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

Major funding to explore genomic changes in dementia

The research seeks to examine the way in which gene function changes at different stages of dementia

Exeter researchers will join forces with global experts to investigate the mechanisms behind Alzheimer’s disease, in a project announced on World Alzheimer’s Day (September 21).

The Exeter team, led by Professor Jonathan Mill, has been awarded almost £450,000 by Alzheimer’s Research UK (ARUK) to research the genomic mechanisms involved in progression of the disease. The University will team up with Eli Lilly and Company Ltd, who will collaborate with Exeter on the project as well as providing considerable matched funding.

Worldwide, nearly 44 million people live with Alzheimer’s disease or a related dementia. Alzheimer’s disease is associated with the build-up of proteins called tau and amyloid which form clumps that are damaging to brain cells. The driving mechanisms behind these changes in the brain involve both genetic and environmental factors, which are only partly understood. Further research is needed to fill the gaps in our knowledge and develop better treatments.

The project, starting in October, will use mouse models that reflect aspects of human Alzheimer’s disease to examine the way in which gene function changes at different stages of the disease. Researchers will measure the expression and regulation of genes in different regions of the brain, aiming to relate changes in gene function to changes in the progression of the disease.

Professor Mill said: “We’re delighted Alzheimer’s Research UK has funded our project, which aims to test the hypothesis that the development of Alzheimer’s disease pathology is associated with changes in the activity of genes in affected brain regions. The project brings together experts in genomics, informatics and neuroscience, and represents a novel approach for identifying the mechanisms involved in the progression of this terrible disease.”

Dr Rosa Sancho, Head of Research, at Alzheimer’s Research UK, said: “Currently 87,000 people in the South West are living with dementia, a condition which can rob people of their most precious memories and turn lives upside-down. Alzheimer’s disease is the most common cause of the condition, and while age is a big risk factor for the disease, it is not a normal part of ageing. Understanding the complex genetic processes contributing to Alzheimer’s disease is crucial in the hunt for new breakthroughs which will save lives.

“Exeter University is world-leading in this area of research, and we are very pleased to be funding Prof Mill’s pioneering project. Alzheimer’s Research UK receives no government funding for the research we support, and it is only thanks to the generosity of our supporters that we’re able to fund vital projects like this.”

The team will investigate how the findings identified in mouse brain compare to human genes by testing specific changes in their Alzheimer’s disease datasets.

Ultimately, we expect that the project will improve our knowledge of the underlying biological mechanisms leading to Alzheimer’s disease, which will allow is to nominate potential drug targets and biomarkers for treatments of the disease.

To find out more about dementia research at Exeter, follow #ExeterDementia on Twitter or visit our dementia website: http://www.exeter.ac.uk/dementia/.

Date: 21 September 2018

 

Twin study highlights importance of both genetics and environment on gene activity

The study shows the role of both genetics and environment on gene activity

New research highlights the extent to which epigenetic variation is influenced by both inherited and environmental factors.

Epigenetic processes affect the expression or activity of genes without changing the underlying DNA sequence and are believed to be one mechanism by which the environment can interact with the genome.

Now, an international group of researchers including teams from the University of Exeter, King’s College London, and Duke University in the USA have published a study in PLOS Genetics, using a unique cohort of over 700 pairs of twins to identify the factors influencing chemical modifications to DNA across the genome. In the study, funded by the Medical Research Council, the team compared the similarities between identical and non-identical twins, and found that epigenetic marks are more similar between identical twins – highlighting the role of DNA sequence variation in regulating gene activity. They also found that sites at which epigenetic variation is strongly linked to environmental exposures – such as smoking and obesity – are also partly under genetic control.

Professor Jonathan Mill, of the University of Exeter Medical School, led the study. He said: “These results highlight how both heritable and environmental factors can influence the way in which genes are expressed and function, with important implications for studies of health and disease.”

Dr Eilis Hannon, of the University of Exeter Medical School, was first author on the paper. She commented “Our study provides a useful framework for interpreting the results of epigenetic epidemiological studies and shows that epigenetic differences are a potential mechanism linking genetic variation to gene regulation.”

The paper, “Characterizing genetic and environmental influences on variable DNA methylation using monozygotic and dizygotic twins”, is published in PLOS Genetics and is available online here.

Authors are Eilis Hannon, Olivia Knox, Karen Sugden, Joe Burrage, Chloe C Y Wong, Daniel W Belsky, David L Corcoran, Louise Arseneault, Terrie E Moffitt, Avshalom Caspi, and Jonathan Mill. Additional support was provided by the National Institute of Child Health and Human Development, a Distinguished Investigator Award from the American Asthma Foundation to Professor Mill, and by the Jacobs Foundation. Some of the work reported in the study used a high-performance computing facility partially supported by a grant from the North Carolina Biotechnology Center.

Date: 3 August 2018

New MRC funding to study genomic changes in schizophrenia brain

The Medical Research Council has funded us to continue our research into the genomic underpinnings of schizophrenia. The project will use cutting-edge methods to profile gene regulation (DNA modifications, histone modifications, gene expression, alternative splicing) in purified neuronal nuclei isolated from a unique collection of post-mortem brain samples.

Given the evidence for a neurodevelopmental component to the aetiology of schizophrenia, we will also annotate patterns of gene regulation across development of the human cortex, enabling us to explore the hypothesis that disease-associated loci are dynamically regulated during this critical period.

Building on our previous work exploring epigenomic variation in schizophrenia, our integrated-genomics project will explore the dynamic regulation of gene function during human brain development and its relevance to the aetiology of schizophrenia.

We’ll be looking for a postdoc and technician to work on this exciting project – so please keep an eye on our jobs page or get in touch directly with Jonathan Mill if you’re interested in joining our team!

New paper highlights how DNA hydroxymethylation in the human brain change during development.

Previous work from our group described dynamic changes in DNA methylation (5mC) occurring during human fetal brain development. Other epigenetic processes operating during this period have not been extensively explored – of particular interest is DNA hydroxymethylation (5hmC), a modification that we have found to be enriched in the human brain, and which is hypothesized to play an important role in neuronal function, learning and memory.

In our latest paper we have quantified 5hmC across the genome of human fetal brain samples spanning 23 to 184 days post-conception. We identify widespread changes in 5hmC occurring during human brain development, notable sex-differences in 5hmC in the fetal brain, and interactions between 5mC and 5hmC at specific sites. We also identify loci where 5hmC in the fetal brain is associated with genetic variation.

This study represents the first systematic analysis of dynamic changes in 5hmC across human neurodevelopment and highlights the potential importance of this modification in the human brain. To accompany our paper we have generated a searchable database of our fetal brain 5hmC data is available as a resource to the research community.

Schizophrenia-Associated Methylomic Variation

We have recently published a new study in Human Molecular Genetics which assesses variation in DNA methylation associated with schizophrenia and schizophrenia polygenic risk score in 262 post-mortem brain samples. We used tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) and identified multiple differentially methylated loci associated with schizophrenia and genetic risk.

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Find out about our London to Paris Cycle Ride with the Alzheimer’s Society!

In July, two members of the Epigenetics Group, Jon Mill and Eilis Hannon, along with 4 other dementia researchers from the University of Exeter are taking part in the Alzheimer’s Society London to Paris Charity cycle ride.

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2017 Software Sustainability Fellows announced

Last week the 2017 cohort of Software Sustainability Institute Fellows was announced and included Epigenetics group member Dr Eilis Hannon. 18 Fellowships were awarded, each of whom will receive £3000 to fund activities over the next 15 months in line with the goals of the organisation.

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