Neurological disease clues revealed in largest ever human genetic study

By Michael Woodhead

11 Oct 2018

The release of “open source” genetic architecture data for brain structure and function from the UK Biobank will enable groundbreaking research into neurological conditions such as MS, Parkinson’s disease and MND, Oxford University researchers say.

Reported in the journal Nature, the researchers say the genome-wide association studies of 3,144 functional and structural brain imaging phenotypes will provide neuroscience researchers into neurodegenerative diseases with a huge amount of material to work on.

The researchers took data from detailed MRI 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.

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.

Prof Stephen Smith

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 ageing, and understanding how it functions, becomes damaged by disease and heals itself, says study investigator Professor Stephen Smith, from Oxford’s Wellcome Trust Centre for Integrative Neuroimaging

“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.”

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 neurone disease (MND). 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.

Victorian researchers are also working on data from the UK Biobank.

“The UK Biobank will transform human genetics research, giving scientists around the world access to a rich sample of unprecedented size and scope on which to explore innumerable hypotheses relating genetics to biology and disease,” said Associate Professor Stephen Leslie, from the University of Melbourne and Murdoch Children’s Research Centre (MCRI).

He is leading a team from the University of Melbourne to generate genetic data related to the immune system, as well as quality testing these data.

Associate Professor Leslie said his team worked on typing the human leukocyte antigen, (HLA) system.

“These cell-surface proteins are a key component of the regulation of the immune system in humans and are therefore central to how the body responds to bacterial and viral infection,” he said.

“They are also associated with many autoimmune diseases like multiple sclerosis (MS) and celiac disease. The HLA genes are best known as the genes that are matched when doing tissue typing for transplantation.

“It is well-known that the HLA region provides protection or susceptibility to many diseases, so we set about typing or characterising these genes for the 500,000 participants in the Biobank project.”

Associate Professor Leslie said because the region is so diverse and complex, it is difficult and expensive to measure them directly, and so they are unavailable in many other genetic studies.

“We developed a method to simplify typing the HLA genes using inexpensive and easily obtained genetic markers such as those typed in the Biobank study,” he said.

“This means that, for the first time, these important genetic variants are available for the large sample sizes that are necessary to better understand the genetics of human disease.”

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