New study uses DNA methylation quantitative trait loci to characterize the relationship between methylomic variation, gene expression and complex traits

A new paper from our group published in the American Journal of Human Genetics highlights the utility of DNA methylation quantitative trait loci (mQTLs), for interpreting the functional consequences of common genetic variation associated with human traits. We describe the first comprehensive analysis of common genetic variation on DNA methylation using the Illumina EPIC array to profile samples from the UK Household Longitudinal (Understanding Society) study. We identified >12 million significant DNA mQTL associations including a large number not identified using previous methylation-profiling methods (i.e. the Illumina 450K array). We demonstrate the utility of these data for interpreting the functional consequences of common genetic variation associated with > 60 human traits, using Summary data–based Mendelian Randomization (SMR) to identify pleiotropic associations between complex traits and DNA methylation sites. We also use SMR to characterize the relationship between DNA methylation and gene expression. Our mQTL database and SMR results are available via a searchable online database as a resource to the research community.

Widespread H3K27ac differences associated with Alzheimer’s disease in the entorhinal cortex

Building on our previous work exploring DNA methylation in Alzheimer’s disease (AD), a new paper from our group just published in Nature Neuroscience has identified extensive differences in the histone modification H3K27ac associated with AD neuropathology. We quantified genome-wide patterns of H3K27ac in entorhinal cortex samples from AD cases and matched controls using chromatin immunoprecipitation and highly parallel sequencing (ChIP-seq). We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. Differentially acetylated peaks were enriched in disease-related biological pathways and included regions annotated to genes involved in the progression of Aβ and tau pathology (e.g. APP, PSEN1, PSEN2, and MAPT), as well as regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly-significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1 and RGCC. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease. Our results can be explored as UCSC Genome Browser tracks and the raw H3K27ac ChIP-seq data is available to download from GEO.

Exeter secures international autism research grant

Painting by Helen Spiers

A three year international research grant of $975,000 USD (almost £750,000) has been awarded to the University of Exeter for research by Professor Jonathan Mill into the genetics of autism.

The Simons Foundation Autism Research Initiative (SFARI) awarded the grant to Mill, who heads the Complex Disease Epigenomics Group at the University of Exeter Medical School. His group researches how genes are controlled in mental health and disease, and this award will enable him to pursue research into the causes of autism in greater detail.

The project, which will be undertaken in collaboration with researchers at the Genome Institute in Singapore, aims to characterise changes in gene regulation across human brain development. It builds on previous work in the Mill lab exploring gene changes during neurodevelopment and neuropsychiatric conditions such as autism. The team will investigate different types of gene function in the developing brain, and use new methods to analyse changes in individual brain cells.

Professor Mill, from the University of Exeter Medical School, said: “The origins of autism are thought to occur very early during development of the brain. Characterising the genomic changes occurring during this period gives us a fantastic opportunity to understand the complex genetic underpinnings of autism.”

Launched in 2003, SFARI is a scientific initiative within the Simons Foundation’s suite of programs. SFARI’s mission is to improve the understanding, diagnosis and treatment of autism spectrum disorders by funding innovative research of the highest quality and relevance.

SFARI Director Louis Reichardt said: “SFARI is pleased to be funding these investigators and supporting their labs’ efforts to better understand the neurobiology of autism.

“We look forward to seeing the outcomes of these projects and hope that the new insights can help accelerate the development of improved diagnostic tools and treatment options for individuals with autism.”

Date: 5 October 2018

Higher Autism Polygenic Risk Scores Linked to Differential Methylation Among Newborns

By studying blood samples taken from infants, researchers have found that higher numbers of alleles associated with risk for autism spectrum disorder are also associated with differential methylation at certain spots in the genome.

Autism spectrum disorder is highly heritable, though environmental factors still influence its risk, possibly through epigenetic variation.

Using blood spot samples collected shortly after birth, a University of Exeter Medical School-led team examined methylomic variation in 1,263 infants, about half of whom were later diagnosed with ASD. While they found no differences in overall methylation between the later affected and unaffected infants, the researchers did find a link between increased polygenic burden for autism and differences in methylation at certain loci. As they reported this week in Genome Medicine, these loci are close to a signal previously uncovered through a genome-wide association study of autism

“Our study represents the first analysis of epigenetic variation at birth associated with autism and highlights the utility of polygenic risk scores for identifying molecular pathways associated with etiological variation.”

Read more at genomeweb.com!

Medicine students’ work published in international science journal

Two students from the University of Exeter Medical School have worked on a scientific paper which has been published in Neuroscience, a well-respected international journal.

Kamuran Akkus, a 2nd year Medicine student, and Aurimas Kudzinskas, a 3rd year Medicine student, were part of a group of students who undertook a 10 week laboratory placement with Dr Asami Oguro-Ando this summer. The pair had no laboratory experience prior to the placement.

Dr Oguro-Ando’s research aims to further our understanding of the molecules, cells and circuits that underlie neurodevelopmental disorders affecting mental health. Kamuran and Aurimas worked as part of Dr Oguro-Ando’s team to research a gene associated with Autism spectrum disorder.

Findings from the paper, CD38 is required for dendritic organisation in visual cortex and hippocampus, suggested that a certain gene called CD38 is implicated in the development of brain areas associated with social behaviour. This type of research is key to expanding our understanding of the brain and behaviour, as well as relatively common conditions such as Autism spectrum disorder, which affects 1 in 100 people in the UK.

Read more here!

Dementia research at Exeter gets £190,000 boost!

The dementia research charity BRACE and Kirby Laing Foundation have together awarded more than £190,000 to the University of Exeter Medical School to support cutting-edge genomic research to better understand the causes of dementia.

Kirby Laing has provided £90,000 of funding to support a three-year PhD post in the Complex Disease Epigenetics Group within the Medical School’s world-leading research team that investigates how the way genes are activated influences disease.

Previously, the team has been involved in identifying a number of regions of the genome that are altered in Alzheimer’s disease. Now, the PhD funding, in partnership with BRACE, will allow them to hone in on a specific region, known as HOXA3, and use state-of-the-art techniques to establish how and why this gene is altered in Alzheimer’s disease.

An additional £100,000 of BRACE funding is supporting a two-year project to compare how gene regulation is altered in Alzheimer’s disease compared to in Parkinson’s disease, in collaboration with researchers at Cardiff University, with the aim of identifying unique genes to each dementia.

For more information follow the link here to read the full story!

 

Congratulations to the new RSE Cloud Computing Fellows

SSI - software.ac.uk“Research Software Engineers drive advances in how research can be done more effectively using all manner of software, computing systems and infrastructure. As a community, RSEs drive positive change to progress the state-of-the-art to do better, faster, and more reproducible research. It’s clear that cloud computing is playing an increasingly important role in research, so Microsoft is privileged to be able to support the RSE community, and researchers across the world, to exploit cloud computing across all domains through our Azure for Research program.

We were delighted to see so many high-quality applications to the RSE Cloud Computing Awards call, and so have decided to give all applicants access to Microsoft Azure to pursue the wide-range of exciting activities proposed. We particularly congratulate the successful awardees from across the UK, who can now pursue their plans for training, workshops, community software development, and cutting-edge research using Microsoft Azure.”

 

Find out more about the Cloud Computing Awards or about the Awardees, including our own Eilis Hannon!

 

“Eilis had a particular focus on schizophrenia and other neuropsychiatric disorders and therefore is interested in the dynamic nature of gene expression and epigenetic variation during human brain development. As strong advocates of open access research, the group routinely share these data through online tools enabling other researchers to explore and visualise specific genes or genomic locations relevant for their work. As the complexity and quantity of data increases, this Cloud Computing award will enable Eilis to develop more advanced tools, increasing the utility of these to the wider genomics community.”

Exeter Professor wins international award for psychiatric genetics research

A genetics researcher has won a prestigious award from the International Society of Psychiatric Genetics (ISPG) for his work on diseases that affect the brain.

Professor Jonathan Mill, of the University of Exeter Medical School, has been presented with the 2017 Theodore Reich Young Investigator Award, a prize which celebrates exceptional research in the field of psychiatric genetics.

The award is named after Theodore (Ted) Reich (1938-2003) who was the first President of the ISPG and was both an outstanding researcher and mentor to young scientists. The award was presented at the recent World Congress of Psychiatric Genetics in Orlando, Florida, an annual international conference for experts in the field.

Professor Mill leads the Complex Disease Epigenetics Group, a team which focuses on understanding the way in which genes function in the brain, and how changes in their activity may influence mental health and disease. Professor Mill’s research explores gene regulation in diseases including schizophrenia, bipolar disorder, Alzheimer’s disease and autism.

Read more at The Exeter Daily!

More than £1 million to identify genomic changes in schizophrenia

The Medical Research Council is awarding more than £1 million to the University of Exeter Medical School to continue their pioneering work into how and why schizophrenia develops.

Scientists have long known that schizophrenia, which usually becomes evident during adolescence or in young adulthood, has its origins in the brain before birth.

The research team which also involves the University of Essex will use cutting-edge DNA sequencing technology funded by a previous Medical Research Council grant to explore patterns of gene activity in the brain as it grows and develops, and the role that changes in these patterns play in schizophrenia. They will also profile a unique collection of post-mortem brain tissue donated by patients with schizophrenia from around the world.

 

Read the full article at the University of Exeter website .

Pioneering schizophrenia research is happening in Exeter

Pioneering research work in Exeter into how and why schizophrenia develops will continue following a grant of more than £1m.

Scientists have long known that schizophrenia, which usually becomes evident during adolescence or in young adulthood, has its origins in the brain before birth.

A research team at the University of Exeter Medical School will use cutting-edge DNA sequencing technology funded by a previous Medical Research Council grant to explore patterns of gene activity in the brain as it grows and develops, and the role that changes in these patterns play in schizophrenia.

To read more visit Devon Live!