A ground-breaking paper is published in Nature this week that describes the release of whole genome genetic data of 500,000 participants of the UK Biobank.

These genetic data are available from UK Biobank, for use in new medical research all around the world. Indeed, hundreds of research projects are already under way or have reported new findings on a wide range of illnesses including cancer, heart disease, diabetes, stroke, osteoporosis and schizophrenia.

A team of Oxford University researchers have worked on behalf of UK Biobank to apply sophisticated new statistical techniques to genetic information from all 500,000 volunteer UK Biobank participants. They have ensured high data quality and been able to impute the number of testable genetic variants — the letters in our DNA code that vary from person to person — from 800,000 to 96 million, a more than 100-fold increase in useful data. Imputation compares the selected genotyped DNA with analysis of the full human genome, to allow scientists to accurately predict DNA code at non-selected sections.

Research triumph

Today’s paper celebrates this research triumph, which is a culmination of several years’ work carried out by a consortium of genetics experts. This has included statistical teams led by Professor Jonathan Marchini and Professor Peter Donnelly at Oxford’s Wellcome Centre for Human Genetics, and the laboratory expertise of Samantha Welsh and her team at the UK Biobank coordinating centre, and at Affymetrix which undertook the genotyping.

Professor Rory Collins, UK Biobank Principal Investigator, said that UK Biobank is enabling novel genetic health research worldwide. Almost 1,000 genetics-based research projects have so far been submitted to UK Biobank, with many more planned.

“Thanks to the vision of UK Biobank’s funders, the altruism of the study participants and the contributions of a large number of scientists who have helped us along the way, UK Biobank is coming of age as a force in health research,” Professor Collins said.

Professor Marchini, who led the imputation work, said: “The UK Biobank dataset represents a step change in the field of human genetics. Research groups all over the world are now actively analysing the data to understand how our genetic code influences disease.

“UK Biobank is a powerful example of the immense value that can be achieved from large scale population studies that combine genetics with other detailed health information and coupled with a strong data sharing policy.

“It is likely to herald a new era of research in which these and related resources drive and enhance our understanding of human biology and disease.”

Professor Donnelly said that UK Biobank was fortunate to have been able to call on experts from many different disease areas to design the purpose-built genotyping array used to gather the genetic data. “This was the largest genetic study ever undertaken on humans. The scale of the data was vast, and we did lots of sanity checks of it. But what is exciting is that there will be really clever scientists who will exploit these data to improve human health and healthcare in ways that currently we can’t imagine.”

The data allow researchers to study a range of important questions such as the underlying genetics of disease, and the interactions between genetic and lifestyle factors, as well as using genetics to learn more about the biology of the diseases themselves, providing insights which can lead to new treatments and preventative measures. Another important feature of the data is the imputation of different gene arrangements in the HLA region, the region of the genome responsible for many of the functions of our immune system. These variants are known to play a key role in many diseases but are difficult to measure directly, and so are unavailable in many other genetic studies.

Participants in UK Biobank provided samples of blood for long-term storage and analysis, including genetic analysis, when they joined the project between 2006-2010. They also agreed to have their health followed over many years.

Since then funding has been provided to enhance the resource in several ways. This includes MR imaging of the brains, hearts and abdomens of 100,000 participants, something never previously done at such scale. Two large projects already underway will further deepen the genetic data available on the entire study. The first will provide detailed DNA sequence information on the regions of the genome that produce proteins (called the exome) that underpin human metabolism. The second will sequence the entire genomes of each individual.

UK Biobank is primarily funded by the Medical Research Council (MRC) and Wellcome. The MRC, DH and British Heart Foundation provided further funding for genotyping. This study was funded by Wellcome and the European Research Council.

1 The UK Biobank resource with deep phenotyping and genomic data: Bycroft et al, Nature.

First genetic analysis of brain function and structure using UK Biobank imaging data yields exciting results

Oxford scientists report in Nature this week on exciting new insights into the structure and function of the brain using genetic information and detailed brain images from UK Biobank.

The researchers took data from detailed MR images from 10,000 UK Biobank participants, which are freely available from the resource to researchers around the world, to examine thousands of different measurements of the brain.

It is hoped their results will provide a huge impetus to new research for a wide range of degenerative and psychiatric disorders. With a further 20,000 participants already imaged, and 70,000 more to be scanned in the next three years, the resource is set to transform research into brain development and aging, and understanding how it functions, becomes damaged by disease and heals itself, the scientists say.

The research has been led by Professor Stephen Smith, from Oxford’s Wellcome Trust Centre for Integrative Neuroimaging and Professor Jonathan Marchini, at the Wellcome Centre for Human Genetics, Oxford2.

“We have had a tantalising glimpse of what could be,” said Professor Smith. “These game-changing data stored within the UK Biobank resource, and growing in size and value all the time, will revolutionise our understanding of complex brain disorders.

“Both the genetics and imaging data are unparalleled in their depth and breadth. With imaging experts working alongside geneticists we hope to discover the causes of a wide range of brain disorders and find new ways to treat them.”

He said researchers were excited about what they had discovered. “We have found a genetic fingerprint on some of the most fundamental processes that allow us to think, act and function, from the size of the parts of the central nervous system that control sight, hearing, speech, emotions and actions to the integrity of the communications channels between them and the strength of the signals within them,” he said. The findings might help to better understand and ultimately improve treatments for a wide range of brain disorders, he said.

In particular, the researchers studied 3,144 different measures of brain structure and function, resulting in the discovery of more than 100 areas of the human genome that influence the brain:

• Results revealed the effects of genes coding for a “scaffold for tissue healing” in white matter pathways, affecting diseases such as multiple sclerosis, stroke and motor neuron disease. This scaffold is crucial for the growth of white matter in early life, and for the white matter to heal itself from damage by disease.
• The researchers mapped for the first time the signature of genetic influences on iron deposits in the brain, for genes related to neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. Researchers hope the work will lead to new insight into how these diseases progress and damage mental capacity, and also help generate new imaging-based ways to evaluate disease treatments in the future.
• Another finding relates to the effect of the ROBO3 gene on the brain’s white matter pathways. Mutations in the gene mean that pathways that normally connect one side of the brain to the other do not develop properly. This can result in gaze palsy, a disorder which affects the movement of the eyes. It was found that the UK Biobank brain imaging is able to non-invasively localise the effects of this gene to exactly the pathways affected in this disorder.
• The work also localised effects in the brain of genes that have been linked to both early-life brain development and mental health disorders such as depression and schizophrenia.

“The genetic basis of brain structure is largely unknown,” said Professor Gwenaëlle Douaud, one of the brain imaging experts who collaborated on the work. “We have found a very rich set of genetic effects which will help us understand better the mechanisms by which the brain develops, functions, becomes damaged by disease and heals itself. And this is from just 10% of the volunteer participants that will eventually get their brains scanned by UK Biobank.

“In the coming years, 100,000 volunteers will be imaged by UK Biobank, giving researchers and doctors around the world a massive resource from which to discover even more genetic influences, hidden to us so far, on the brain and its disorders.”

UKRI Chief Executive Professor Sir Mark Walport said: “UK Biobank is one of the largest and most comprehensive studies of population health in the world. Genetic variation helps to explain important differences between people in health and disease. This largest ever investigation of the genetic basis of brain structure and function will provide unrivalled insights into neurodegenerative and psychological disorders, including Parkinson’s and Alzheimer’s diseases, depression and schizophrenia.

“The scale of this study is quite extraordinary, looking at over 3000 different measures of brain structure and function in 10000 Biobank volunteers who have had MRI brain scans, and finding over 100 areas of the human genome that influence these. None of this could be achieved without the generosity and trust of the half million participants in UK Biobank, and the global leadership of the outstanding team that runs it and makes the data globally available. The data from UK Biobank is fuelling a new era of genetic medicine. The NHS will be amongst the leading beneficiaries.”

Sara Marshall, Head of Clinical Research and Physiological Sciences at Wellcome, said: “The UK Biobank initiative is an extraordinary joint venture between researchers, funders, and the general public who have come together to transform our understanding of disease. The research published today brings together a combination of genetic and brain imaging data at an unparalleled scale, and allows us to ask questions about common brain disorders such as Parkinson’s disease, depression and Alzheimer’s disease in a completely new way. It is exciting to see the potential of this powerful resource being realised.”

The entire set of imaging-genetic associations — linking 3,000 brain measures against 11 million genetic markers — is openly available for researchers to access, at an interactive website: big.stats.ox.ac.uk

UK Biobank resource is primarily funded by the Medical Research Council (MRC) and Wellcome. The MRC, DH and British Heart Foundation provided further funding for genotyping and Wellcome and the MRC provided funding for UK Biobank to image 100,000 of its half a million volunteer participants. This study was funded by Wellcome, the MRC and the European Research Council.

UK Biobank acknowledges the support of its 500,000 volunteer participants who still give up considerable time and effort to take part and to ensure its success.

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