinical significance in the future.
"The link between type 1 diabetes and Crohn's disease is one of the most exciting findings to come out of the Consortium," says Professor John Todd from the University of Cambridge, who led the study into type 1 diabetes. "It is a promising avenue for us to understand how the two diseases occur. The pathways that lead to Crohn's disease are increasingly well understood and we hope that progress in treating Crohn's disease may give us clues on how to treat type 1 diabetes in the future."
Research from the Consortium has already played a major part in identifying the clearest genetic link yet to obesity and three new genes linked to type 2 diabetes, published in April in advance of the main study. It has found independently a major gene region on chromosome 9, identified by independent studies on coronary heart disease.
Researchers analysed DNA samples taken from people in the UK – 2000 patients for each disease and 3000 control samples – to identify common genetic variations for seven major diseases. These are: bipolar disorder, Crohn's disease, coronary heart disease, hypertension, rheumatoid arthritis, and type 1 and type 2 diabetes. For each disease, the researchers will study larger population samples to confirm their results.
Although the human genome is made up of more than three billion sub-units of DNA, called nucleotides (or bases), most of these show little in the way of differences between individuals. A substantial part of the variation in DNA sequence between individuals is due to single nucleotide polymorphisms (differences), also known as SNPs. There are approximately 8 million common SNPs in European populations. Fortunately, because SNPs that lie close together on chromosomes often tell quite similar stories, researchers in the Consortium were able to explore this variation through analysing a subset of these SNPs (in fact approximately 500 000).
"Human genetics has a chequered history of irreproducible results, but this landmark collaboration of scientists in Britain has shown conclusively that the new approach of analysing a large subset of genetic variants in large samples of patients and healthy individuals works," says Professor Donnelly. "We are now able to effectively scan most of the common variation in the human genome to look for variants associated with diseases. This approach will undoubtedly herald major advances in how we understand and tackle disease in the future."
Further analysis as part of the Consortium will be looking at tuberculosis, breast cancer, autoimmune thyroid disease, multiple sclerosis and ankylosing spondylitis. The results are expected later this year.
Findings from the Wellcome Trust Case Control Consortium:
The first genome-wide association study of bipolar disorder has shown that there are many genes that influence an individual's susceptibility to bipolar disorder and that each gene on its own makes a relatively small contribution to risk.
The results provide an indication of the biological systems that are important in bipolar disorder. For example, several of the genes identified play a key role in the way the nerve cells in our brains talk to each other.
Professor Nick Craddock of Cardiff University, Scientific Advisor for MDF The Bipolar Organisation, says: "The powerful molecular genetic approaches that we are using provide a window into the workings of the brain in those suffering from bipolar illness. By helping to unravel the mechanisms of illness, the findings will help pave the way to better diagnosis and treatment. Some new therapies based on a better understanding of the illness will involve novel drugs but others are likely to include forms of education, lifestyle advice and talking treatments.
"The current focus of the Government's approach to severe mental illness often amounts to a pessimistic 'palliative care' model. With the ongoing scientific advances in understanding of illness we have the opportunity to make things very different for the next generation.
"This should be a time of great optimism for those individuals and families that have experienced illnesses like bipolar disorder, schizophrenia and depression."
About the disease
Bipolar mood disorders affect around 100 million people worldwide.
Coronary heart disease
The study found several new genetic loci (regions) that increased the risk of coronary artery disease. Most notable was a locus on chromosome 9 that increased risk by almost 50 per cent in the half of subjects carrying one copy of the risk variant, and almost doubled the risk in the 20 per cent of subjects who carried both copies. The same locus has also been identified in two other recent studies and altogether the data provide irrefutable evidence that this is a genuine and important genetic risk factor for heart disease.
Professor Nilesh Samani, of the University of Leicester, says: "Coronary artery disease, which commonly leads to heart attacks or angina, is the most frequent cause of death in the industrialised world and by 2020 will be the most important cause of death worldwide. In addition to known risk factors such as high blood pressure, elevated cholesterol, smoking and diabetes, genetic factors play an important role in causing coronary artery disease. Almost invariably patients who develop coronary artery disease early report a family history of the condition.
"Identifying these new genetic variants is a first step that can help us in many ways – to better predict who are at higher risk; to identify more specific ways of prevention by understanding how these genes operate and potentially, and most excitingly, in developing new treatments."
Professor Peter Weissberg, Medical Director of the British Heart Foundation, says: "This is an exciting outcome from what is a huge collaborative effort. Although it will take some time yet to establish the importance of the identified genes for families at risk of heart disease it is very significant that the study confirms results of two other recently reported genetic surveys.
"The results should help us develop better tests to identify people at highest risk of heart disease and will enhance our understanding of its underlying mechanisms, ultimately leading to new treatments."
About the disease
Coronary Heart Disease is the UK's biggest killer, accounting for 105 000 deaths annually – British Heart Foundation.
Three new genes increasing a person's susceptibility to the disease (IRGM, NKX2-3 and PTPN2) and a region containing several genes have been discovered. In addition, the researchers have identified an important role for two 'gene deserts', areas of the genome that are devoid of genes but that might contribute to Crohn's disease by influence how genes work nearby or even a long way away. The study has also confirmed the importance of a process known as autophagy in the development of Crohn's disease.
PTPN2, which is involved in regulation of the immune system, was also found to be shared with type 1 diabetes. This is the first time a genetic link has been identified between the two diseases.
Dr Miles Parkes, Consultant Gastroenterologist at Addenbrooke's Hospital and the University of Cambridge, says: "The study has substantially advanced our understanding of what causes Crohn's disease, with the scale of this study providing the most comprehensive evaluation to date of the genetic basis of this disease. There is a lot of follow-up work required to fully understand the immunological impact of the genetic associations that we have identified. However the genetic findings themselves have already provided some major leads regarding possible new treatment options."
Richard Driscoll, Director, National Association for Colitis and Crohn's Disease, says: "People who have Crohn's Disease are often diagnosed at a young age and have to live with the distressing and painful symptoms for the remainder of their lives. These new genetic findings will encourage everyone that real progress is at last being made in understanding how Crohn's develops. With a greater understanding we are that much closer to being able to give people a more accurate prognosis of how their illness may develop and which treatments may work best for them."
About the disease
Between 30 000 and 60 000 people in the UK have Crohn's Disease – National Association for Colitis and Crohn's Disease.
The hypertension genome-wide scan shows a comparable number of signals to the other diseases studied. These are now being evaluated in additional populations. The results suggest that hypertension is less likely to arise due to a small number of major genetic influences, but is due to numerous interacting factors.
Professor Mark Caulfield, Barts and The London School of Medicine, Queen Mary's School of Medicine and Dentistry, London, says: "Hypertension, or high blood pressure, is an incredibly common disorder, affecting one billion people worldwide. Our study has highlighted the complex nature of the disease with many signals for further follow-up. This is probably in part because of the high number of genes involved, which helps to explain why patients with hypertension need to be treated with a combination of multiple drugs. These findings bring us closer to understanding the mechanisms by which hypertension may arise. We are now following up the signals work in much larger numbers to verify our positive findings."
About the disease
High blood pressure affects over 16 million people in the UK and 1 billion people worldwide. It can cause stroke, heart attack and kidney failure.
A number of markers were found to be associated with rheumatoid arthritis, implicating several genes for the first time in this disease process. Further work will be required to validate the findings and understand how the variation within key genes influences the development of rheumatoid arthritis, the course of the disease and response to treatment.
Professor Jane Worthington, University of Manchester, says: "Rheumatoid arthritis is a complex disease with considerable variation observed between patients both in terms of the severity of the symptoms and the response to therapies. The findings of the Wellcome Trust Case Control Consortium make a major step forward in terms of understanding how multiple genetic factors may influence this disease process.
"Patients with rheumatoid arthritis are also at increased risk of other conditions such as cardiovascular disease and an increase in type 1 diabetes has been observed in families with rheumatoid arthritis. The collaborative nature of this groundbreaking study will greatly facilitate our investigation of genetic risk factors that may be common to different diseases.
"Despite recent advances in the treatment of rheumatoid arthritis this disease continues to present a significant healthcare burden. Greater understanding of the genetic basis of susceptibility is important to the development of novel therapeutic approaches, particularly those aimed at arresting the disease process before significant disability has occurred."
Alan Silman, medical director of the Arthritis Research Campaign, says: "Rheumatoid arthritis is a serious form of arthritis and we have known for some time that there is a major genetic component to this disease. The results from this unique study have highlighted some exciting opportunities to explore the role of genes, previously unsuspected as being important in increasing the risk of arthritis. We will be supporting urgent follow-up of these findings, which hopefully could lead to both an increased understanding of what cause rheumatoid arthritis as well as pointing to possible new cures."
About the disease
387 000 people in the UK have rheumatoid arthritis – Arthritis Research Campaign.
Type 1 diabetes
Four new chromosome regions have been confirmed to increase the risk of developing this autoimmune disease, and two further possible regions have been identified. One region, the gene PTPN2, is shared with Crohn's disease and is involved in regulation of the immune system. This is the first time a genetic link has been identified between the two diseases.
Professor John Todd, University of Cambridge, says: "We now have confirmation that there are at least ten genes or chromosome regions that increase the chances of developing type 1 diabetes. We know that the causes of diabetes are complex and that there is an interaction between genetic and environmental factors, such as diet, low levels of vitamin D and viral infections, leading to development of the disease in 1 in 300–400 children. This is the first time that we have seen a specific genetic link between type 1 diabetes and Crohn's disease.
"This new link between the two diseases is a possible new avenue for us to understand how they occur. The pathways that lead to Crohn's disease are increasingly well understood, particularly when enhanced by these new findings. We hope that progress in treating Crohn's disease will give us clues on how to treat type 1 diabetes."
Karen Addington, CEO of the Juvenile Diabetes Research Foundation in the UK: "This study is a landmark in the field of diabetes research. For the first time we can pinpoint which genes increase the likelihood of developing type 1 diabetes. The more that we understand how and why the condition occurs, the closer we come to being able to prevent and cure it."
About the disease
350 000 people, including 20 000 children, have type 1 diabetes in the UK – Juvenile Diabetes Research Foundation.
Type 2 diabetes
Using data generated by the Wellcome Trust Case Control Consortium, the type 2 diabetes research groups (based in Oxford and Exeter) recently reported the discovery of several novel genes involved in the development of type 2 diabetes and obesity. One of these genes (FTO) influences risk of diabetes through an effect on weight and risk of obesity. The other three regions contain genes (CDKAL1, CDKN2A and IGF2BP2) that have a direct effect on diabetes risk.
This work also confirmed several diabetes susceptibility genes identified in other genome scans.
Professor Mark McCarthy from the University of Oxford says: "This research helps us to understand that, for most people at least, an individual's risk of developing diabetes as they get older is influenced by a number of genes, as well as by their environment. Clearly, the more 'high-risk' alleles a person inherits, the higher the likelihood that they will go on to develop diabetes."
Professor Andrew Hattersley of the Peninsula Medical School, Exeter, says: "We now have significantly more pieces to the jigsaw that will help us understand the mechanisms behind type 2 diabetes. Each piece of new knowledge takes us a step closer towards a future with improved prevention and treatment of this very significant condition."
Dr Iain Frame, Research Manager at Diabetes UK, says: "The Wellcome Trust Case Control Consortium has been an excellent example of collaborative working and has produced some exciting results about the genetics of type 2 diabetes.
"It is important to remember that type 2 diabetes is a genetic condition which is not only associated with lifestyle factors. The more we unravel about the genetics of type 2 diabetes, the bigger the steps we take towards new ways to treat and prevent the condition.
"Diabetes UK funded the original collection of case samples for type 2 diabetes at the beginning of this study. It is thanks to the joint efforts of Diabetes UK, a number of excellent researchers and the Wellcome Trust that these discoveries have been possible."
About the disease
1.9 million people in the UK live with type 2 diabetes – Diabetes UK.
About the Wellcome Trust
The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending around £500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.
About the Wellcome Trust Case Control Consortium
The Wellcome Trust Case Control Consortium was supported by: the Medical Research Council, the British Heart Foundation, the Juvenile Diabetes Research Foundation, Diabetes UK, the Arthritis Research Campaign, the National Association for Colitis and Crohn's Disease and MDF The Bipolar Organisation.