Epigenetics of complex traits and diseases

Thousands of genetic and epigenetic variants have been identified for many common diseases including cancer through genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS). To advance the complex interpretation of both GWAS and EWAS results, I developed new software tools (FORGE2 and eFORGE) for the analysis and interpretation of GWAS and EWAS data, respectively. Both tools determine the cell type-specific regulatory component of a set of target regions (either GWAS-identified genetic variants or EWAS-identified differentially methylated positions). This is achieved by detecting enrichment of overlap with histone mark peaks or DNase I hypersensitive sites across hundreds of tissues, primary cell types, and cell lines from the ENCODE, Roadmap Epigenomics, and BLUEPRINT projects. Application of both tools to publicly available datasets identified novel disease-relevant cell types for many common diseases, a stem cell-like signature in cancer EWAS, and also demonstrated the ability to detect cell-composition effects for EWAS performed on heterogeneous tissues. To complement these bioinformatics efforts and validate selected variants predicted by FORGE2, eFORGE and additional analyses, I performed conformation capture using 4C-seq to fine-map the 3D context of the genomic regions involved, uncovering novel interactions for autoimmunity-associated variants and IKZF3

King Arthur 'Dux Bellorum': Welsh Penteulu 'Chief of the Royal Host'

Although the North British hero Arthur (d. 537) is described in medieval romance as a king, he is not so termed in the earliest documents relating to him. The ninth-century 'Historia Brittonum' states merely that he fought 'cum regibus Brittonum' ('alongside kings of the Britons'), but was himself merely 'dux bellorum'. What this means has been long disputed. It has been taken to represent a senior rank in the Roman army, with Arthur as a commander of cavalry forces fighting up and down Britain. Closer analysis shows this as a fantasy. Comparison with medieval Welsh texts indicates that 'dux bellorum' instead corresponds to the Welsh 'penteulu' ('captain of the bodyguard, chief of the royal host'). As commander of the king's bodyguard, the 'penteulu' was the most important of the 24 officers of the court. He had a position of supreme trust, invariably being the ruler's own son or nephew or another man of rank. Setting out his income and status (which included the right to praise by the official poet of the bodyguard), medieval Welsh legal and other sources are thus the most reliable sources of information on what the Arthur of history was and was not

The River Wharfe and Verbeia, Celtic Goddess

The Wharfe is a river of Yorkshire, in northern England. It was known to the Romans as 'Verbeia', also used of their fortress in what is now the town of Ilkley. Although 'Verbeia' is surely Celtic and ultimately gives the modern hydronym 'Wharfe', its meaning has been obscure. Comparison with other Celtic forms yet suggests the sense 'Powerful Striker, she who is Strong in Hitting'', with 'ver' as an intensive prefix and 'beia' related to British and Irish words for 'axe' and the like. The pagan Celts worshipped rivers as goddesses; the Wharfe is a formidable stream, liable to dangerous floods; the name hence indicates a female deity regarded with awe, whose name survives to this day on a Roman altar in Ilkley Museum

The Four Branches of the Mabinogi: Gwynedd and the Glamorgan Bards

Pedeir Keinc y Mabinogi or 'The Four Branches of the Mabinogi', surely the work of an author from Gwynedd or north-west Wales, are twelfth-century tales of love and adventure; and one character in them is Gwydion, a magician of Gwynedd. Amongst his exploits is disguising himself as a poet from Glamorgan (in South Wales) and thereby deceiving a Gwynedd sorceress, who is fooled into welcoming him as a story-teller and entertainer. In a similar way he had already tricked a prince of Dyfed (or south-west Wales). Although pure legend, the episodes have a semi-historical parallel in bards who unwittingly produced conflict between Deheubarth (southern Wales) and Glamorgan. According to the antiquary Rice Merrick (d. 1587), the feud was the result of royal passion, as at Troy. Its Helen was the wife of Iestyn (d. 1100?), Lord of Glamorgan; its Paris was Rhys (d. 1093), Prince of Deheubarth. Rhys became obsessed with Iestyn's wife after hearing poets describe her. Yet she was loyal to her husband as Helen was not to Menelaus. Disappointed in his lust, Rhys began threatening his neighbour. Hence an antagonism between Dyfed and Glamorgan that led to disaster for both. The 'Glamorgan bards' in these two narratives are the theme of this paper, with three main conclusions: (a) The sources are evidence neither for the eleventh century nor for the special excellence of verse in Glamorgan; (b) Glamorgan's representation in the Four Branches is consistent with authorship by a member of Gwynedd's ruling house who (through marriage) lived in Dyfed; (c) there is, in contrast, no link whatever between the tales and the Celtic monastery of Clynnog (in west Gwynedd), despite assertions by some

Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci

Background DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Methods The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. Results We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. Conclusions We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context

Diversity in EWAS: current state, challenges, and solutions

Here, we report a lack of diversity in epigenome-wide association studies (EWAS) and DNA methylation (DNAm) data, discuss current challenges, and propose solutions for EWAS and DNAm research in diverse populations. The strategies we propose include fostering community involvement, new data generation, and cost-effective approaches such as locus-specific analysis and ancestry variable region analysis

A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution

Bulk-tissue DNA methylomes represent an average over many different cell types, hampering our understanding of cell-type-specific contributions to disease development. As single-cell methylomics is not scalable to large cohorts of individuals, cost-effective computational solutions are needed, yet current methods are limited to tissues such as blood. Here we leverage the high-resolution nature of tissue-specific single-cell RNA-sequencing datasets to construct a DNA methylation atlas defined for 13 solid tissue types and 40 cell types. We comprehensively validate this atlas in independent bulk and single-nucleus DNA methylation datasets. We demonstrate that it correctly predicts the cell of origin of diverse cancer types and discovers new prognostic associations in olfactory neuroblastoma and stage 2 melanoma. In brain, the atlas predicts a neuronal origin for schizophrenia, with neuron-specific differential DNA methylation enriched for corresponding genome-wide association study risk loci. In summary, the DNA methylation atlas enables the decomposition of 13 different human tissue types at a high cellular resolution, paving the way for an improved interpretation of epigenetic data

A mammalian methylation array for profiling methylation levels at conserved sequences

Infinium methylation arrays are not available for the vast majority of non-human mammals. Moreover, even if species-specific arrays were available, probe differences between them would confound cross-species comparisons. To address these challenges, we developed the mammalian methylation array, a single custom array that measures up to 36k CpGs per species that are well conserved across many mammalian species. We designed a set of probes that can tolerate specific cross-species mutations. We annotate the array in over 200 species and report CpG island status and chromatin states in select species. Calibration experiments demonstrate the high fidelity in humans, rats, and mice. The mammalian methylation array has several strengths: it applies to all mammalian species even those that have not yet been sequenced, it provides deep coverage of conserved cytosines facilitating the development of epigenetic biomarkers, and it increases the probability that biological insights gained in one species will translate to others

Epigenome-Wide Association Study of Kidney Function Identifies Trans-Ethnic and Ethnic-Specific Loci

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. RESULTS: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. CONCLUSIONS: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context

DNA methylation predicts age and provides insight into exceptional longevity of bats

This work was supported by a Paul G. Allen Frontiers Group grant to S.H., the University of Maryland, College of Computer, Mathematical and Natural Sciences to G.S.W., an Irish Research Council Consolidator Laureate Award to E.C.T., a UKRI Future Leaders Fellowship (MR/T021985/1) to S.C.V. and a Discovery Grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada to P.A.F. S.C.V. and P.D. were supported by a Max Planck Research Group awarded to S.C.V. by the Max Planck Gesellschaft, and S.C.V. and E.Z.L. were supported by a Human Frontiers Science Program Grant (RGP0058/2016) awarded to S.C.V. L.J.G. was supported by an NSERC PGS-D scholarship.Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.Publisher PDFPeer reviewe