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.”

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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!