Biology subjects

Hayward, C.

Publications and source records attributed to Hayward, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Rheumatoid Arthritis-associated IgG N-glycan agalactosylation diminishes neutrophilic inflammation by reducing FcgammaR binding and downstream signaling

The IgG Fc chain carries a single N-linked glycan which may undergo changes. Increased agalactosylated N-glycans are associated with rheumatoid arthritis (RA) and regarded as pro-inflammatory. Dysregulated neutrophils can make important contributions to host tissue damage. In RA, immune complexes (ICs) that have precipitated onto synovial joint surfaces activate neutrophils via Fc receptors, promoting localised inflammation. We engineered recombinant human monoclonal IgG with agalactosylated or galactosylated N-glycans, generated immobilised ICs and stimulated healthy donor and RA patient blood-derived neutrophils, comparing reactive oxygen species (ROS) production as read-out of neutrophilic inflammation. Both healthy donor and RA patient neutrophils generated less ROS when stimulated with ICs made from agalactosylated IgG. Mechanistically this was due to poorer binding of agalactosylated ICs to neutrophil Fc{gamma}Rs, causing lower activation of Akt and p38 MAPK. Both are required for immobilised IC-mediated stimulation of the neutrophil NADPH oxidase. Taken together, this suggests that disease-associated, agalactosylated IgG does not in fact promote inflammation and host tissue injury, at least not by acting on neutrophils. We propose that rather than promoting inflammation, agalactosylated IgG N-glycans that accompany inflammatory disease may arise as part of a compensatory mechanism that is aimed at reducing excessive inflammation and host tissue injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/735866v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@18a7178org.highwire.dtl.DTLVardef@1f8d75org.highwire.dtl.DTLVardef@1801a22org.highwire.dtl.DTLVardef@133e657_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Sex differences in the genetic basis of human recombination within 190,000 parent-child pairs

Structured AbstractO_ST_ABSIntroductionC_ST_ABSSexual reproduction uses a specialized cell division called meiosis, in which a single round of DNA replication is followed by two cell divisions to create hap-loid gametes. Genetic recombination in meiosis assures faithful segregation of chromosomes and establishes patterns of genetic linkage and inheritance. Meiotic recombination is thus a fundamental genomic process that shapes major features of the genomic landscape, influences mutation, and creates genetic diversity. RationaleThe genetic basis of between-individual variation in the occurrence and genomic location of meiotic recombination events remains poorly understood in humans. In particular, we lack an understanding of whether the same DNA regions shape vari-ation in recombination rates across studies. We address this by curating 112,144 maternal and 78,653 paternal meiosis events (parent-child pairs) across cohorts from four countries, creating the largest dataset of its kind. ResultsWe identify 58 independent genomic regions associated with the occurrence and genomic location of recombination events, 24 of which are unique across phe-notypes. Of the 24 unique regions, 6 are novel and specific to female meiotic recombination harboring genes linked to ovarian function, a 7th novel region is linked to male recombination. Many regions have significant sex-dependent ef-fects across studies. We estimate the between-sex genetic correlation for meiotic recombination rate to be 0.374 (0.072 SD), which captures the extent to which the genetic factors influencing a trait in one sex also impact the same trait in the other. 30-40% of the individual-level variation in recombination rate is at-tributable to DNA markers, of which only 37.7% (2.7% SD) and 47.1% (3.8% SD) is attributable to previously known global modulators of meiotic recombi-nation, in females and males respectively. We create a polygenic predictor that significantly predicts recombination rates of both women and men after adjusting for age and year of birth. We find significant correlations between female meiotic recombination, reproductive outcomes and reproductive aging, after adjusting for study ascertainment. ConclusionsIn the largest meta-analysis to date of human meiotic recombination, we identify novel loci with sex-specific effects that influence male and female recombination rate across multiple cohorts.

genomics↗

bioRxiv2025

Interactions between the 2C protein of FMDV and components of the viral replication machinery are mediated by ER-derived membranes

Foot-and-mouth disease virus (FMDV) remains an ever-present threat to the economic stability of the livestock industry and global trade. Despite this, questions remain regarding the fundamental biology underpinning the replication of this virus. Here, we examine components of the FMDV replication machinery (focussing on the viral 2C protein) and investigate the conditions under which they interact. Using a novel 2C antibody in co-immunoprecipitation experiments under different conditions followed by mass spectrometry, we identify membrane-associated proteins (such as the viral proteins 2B and precursors of 3A, which are poorly-characterised proteins involved in viral replication) along with ER-associated host proteins. In addition, our analysis shows that a number of nuclear factors interact with 2C in a membrane-independent manner, potentially being co-opted to support RNA replication of the virus. Furthermore, we demonstrate that the interaction of 2C with several viral proteins (including key members of the replication machinery and viral RNA) is maintained following ultracentrifugation, suggesting that these co-sediment as part of a complex. Our data suggest that the replication complex is ER-derived and highlight several new avenues of investigation for the disruption of the FMDV lifecycle.

microbiology↗

bioRxiv2025

An Updated Polygenic Index Repository: Expanded Phenotypes, New Cohorts, and Improved Causal Inference

Polygenic indexes (PGIs) -- DNA-based predictors of individual phenotypes -- have become essential tools across biomedical and social sciences. We introduce Version 2 of the Polygenic Index Repository, which expands phenotype coverage from 47 to 61, increases the number of participating datasets from 11 to 20, and adopts a more consistent and improved methodology for PGI construction. For 16 phenotypes, we leverage summary statistics from an updated GWAS meta-analysis with greater statistical power compared to the original release, thereby improving the PGIs predictive power. To improve power for family-based analyses, we provide imputed parental PGIs in all datasets with first-degree relatives and offer a framework for interpreting results from analyses that control for parental PGIs. We illustrate the utility of parental PGIs using two applications: (1) comparing PGI associations with and without parental PGI controls for all phenotypes in two Repository datasets with family data, and (2) for BMI and diastolic blood pressure, exploring the contribution of causal versus non-causal components of PGI associations to the imperfect portability of PGIs across subgroups within a genetic ancestry. Collectively, the updates enhance predictive performance, broaden the Repositorys scope, and introduce novel resources that reduce confounding bias and improve interpretability.

genomics↗

bioRxiv2025

Separating direct, indirect and parent-of-origin genetic effects in the human population

Here, we present a novel approach to estimate the degree to which the phenotypic effect of a DNA locus is attributable to four components: alleles in the child (direct genetic effects), alleles in the mother and the father (indirect genetic effects), or is dependent upon the parent from which it is inherited (parent-of-origin, PofO effects). Applying our model, JODIE, to 30,000 child-mother-father trios with phased DNA information from the Estonian Biobank (EstBB) and the Norwegian Mother, Father, Child Cohort (MoBa), we jointly estimate the phenotypic variance attributable to these four effects unbiased of assortative mating (AM) for height, body mass index (BMI) and childhood educational test score (EA). For all three traits, direct effects make the largest contribution to the genetic effect variance. But we find that parental indirect genetic effects make an equivalent combined contribution, and that there is a non-zero PofO effect variance for all traits. We calculate the heritability that would be obtained at the populationlevel in the absence of AM for common DNA loci, and show that the proportional contribution of direct effects to these heritability values can be calculated as 64.0% for EA in MoBa, 77.1% and 63.4% for height in MoBa and EstBB, and 81.2% and 88.0% for BMI in MoBa and EstBB. Additionally, using within-family genome-wide association testing, we identify 276 independently associated DNA regions that replicate across two additional biobanks, which all show a genotype-phenotype relationship that reflects an interplay of direct, indirect and PofO effects. Determining how direct, parental and PofO genetic effects combine across loci genome-wide to influence human phenotypic variation requires joint modeling of parental and child genotypes alongside the parental origin of loci and here, we make the first attempt to do this in the human population.

genetics↗

bioRxiv2024

Virus-induced paraspeckle-like condensates are essential hubs for gene expression and their formation drives genomic instability

The nucleus is a highly structured environment containing multiple membrane-less bodies formed through liquid-liquid phase separation. These provide spatial separation and concentration of specific biomolecules enabling efficient and discrete processes to occur which regulate gene expression. One such nuclear body, paraspeckles, are comprised of multiple paraspeckle proteins (PSPs) built around the architectural RNA, NEAT1_2. Paraspeckle function is yet to be fully elucidated but has been implicated in a variety of developmental and disease scenarios. We demonstrate that Kaposis sarcoma-associated herpesvirus (KSHV) drives formation of structurally distinct paraspeckles with a dramatically increased size and altered protein composition that are essential for productive lytic replication. We highlight these virus-induced paraspeckle-like structures form adjacent to virus replication centres, functioning as RNA processing hubs for both viral and cellular transcripts during infection. Notably, we reveal that PSP sequestration into virus-induced paraspeckle-like structures results in increased genome instability during both KSHV and Epstein Barr virus (EBV) infection, implicating their formation in virus-mediated tumorigenesis.

microbiology↗

bioRxiv2024

Collagen fibril formation at the plasma membrane occurs independently from collagen secretion

Collagen fibrils are the primary supporting scaffold of vertebrate tissues but how they are assembled is unclear. Here, using CRISPR-tagging of type I collagen and SILAC labelling, we elucidate the cellular mechanism for the spatiotemporal assembly of collagen fibrils, in cultured fibroblasts. Our findings reveal multifaceted trafficking of collagen, including constitutive secretion, intracellular pooling, and plasma membrane-directed fibrillogenesis. Notably, we differentiate the processes of collagen secretion and fibril assembly and identify the crucial involvement of endocytosis in regulating fibril formation. By employing Col1a1 knockout fibroblasts we demonstrate the incorporation of exogenous collagen into nucleation sites at the plasma membrane through these recycling mechanisms. Our study sheds light on the assembly process and its regulation in health and disease. Mass spectrometry data are available via ProteomeXchange with identifier PXD036794.

cell biology↗

bioRxiv2023

Methylome-wide association studies of traumatic physical injury identifies differential DNA methylation of synaptic plasticity and GABAergic-signalling.

Traumatic physical injury is often associated with psychological trauma and is a risk factor for major depressive disorder (MDD). In Generation Scotland traumatic injury was significantly associated with recurrent major depression (OR = 2.10, 95% CI 1.33-3.33, PLJ=LJ0.0016). and schizotypal symptoms, particularly disorganised thought ({beta}LJ=LJ0.111, 95% CI 0.049-0.177, PLJ=LJ0.0004). We performed methylome-wide analyses of traumatic injury in individuals with MDD and controls separately to investigate the link between traumatic injury and MDD. Nominally significant differences in differential DNA methylation between MDD and control groups were identified at 40 003 CpG sites (p < 0.05). Individuals with recurrent MDD showed significantly higher levels of DNA methylation associated with traumatic injury at CpG sites at the first exon and lower levels at exon boundaries, this was significant different to the association pattern at these sites in controls (mean difference in M-value = 0.0083, P = 21.1x10-10, and -0.0125, P = 2.1x10-174, respectively). Analyses at the level of CpG site, genes and gene ontologies implicated dysregulation of processes related to synaptic plasticity, including dendrite development, excitatory synapse and GABAergic signalling (normalised enrichment values > 2, FDR q-values < 0.01). Enrichment analyses for regional brain-expression in the recurrent MDD group highlight the limbic lobe and supraoptic nuclei (recurrent MDD FWER = 0.028 and 0.034, respectively). These results suggest that traumatic injury is associated with patterns of DNA methylation differentially in individuals with MDD compared to controls, highlighting the need for novel analysis approaches.

genomics↗

bioRxiv2023

Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

genetics↗

bioRxiv2023

Phenome-wide analysis identifies parent-of-origin effects on the human methylome associated with changes in the rate of aging

Variation in the rate at which humans age may be rooted in early life events acting through genomic regions that are influenced by such events and subsequently are related to health phenotypes in later life. The parent-of-origin-effect (POE)-regulated methylome includes regions either enriched for genetically controlled imprinting effects (the typical type of POE) or atypical POE introduced by environmental effects associated with parents. This part of the methylome is heavily influenced by early life events, making it a potential route connecting early environmental exposures, the epigenome and the rate of aging. Here, we aim to test the association of POE-influenced methylation of CpG dinucleotides (POE-CpG sites) with early and later environmental exposures and subsequently with health-related phenotypes and adult aging phenotypes. We do this by performing phenome-wide association analyses of the POE-influenced methylome using a large family-based population cohort (GS:SFHS, Ndiscovery=5,087, Nreplication=4,450). At the single CpG level, 92 associations of POE-CpGs with phenotypic variation were identified and replicated. Most of the associations were contributed by POE-CpGs belonging to the atypical class and the most strongly enriched associations were with aging (DNAmTL acceleration), intelligence and parental (maternal) smoking exposure phenotypes. We further found that a proportion of the atypical-POE-CpGs formed co-methylation networks (modules) which are associated with these phenotypes, with one of the aging-associated modules displaying increased internal module connectivity (strength of methylation correlation across constituent CpGs) with age. Atypical POE-CpGs also displayed high levels of methylation heterogeneity and epigenetic drift (i.e. information loss with age) and a strong correlation with CpGs contained within epigenetic clocks. These results identified associations between the atypical-POE-influenced methylome and aging and provided new evidence for the "early development of origin" hypothesis for aging in humans.

genetics↗

bioRxiv2022

Refining epigenetic prediction of chronological and biological age

Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort sample sizes increase, estimates of cAge and bAge become more precise. Here, we aim to refine predictors and improve understanding of the epigenomic architecture of cAge and bAge. First, we perform large-scale (N = 18,413) epigenome-wide association studies (EWAS) of chronological age and all-cause mortality. Next, to improve cAge prediction, we use methylation data from 24,673 participants from the Generation Scotland (GS) study, the Lothian Birth Cohorts (LBC) of 1921 and 1936 and 8 publicly available datasets. Through the inclusion of linear and non-linear age-CpG associations from the EWAS, feature pre-selection/dimensionality reduction in advance of elastic net regression, and a leave-one-cohort-out (LOCO) cross validation framework, we arrive at an improved cAge predictor (median absolute error = 2.3 years across 10 cohorts). In addition, we train a predictor of bAge on 1,214 all-cause mortality events in GS, based on epigenetic surrogates for 109 plasma proteins and the 8 component parts of GrimAge, the current best epigenetic predictor of all-cause mortality. We test this predictor in four external cohorts (LBC1921, LBC1936, the Framingham Heart Study and the Womens Health Initiative study) where it outperforms GrimAge in its association to survival (HRGrimAge = 1.47 [1.40, 1.54] with p = 1.08 x 10-52, and HRbAge = 1.52 [1.44, 1.59] with p = 2.20 x 10-60). Finally, we introduce MethylBrowsR, an online tool to visualize epigenome-wide CpG-age associations.

genomics↗

bioRxiv2022

The influence of biological and statistical properties of CpGs on epigenetic predictions of eighteen traits

BackgroundCpG methylation levels can help to explain inter-individual differences in phenotypic traits. Few studies have explored whether identifying CpG subsets based on biological and statistical properties can maximise predictions while minimising array content. MethodsVariance component analyses and penalised regression (epigenetic predictors) were used to test the influence of (i) the number of CpGs considered, (ii) mean CpG methylation variability and (iii) methylation QTL status on the variance captured in eighteen traits by blood DNA methylation. Training and test sets comprised [≤]4,450 and [≤]2,578 unrelated individuals from Generation Scotland, respectively. ResultsAs the number of CpG sites under consideration decreased, so too did the estimates from the variance components and prediction analyses. Methylation QTL status and mean CpG variability did not influence variance components. However, relative effect sizes were 15% larger for epigenetic predictors based on CpGs with methylation QTLs compared to sites without methylation QTLs. Relative effect sizes were 45% larger for predictors based on CpGs with mean beta-values between 10%-90% compared to those using hypo- or hypermethylated CpGs (beta-value [≤]10% or [≥]90%). ConclusionArrays with fewer CpGs could reduce costs, leading to increased sample sizes for analyses. Our results show that reducing array content can restrict prediction metrics and careful attention must be given to the biological and distribution properties of CpGs in array content selection.

genomics↗

bioRxiv2022

Genetic control of KRAB-ZFP genes explains distal CpG-site methylation which associates with human disease phenotypes.

Kruppel-associated box zinc finger proteins (KRAB-ZFPs) are the largest gene family of transcriptional regulators in higher vertebrates. We have developed a method for inferring these factors DNA binding-sites in vivo. We achieved this by combining the genome-wide association of methylation at 573,027 CpG-sites (meQTL) in blood and KRAB-ZFP RNA expression changes (eQTL). This methods efficacy is clearly demonstrated by showing that the CpG-sites whose methylation is affected by KRAB-ZFP expression changes occur preferentially near KRAB-ZFP binding-sites in the HEK293T cell line. We found such an enrichment to be significant for 31% of factors tested. In addition, we found that binding-sites of many KRAB-ZFPs are significantly enriched (or sometimes depleted) in disease-associated CpG-sites. In total, 9% (11 of 125) of the traits tested, and 14% (32 of 222) of the factors (KRAB-ZFPs and TIF1-beta) tested, were enriched or depleted in one or more trait-factor pairing. Rheumatoid arthritis and human immunodeficiency virus (HIV) infection were associated with the largest number of KRAB-ZFP enrichments. There have been variable reports on the effects on HIV infection dynamics of transcription intermediary factor 1-beta (TIF1-beta, also known as KAP1 or TRIM28), a nuclear corepressor for KRAB-ZFPs. We provide evidence that KRAB-ZFP-independent effects of TIF1-beta are responsible for the decreased methylation of CpG-sites within its binding-sites that is observed in HIV infection. In conclusion, KRAB-ZFPs often affect CpG-site methylation within the proximity of their binding-sites, and CpG-sites within the binding-sites of KRAB-ZFPs are enriched for association with many traits, including rheumatoid arthritis and HIV infection.

genomics↗

bioRxiv2021

Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome

Backgroundparent-of-origin effects (POE) play important roles in development and complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies have mainly focused on the detection of genomic regions or phenotypes regulated by POE. Understanding whether POE may be modified by environmental or genetic exposures is important for understanding of the source of POE-associated variation, but only a few case studies addressing these modifiable POE exist. Methodsin order to understand this high order of POE regulation, we screened 101 genetic and environmental factors such as "predicted mRNA expression levels" of DNA methylation/imprinting machinery genes and early/late lifestyle/environmental exposures. POE-mQTL-modifier interaction models were proposed to test the potential of these factors to modify POE at DNA methylation using data from Generation Scotland: The Scottish Family Health Study(N=2315). Resultsa set of vulnerable/modifiable POE-CpGs were identified (modifiable-POE-regulated CpGs, N=3). Four factors, "lifetime smoking status" and "predicted mRNA expression levels" of TET2, SIRT1 and KDM1A, were found to significantly modify the POE on the three CpGs in both discovery and replication datasets. Importantly, the POE on one of the CpGs were modified by both genetic and environmental factors. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs. Conclusionsthe modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation, motivating future comprehensive evaluation of the role of these modifiers in complex diseases. Key MessagesO_LIPrevious population studies showed that parent-origin-effects(POE) on human methylome can be widespread and affect health-related traits and diseases. C_LIO_LIWhether the POE remained stable throughout the life or can be modified by genetic or environmental factors were largely unknown. C_LIO_LIBy systematically screening 101 genetic and environmental factors in a large cohort(GS:SFHS) we provided the first population-level replicated evidence that those measuring lifestyle (smoking) and predicted expression of DNA methylation- or imprinting-machinery genes are amongst the factors that can modulate the POE of mQTLs for a set of CpG sites. C_LIO_LIWe found those modifiable-POE-regulated CpGs are also phenotypically relevant - one is associated with the plasma levels of CLEC4C and health-related phenotypes such as HDL levels. C_LIO_LIThe modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation and their potential phenotypic consequences. This also provided a paradigm for further studies to explore how environmental and genetic effects can be integrated at methylation level. C_LI

genetics↗

bioRxiv2021

Same role but different actors: genetic regulation of post-translational modification of two distinct proteins

Post-translational modifications (PTMs) diversify protein functions and dynamically coordinate their signalling networks, influencing most aspects of cell physiology. Nevertheless, their genetic regulation or influence on complex traits is not fully understood. Here, we compare for the first time the genetic regulation of the same PTM of two proteins - glycosylation of transferrin and immunoglobulin G (IgG). By performing genome-wide association analysis of transferrin glycosylation, we identified 10 significantly associated loci, all novel. Comparing these with IgG glycosylation-associated genes, we note protein-specific associations with genes encoding glycosylation enzymes (transferrin - MGAT5, ST3GAL4, B3GAT1; IgG - MGAT3, ST6GAL1) as well as shared associations (FUT6, FUT8). Colocalisation analyses of the latter suggest that different causal variants in the FUT genes regulate fucosylation of the two proteins. We propose that they affect the binding of different transcription factors in different tissues, with fucosylation of IgG being regulated by IKZF1 in B-cells and of transferrin by HNF1A in liver.

genomics↗

bioRxiv2021

A catalogue of omics biological ageing clocks reveals substantial commonality and associations with disease risk

Biological age (BA), a measure of functional capacity and prognostic of health outcomes that discriminates between individuals of the same chronological age (chronAge), has been estimated using a variety of biomarkers. Previous comparative studies have mainly used epigenetic models (clocks), we use ~1000 participants to create eleven omics ageing clocks, with correlations of 0.45-0.97 with chronAge, even with substantial sub-setting of biomarkers. These clocks track common aspects of ageing with 94% of the variance in chronAge being shared among clocks. The difference between BA and chronAge - omics clock age acceleration (OCAA) - often associates with health measures. One years OCAA typically has the same effect on risk factors/10-year disease incidence as 0.46/0.45 years of chronAge. Epigenetic and IgG glycomics clocks appeared to track generalised ageing while others capture specific risks. We conclude BA is measurable and prognostic and that future work should prioritise health outcomes over chronAge.

bioinformatics↗

bioRxiv2020

DNA methylation proxies for 16 plasma proteins predict the incidence of 7 leading causes of morbidity

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNAm signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample, (Generation Scotland; n=9,537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore - disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.

genomics↗

bioRxiv2020

Omics versus Questionnaires: Using methylation data to assess the environmental impact of smoking on obesity-related traits

Variation in obesity-related traits has a genetic basis with heritabilities between 40 and 70%. While the global obesity pandemic is usually associated with environmental changes related to lifestyle and socioeconomic changes, most genetic studies do not include all relevant environmental covariates, so genetic contribution to variation in obesity-related traits cannot be accurately assessed. Some studies have described interactions between a few individual genes linked to obesity and environmental variables but there is no agreement on their total contribution to differences between individuals. Here we compared self-reported smoking data and a methylation-based proxy to explore the effect of smoking and genome-by-smoking interactions on obesity related traits from a genome-wide perspective to estimate the amount of variance they explain. Our results indicate that exploiting omic measures can improve models for complex traits such as obesity and can be used as a substitute for, or jointly with, environmental records to better understand causes of disease.

genomics↗