In the largest study of its kind, nine novel genes for osteoarthritis have been discovered by scientists from the Wellcome Sanger Institute and their collaborators. Results of the study, published today (19 March) in Nature Genetics, could open the door to new targeted therapies for this debilitating disease in the future.
Almost nine million people in the UK suffer from osteoarthritis, a degenerative joint disease in which a person's joints become damaged, stop moving freely and become painful. Osteoarthritis is the most prevalent musculoskeletal disease and a leading cause of disability worldwide.
There is no treatment for osteoarthritis. The disease is managed with pain relief and culminates in joint replacement surgery, which has variable outcomes.
In the largest study of its kind, scientists from the Wellcome Sanger Institute and their collaborators* investigated the genetics behind osteoarthritis, as well as the diseases and traits that are linked to it.
To understand more about the genetic basis of osteoarthritis, the team studied 16.5 million DNA variations from the UK Biobank resource. Following combined analysis in up to 30,727 people with osteoarthritis and nearly 300,000 people without osteoarthritis in total -- the controls -- scientists discovered nine new genes that were associated with osteoarthritis, a significant result for this disease.
Professor Eleftheria Zeggini, senior author from the Wellcome Sanger Institute, said: "Osteoarthritis is challenging to study because the disease can vary among people, and also between the different joints affected, for example knee, hip, hand and spine. Using data from the UK Biobank resource, we have undertaken the largest genetic study of osteoarthritis to date and uncovered nine new genes associated with the disease."
Researchers then investigated the role of the nine new genes in osteoarthritis, by studying both normal cartilage and diseased cartilage from individuals who had a joint replacement.
The team looked for genes that were active in the progression of the disease by extracting the relevant cells from healthy and diseased tissue, studying the levels of proteins in the tissue and sequencing the RNA -- the messenger that carries instructions from DNA for controlling the production of proteins.
Of the nine genes associated with osteoarthritis, researchers identified five genes in particular that differed significantly in their expression in healthy and diseased tissue. The five genes present novel targets for future research into therapies.
Ms Eleni Zengini, joint first author from the University of Sheffield and Dromokaiteio Psychiatric Hospital in Athens, said: "These results are an important step towards understanding the genetic causes of osteoarthritis and take us closer to uncovering the mechanism behind the disease. Once we know that, it opens the door to developing new therapies for this debilitating disease."
The team also explored genetic correlations between osteoarthritis and obesity, bone mineral density, type 2 diabetes, and raised blood lipid levels.
Researchers applied a statistical technique known as causal inference analysis to uncover which traits and diseases cause osteoarthritis, and which do not.
Within the limits of their study, scientists discovered that type 2 diabetes and high levels of lipids in the blood do not have causal effects on osteoarthritis, but reaffirm that obesity does.
Dr Konstantinos Hatzikotoulas, joint first author from the Wellcome Sanger Institute, said: "Using genetic data, we have shown that type 2 diabetes and increased blood lipid levels do not appear to be on the causal path to osteoarthritis. We also reconfirmed that obesity is on the causal path to osteoarthritis."
Dr Natalie Carter, Head of research liaison & evaluation at Arthritis Research UK, who did not fund the study, said: "The discovery of these genes is positive news for the 8.5 million people in the UK living with osteoarthritis. People living with this debilitating condition currently have limited treatment options. Meanwhile, they can struggle to do the day-to-day things most of us take for granted, like going to work or getting dressed independently. By revealing how these genes contribute to osteoarthritis, this research could open the door for new treatments to help millions of people live the pain free life they deserve."
Wellcome Sanger Institute
Cambridge, CB10 1SA
Notes to Editors:
*This study was made possible by a collaboration between the Wellcome Sanger Institute, University of Sheffield, MRC Integrative Epidemiology Unit at the University of Bristol, Erasmus University Medical Centre in Rotterdam, deCODE genetics in Iceland, and others.
To ask Arthritis Research UK your arthritis questions please visit: https:/
Dial 0800-5200-520 for free
Eleni Zengini et al. (2018) Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nature Genetics. DOI: 10.1038/s41588-018-0079-y
This work was supported by Wellcome (grant WT098051).
The University of Sheffield With almost 29,000 of the brightest students from over 140 countries, learning alongside over 1,200 of the best academics from across the globe, the University of Sheffield is one of the world's leading universities. A member of the UK's prestigious Russell Group of leading research-led institutions, Sheffield offers world-class teaching and research excellence across a wide range of disciplines. Unified by the power of discovery and understanding, staff and students at the university are committed to finding new ways to transform the world we live in. Sheffield is the only university to feature in The Sunday Times 100 Best Not-For-Profit Organisations to Work for 2017 and was voted number one university in the UK for Student Satisfaction by Times Higher Education in 2014. In the last decade it has won four Queen's Anniversary Prizes in recognition of the outstanding contribution to the United Kingdom's intellectual, economic, cultural and social life. Sheffield has six Nobel Prize winners among former staff and students and its alumni go on to hold positions of great responsibility and influence all over the world, making significant contributions in their chosen fields. Global research partners and clients include Boeing, Rolls-Royce, Unilever, AstraZeneca, Glaxo SmithKline, Siemens and Airbus, as well as many UK and overseas government agencies and charitable foundations.
UK Biobank is a national and international health resource with unparalleled research opportunities, open to all bona fide health scientists. The resource was created by the Wellcome Trust charity and the Medical Research Council (MRC) to help improve the prevention, diagnosis and treatment of a wide range of serious, painful and life-threatening illnesses - including cancer, heart disease, stroke, diabetes and arthritis and osteoporosis. It is following the health and well-being of 500,000 volunteer participants and provides health information, which does not identify them, to approved researchers in the UK and overseas. UK Biobank has permission to follow participants' health and has undertaken genetic and other analyses. It is currently working to MR image 100,000 participants. http://www.
The Wellcome Sanger Institute
The Wellcome Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. To celebrate its 25th year in 2018, the Institute is sequencing 25 new genomes of species in the UK. Find out more at http://www.
Wellcome exists to improve health for everyone by helping great ideas to thrive. We're a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations and spark debate. http://www.