Biology subjects

Min, J. L.

Publications and source records attributed to Min, J. L..

7 recordsLinked to original sources

bioRxiv2021

Evidence of positive and negative selection associated with DNA methylation

Signatures of negative selection are pervasive amongst complex traits and diseases. However, it is unclear whether such signatures exist for DNA methylation (DNAm) that has been proposed to have a functional role in disease. We estimate polygenicity, SNP-based heritability and model the joint distribution of effect size and minor allele frequency (MAF) to estimate a selection coefficient (S) for 2000 heritable DNAm sites in 1774 individuals from the Avon Longitudinal Study of Parents and Children. Additionally, we estimate S for meta stable epi alleles and DNAm sites associated with aging and mortality, birthweight and body mass index. Quantification of MAF-dependent genetic architectures estimated from genotype and DNAm reveal evidence of positive (S > 0) and negative selection (S < 0) and confirm previous evidence of negative selection for birthweight. Evidence of both negative and positive selection highlights the role of DNAm as an intermediary in multiple biological pathways with competing function.

genetics↗

bioRxiv2020

Genome-wide association studies identify 137 loci for DNA methylation biomarkers of ageing

Biological ageing estimators derived from DNA methylation (DNAm) data are heritable and correlate with morbidity and mortality. Leveraging DNAm and SNP data from >41,000 individuals, we identify 137 genome-wide significant loci (113 novel) from meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We report strong genetic correlations with longevity and lifestyle factors such as smoking, education, and obesity. Significant associations are observed in polygenic risk score analysis and to a lesser extent in Mendelian randomization analyses. This study illuminates the genetic architecture underlying epigenetic ageing and its shared genetic contributions with lifestyle factors and longevity.

genetics↗

bioRxiv2020

Investigating DNA methylation as a potential mediator between pigmentation genes, pigmentary traits and skin cancer

BackgroundIncidence rates for melanoma and non-melanoma skin cancer (NMSC), which includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), have been steadily increasing in all populations. Populations of European ancestry exhibit the highest rates and therefore, have been widely studied. Pigmentation characteristics are well-known risk factors for skin cancer, particularly fair skin, red hair, blue eyes and the inability to tan. Polymorphisms in established pigmentation-related genes have been associated with these traits and with an increased risk of malignancy. However, the functional relationship between genetic variation and disease is still unclear, with the exception of red hair colour variants in the melanocortin 1 receptor (MC1R) gene. ObjectivesThe aim of this study was to explore the possibility that non-coding pigmentation SNPs are associated with pigmentary traits and skin cancer via DNA methylation (DNAm). Methods and ResultsUsing a meta-GWAS of whole blood DNAm from 36 European cohorts (N=27,750; the Genetics of DNA Methylation Consortium, GoDMC), we found that 19 out of 27 pigmentation-associated SNPs distributed within 10 genes (ASIP, BNC2, IRF4, HERC2, MC1R, OCA2, SLC24A4, SLC24A5, SLC45A2, TYR) were associated with 391 DNAm sites across 30 genomic regions. We selected 25 DNAm sites for further analysis. We examined the effect of the chosen DNAm sites on pigmentation traits, sun exposure phenotypes, and skin cancer, and on gene expression in whole blood. We found an association of decreased DNAm at cg07402062 with red hair in the Avon Longitudinal Study of Parents and Children (ALSPAC), and a strong positive association of DNAm at this and correlated sites with higher expression of SPIRE2. Additionally, we investigated the association of gene expression in skin with pigmentation traits and skin cancer. The expression of ASIP, FAM83C, NCOA6, CDK10, and EXOC2 was associated with hair colour, whilst that of ASIP and CDK10 also had an effect on melanoma and BCC. ConclusionsOur results indicate that DNAm and expression of genes in the 16q24.3 and 20q11.22 regions, deserve to be further investigated as potential mediators of the relationship between genetic variants, pigmentation/sun exposure phenotypes, and some types of skin cancer.

genetics↗

bioRxiv2019

The effect of pre-analytical conditions on blood metabolomics in epidemiological studies

BackgroundSerum and plasma are commonly used biofluids for large-scale metabolomic-epidemiology studies. Their metabolomic profile is susceptible to changes due to variability in pre-analytical conditions and the impact of this is unclear.\n\nMethodsParticipant-matched EDTA-plasma and serum samples were collected from 37 non-fasting volunteers and profiled using a targeted nuclear magnetic resonance (NMR) metabolomics platform (N=151 traits). Metabolic concentrations were compared between reference (pre-storage: 4{degrees}C, 1.5h; post-storage: no sample preparation or NMR-analysis delays) and four, pre-storage, blood processing conditions, where samples were incubated at (i) 4{degrees}C, 24h; (ii) 4{degrees}C, 48h; (iii) 21{degrees}C, 24h; (iv) 21{degrees}C, 48h, before centrifugation; and two, post-storage, sample processing conditions in which samples (i) thawed overnight, then left for 24h before addition of sodium buffer followed by immediate NMR analysis; (ii) thawed overnight, addition of sodium buffer, then left for 24h before profiling. Linear regression models with random-intercepts were used to assess the impact of these six pre-analytical conditions on EDTA-plasma/serum metabolome.\n\nResultsFatty acids, beta-hydroxybutyrate, glycoprotein-acetyls and most lipid-related traits, in serum and plasma, were robust to the tested pre and post-storage conditions. Pre-storage conditions impacted concentrations of glycolysis metabolites, acetate, albumin and amino-acids by levels that could potentially bias research results (up to 1.4SD difference compared with reference). Post-storage conditions affected histidine, phenylalanine and LDL-particle-size, with differences up to 1.4SD.\n\nConclusionsMost metabolic traits are robust to the pre- and post-storage conditions tested here and that may commonly occur in large-scale cohorts. However, concentrations of glycolysis metabolites, and amino-acids may be compromised.\n\nKey messagesO_LIIn large scale epidemiological studies, blood processing delays, incubation at high temperature prior to long term storage, and NMR profiling delays after long term storage, may occur.\nC_LIO_LIConcentrations of fatty acids, beta-hydroxybutyrate, glycoprotein acetyls and most lipid-related traits are robust to variations in pre-storage temperature and duration of incubation (4{degrees}C or 21{degrees}C for up to 48h prior to centrifugation) and post-storage sample handling (24h delay in sample preparation or NMR profiling).\nC_LIO_LIGlycolytic metabolite concentrations are altered by pre-storage conditions and amino-acids, particularly histidine and phenylalanine, by both, pre and post-storage conditions.\nC_LI

epidemiology↗

bioRxiv2018

Epigenetic regulation of PAR4-related platelet activation: mechanistic links between environmental exposure and cardiovascular disease

Protease-activated receptor 4 (PAR4) is a potent thrombin receptor. Epigenetic control of the F2RL3 locus (which encodes for PAR4) via DNA methylation is associated with both smoking and cardiovascular disease. We examined the association between DNA hypomethylation at F2RL3 and risk of cardiovascular disease, focusing on acute myocardial infarction (AMI) (n=853 cases / 2,352 controls). We used in vitro cell models to dissect the role of DNA methylation in regulating expression of F2RL3. We investigated the interplay between F2RL3 DNA methylation and platelet function in human (n=41). Lastly, we used Mendelian randomization to unify observational and functional work by assessing evidence for causal relationships using data from UK Biobank (n=407,141) and CARDIoGRAMplusC4D (n=184,305). Observationally, one standard deviation (SD) decrease in DNA methylation at F2RL3 was associated with a 25% increase in the odds of AMI. In vitro, short-term exposure of cells to cigarette smoke reduced F2RL3 DNA methylation and increased gene expression. Transcriptional assays flagged a role for a CEBP recognition sequence in modulating the enhancer activity of F2RL3 exon 2. Lower DNA methylation at F2RL3 was associated with increased platelet reactivity in human. The estimated casual odds ratio of ischaemic heart disease was 1.03 (95% CI: 1.00, 1.07) per 1 SD decrease in F2RL3 DNA. In conclusion, we show that DNA methylation-dependent platelet activation is part of a complex system of features contributing to cardiovascular health. Tailoring therapeutic intervention to new knowledge of F2RL3/PAR4 function should be explored to ameliorate the detrimental effects of this risk factor on cardiovascular health.\n\nOne sentence summaryDNA methylation-dependent platelet activation is a likely causal contributor to cardiovascular health.

epidemiology↗

bioRxiv2018

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Cranial growth and development affects the closely related traits of head circumference (HC) and intracranial volume (ICV). Here we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV+HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood.

genetics↗

bioRxiv2016

GARFIELD - GWAS Analysis of Regulatory or Functional Information Enrichment with LD correction

Loci discovered by genome-wide association studies (GWAS) predominantly map outside protein-coding genes. The interpretation of functional consequences of non-coding variants can be greatly enhanced by catalogs of regulatory genomic regions in cell lines and primary tissues. However, robust and readily applicable methods are still lacking to systematically evaluate the contribution of these regions to genetic variation implicated in diseases or quantitative traits. Here we propose a novel approach that leverages GWAS findings with regulatory or functional annotations to classify features relevant to a phenotype of interest. Within our framework, we account for major sources of confounding that current methods do not offer. We further assess enrichment statistics for 27 GWAS traits within regulatory regions from the ENCODE and Roadmap projects. We characterise unique enrichment patterns for traits and annotations, driving novel biological insights. The method is implemented in standalone software and R package to facilitate its application by the research community.

genomics↗