Inside AJHG: A Chat with Jonathan Mill

Each month, the editors of The American Journal of Human Genetics interview an author(s) of a recently published paper. This month, we check in with Jonathan Mill to discuss his paper, “Leveraging DNA-Methylation Quantitative-Trait Loci to Characterize the Relationship between Methylomic Variation, Gene Expression, and Complex Traits.”

AJHG: What caused you to start working on this project? 

Jonathan: Our lab studies the genomic basis of complex human diseases, and we’re particularly interested in the mechanisms underpinning transcriptional regulation. The last decade has seen tremendous advances in understanding the role of common genetic variation in health and disease, but genome-wide association studies (GWAS) don’t always identify specific causal genes, and we know that the variants associated with disease are likely to influence gene expression rather than causing changes to the transcribed protein. We have been quantifying genetic and epigenetic variation in large numbers of samples and have been thinking about ways of integrating these datasets to fine-map GWAS regions.

This project built on our previous work using DNA methylation quantitative trait loci (mQTLs) to interpret the functional consequences of common genetic variation associated with neuropsychiatric disease and other human traits. We generated blood mQTL data in the Understanding Society UK Household Longitudinal Study (UKHLS) and used these to refine genetic association data from publicly available GWAS datasets in order to prioritize genes involved in complex traits and diseases. We also sought to identify pleiotropic relationships between DNA methylation and variable gene expression by using publicly available whole-blood gene expression QTL (eQTL) data.

AJHG: What about this paper most excites you? 

Jonathan: First, we have generated an extensive mQTL dataset, using the new Illumina EPIC DNA methylation array to identify over 12 million associations between genetic variants and DNA methylation sites, including a large number not identified by previous DNA methylation-profiling methods. We show that there are many instances of shared genetic signals on neighboring DNA methylation sites and that these associations are structured around both genes and CpG islands. We hope these will be a valuable resource for the genetics community, and our data can be downloaded from our website.

Second, we demonstrate the utility of these data for interpreting the functional consequences of common genetic variation associated with human traits by using summary-data-based Mendelian randomization (SMR) to identify >1500 pleiotropic associations between complex traits and DNA methylation sites. Finally, we use these data to explore the relationship between DNAm and gene expression by using genetic instruments rather than correlations to infer associations between specific DNA methylation sites and genes.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Jonathan: Our results add to an increasing body of evidence showing that genetic influences on DNA methylation are widespread across the genome. We show that integrating these relationships with the results from GWAS of complex traits and genetic studies of gene expression can improve our understanding about the interplay between gene regulation and expression and facilitate the prioritization of candidate genes implicated in disease etiology.

AJHG: What advice do you have for trainees/young scientists?

Jonathan: Most importantly, pick a subject you are passionate about and make sure your science continues to be fun! The biggest and best-funded labs are not necessarily the best places to train; research is all about teamwork and collaboration, and to me, these are key attributes that trainees and young scientists should look for in selecting a place to study and learn. Don’t be afraid to be wrong, and you should never worry about questioning your supervisor or mentor; I have learned so much from the exceptional postdocs and students in my lab who generally know a lot more than I do! Finally, make sure you keep a good work-life balance; it’s important to switch off and realize there is more to life than grant funding and papers.

AJHG: And for fun, tell us something about your life outside of the lab.

Jonathan: I live in a small fishing village on the Devon coast just outside Exeter in the UK. When I’m not trying to understand gene regulation in the brain, I spend a lot of time in my allotment attempting to grow enormous vegetables. I also cycle a lot, and last year rode to Paris from the UK along with Eilis Hannon (first author on this paper) to raise money for the amazing Alzheimer’s Society who fund our work into dementia.

Jonathan Mill, PhD, is a Professor of Epigenetics at the University of Exeter and Psychiatric Epigenetics at Kings College London. 

Original article available at:

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!

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!