| 61. |
- Bell, Jordana T, et al.
(författare)
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Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.
- 2012
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.
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| 62. |
- Bermingham, Kate M., et al.
(författare)
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Characterisation of Fasting and Postprandial NMR Metabolites : Insights from the ZOE PREDICT 1 Study
- 2023
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Ingår i: Nutrients. - 2072-6643. ; 15:11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Postprandial metabolomic profiles and their inter-individual variability are not well characterised. Here, we describe postprandial metabolite changes, their correlations with fasting values and their inter- and intra-individual variability, following a standardised meal in the ZOE PREDICT 1 cohort. Methods: In the ZOE PREDICT 1 study (n = 1002 (NCT03479866)), 250 metabolites, mainly lipids, were measured by a Nightingale NMR panel in fasting and postprandial (4 and 6 h after a 3.7 MJ mixed nutrient meal, with a second 2.2 MJ mixed nutrient meal at 4 h) serum samples. For each metabolite, inter- and intra-individual variability over time was evaluated using linear mixed modelling and intraclass correlation coefficients (ICC) were calculated. Results: Postprandially, 85% (of 250 metabolites) significantly changed from fasting at 6 h (47% increased, 53% decreased; Kruskal–Wallis), with 37 measures increasing by >25% and 14 increasing by >50%. The largest changes were observed in very large lipoprotein particles and ketone bodies. Seventy-one percent of circulating metabolites were strongly correlated (Spearman’s rho >0.80) between fasting and postprandial timepoints, and 5% were weakly correlated (rho <0.50). The median ICC of the 250 metabolites was 0.91 (range 0.08–0.99). The lowest ICCs (ICC <0.40, 4% of measures) were found for glucose, pyruvate, ketone bodies (β-hydroxybutyrate, acetoacetate, acetate) and lactate. Conclusions: In this large-scale postprandial metabolomic study, circulating metabolites were highly variable between individuals following sequential mixed meals. Findings suggest that a meal challenge may yield postprandial responses divergent from fasting measures, specifically for glycolysis, essential amino acid, ketone body and lipoprotein size metabolites.
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| 63. |
- Bermingham, Kate M., et al.
(författare)
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Exploring the relationship between social jetlag with gut microbial composition, diet and cardiometabolic health, in the ZOE PREDICT 1 cohort
- 2023
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Ingår i: European Journal of Nutrition. - 1436-6207. ; 62:8, s. 3135-3147
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: In this study, we explore the relationship between social jetlag (SJL), a parameter of circadian misalignment, and gut microbial composition, diet and cardiometabolic health in the ZOE PREDICT 1 cohort (NCT03479866). Methods: We assessed demographic, diet, cardiometabolic, stool metagenomics and postprandial metabolic measures (n = 1002). We used self-reported habitual sleep (n = 934) to calculate SJL (difference in mid-sleep time point of ≥ 1.5 h on week versus weekend days). We tested group differences (SJL vs no-SJL) in cardiometabolic markers and diet (ANCOVA) adjusting for sex, age, BMI, ethnicity, and socio-economic status. We performed comparisons of gut microbial composition using machine learning and association analyses on the species level genome bins present in at least 20% of the samples. Results: The SJL group (16%, n = 145) had a greater proportion of males (39% vs 25%), shorter sleepers (average sleep < 7 h; 5% vs 3%), and were younger (38.4 ± 11.3y vs 46.8 ± 11.7y) compared to the no-SJL group. SJL was associated with a higher relative abundance of 9 gut bacteria and lower abundance of 8 gut bacteria (q < 0.2 and absolute Cohen’s effect size > 0.2), in part mediated by diet. SJL was associated with unfavourable diet quality (less healthful Plant-based Diet Index), higher intakes of potatoes and sugar-sweetened beverages, and lower intakes of fruits, and nuts, and slightly higher markers of inflammation (GlycA and IL-6) compared with no-SJL (P < 0.05 adjusted for covariates); rendered non-significant after multiple testing adjustments. Conclusions: Novel associations between SJL and a more disadvantageous gut microbiome in a cohort of predominantly adequate sleepers highlight the potential implications of SJL for health.
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| 64. |
- Bermingham, Kate M., et al.
(författare)
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Menopause is associated with postprandial metabolism, metabolic health and lifestyle : The ZOE PREDICT study
- 2022
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 85
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Tidskriftsartikel (refereegranskat)abstract
- Background: The menopause transition is associated with unfavourable alterations in health. However, postprandial metabolic changes and their mediating factors are poorly understood. Methods: The PREDICT 1 UK cohort (n=1002; pre- n=366, peri- n=55, and post-menopausal females n=206) assessed phenotypic characteristics, anthropometric, diet and gut microbiome data, and fasting and postprandial (0–6 h) cardiometabolic blood measurements, including continuous glucose monitoring (CGM) data. Differences between menopausal groups were assessed in the cohort and in an age-matched subgroup, adjusting for age, BMI, menopausal hormone therapy (MHT) use, and smoking status. Findings: Post-menopausal females had higher fasting blood measures (glucose, HbA1c and inflammation (GlycA), 6%, 5% and 4% respectively), sugar intakes (12%) and poorer sleep (12%) compared with pre-menopausal females (p<0.05 for all). Postprandial metabolic responses for glucose2hiauc and insulin2hiauc were higher (42% and 4% respectively) and CGM measures (glycaemic variability and time in range) were unfavourable post- versus pre-menopause (p<0.05 for all). In age-matched subgroups (n=150), postprandial glucose responses remained higher post-menopause (peak0-2h 4%). MHT was associated with favourable visceral fat, fasting (glucose and insulin) and postprandial (triglyceride6hiauc) measures. Mediation analysis showed that associations between menopause and metabolic health indicators (visceral fat, GlycA360mins and glycaemia (peak0-2h)) were in part mediated by diet and gut bacterial species. Interpretation: Findings from this large scale, in-depth nutrition metabolic study of menopause, support the importance of monitoring risk factors for type-2 diabetes and cardiovascular disease in mid-life to older women to reduce morbidity and mortality associated with oestrogen decline. Funding: Zoe Ltd.
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| 65. |
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| 66. |
- Demerath, Ellen W., et al.
(författare)
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Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:15, s. 4464-4479
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 x 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches.
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| 67. |
- den Hoed, Marcel, et al.
(författare)
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Heritability of objectively assessed daily physical activity and sedentary behavior
- 2013
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 98:5, s. 1317-1325
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Tidskriftsartikel (refereegranskat)abstract
- Background: Twin and family studies that estimated the heritability of daily physical activity have been limited by poor measurement quality and a small sample size. Objective: We examined the heritability of daily physical activity and sedentary behavior assessed objectively by using combined heart rate and movement sensing in a large twin study. Design: Physical activity traits were assessed in daily life for a mean (+/- SD) 6.7 +/- 1.1 d in 1654 twins from 420 monozygotic and 352 dizygotic same-sex twin pairs aged 56.3 +/- 10.4 y with body mass index (in kg/m(2)) of 26.1 +/- 4.8. We estimated the average daily movement, physical activity energy expenditure, and time spent in moderate-to-vigorous intensity physical activity and sedentary behavior from heart rate and acceleration data. We used structural equation modeling to examine the contribution of additive genetic, shared environmental, and unique environmental factors to between-individual variation in traits. Results: Additive genetic factors (le, heritability) explained 47% of the variance in physical activity energy expenditure (95% CI: 23%, 53%) and time spent in moderate-to-vigorous intensity physical activity (95% CI: 29%, 54%), 35% of the variance in acceleration of the trunk (95% CI: 0%, 44%), and 31% of the variance in the time spent in sedentary behavior (95% CI: 9%, 51%). The remaining variance was predominantly explained by unique environmental factors and random error, whereas shared environmental factors played only a marginal role for all traits with a range of 0-15%. Conclusions: The between-individual variation in daily physical activity and sedentary behavior is mainly a result of environmental influences. Nevertheless, genetic factors explain up to one-half of the variance, suggesting that innate biological processes may be driving some of our daily physical activity.
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| 68. |
- Dick, Katherine J., et al.
(författare)
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DNA methylation and body-mass index : a genome-wide analysis
- 2014
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 383:9933, s. 1990-1998
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Tidskriftsartikel (refereegranskat)abstract
- Background Obesity is a major health problem that is determined by interactions between lifestyle and environmental and genetic factors. Although associations between several genetic variants and body-mass index (BMI) have been identified, little is known about epigenetic changes related to BMI. We undertook a genome-wide analysis of methylation at CpG sites in relation to BMI. Methods 479 individuals of European origin recruited by the Cardiogenics Consortium formed our discovery cohort. We typed their whole-blood DNA with the Infinium HumanMethylation450 array. After quality control, methylation levels were tested for association with BMI. Methylation sites showing an association with BMI at a false discovery rate q value of 0.05 or less were taken forward for replication in a cohort of 339 unrelated white patients of northern European origin from the MARTHA cohort. Sites that remained significant in this primary replication cohort were tested in a second replication cohort of 1789 white patients of European origin from the KORA cohort. We examined whether methylation levels at identified sites also showed an association with BMI in DNA from adipose tissue (n=635) and skin (n=395) obtained from white female individuals participating in the MuTHER study. Finally, we examined the association of methylation at BMI-associated sites with genetic variants and with gene expression. Findings 20 individuals from the discovery cohort were excluded from analyses after quality-control checks, leaving 459 participants. After adjustment for covariates, we identified an association (q value <= 0.05) between methylation at five probes across three different genes and BMI. The associations with three of these probes-cg22891070, cg27146050, and cg16672562, all of which are in intron 1 of HIF3A-were confirmed in both the primary and second replication cohorts. For every 0.1 increase in methylation beta value at cg22891070, BMI was 3.6% (95% CI 2.4-4.9) higher in the discovery cohort, 2.7% (1.2-4.2) higher in the primary replication cohort, and 0.8% (0.2-1.4) higher in the second replication cohort. For the MuTHER cohort, methylation at cg22891070 was associated with BMI in adipose tissue (p=1.72 x 10(-5)) but not in skin (p=0.882). We observed a significant inverse correlation (p=0.005) between methylation at cg22891070 and expression of one HIF3A gene-expression probe in adipose tissue. Two single nucleotide polymorphisms-rs8102595 and rs3826795-had independent associations with methylation at cg22891070 in all cohorts. However, these single nucleotide polymorphisms were not significantly associated with BMI. Interpretation Increased BMI in adults of European origin is associated with increased methylation at the HIF3A locus in blood cells and in adipose tissue. Our findings suggest that perturbation of hypoxia inducible transcription factor pathways could have an important role in the response to increased weight in people.
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| 69. |
- Drong, Alexander W, et al.
(författare)
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The presence of methylation quantitative trait loci indicates a direct genetic influence on the level of DNA methylation in adipose tissue.
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants that associate with DNA methylation at CpG sites (methylation quantitative trait loci, meQTLs) offer a potential biological mechanism of action for disease associated SNPs. We investigated whether meQTLs exist in abdominal subcutaneous adipose tissue (SAT) and if CpG methylation associates with metabolic syndrome (MetSyn) phenotypes. We profiled 27,718 genomic regions in abdominal SAT samples of 38 unrelated individuals using differential methylation hybridization (DMH) together with genotypes at 5,227,243 SNPs and expression of 17,209 mRNA transcripts. Validation and replication of significant meQTLs was pursued in an independent cohort of 181 female twins. We find that, at 5% false discovery rate, methylation levels of 149 DMH regions associate with at least one SNP in a ±500 kilobase cis-region in our primary study. We sought to validate 19 of these in the replication study and find that five of these significantly associate with the corresponding meQTL SNPs from the primary study. We find that none of the 149 meQTL top SNPs is a significant expression quantitative trait locus in our expression data, but we observed association between expression levels of two mRNA transcripts and cis-methylation status. Our results indicate that DNA CpG methylation in abdominal SAT is partly under genetic control. This study provides a starting point for future investigations of DNA methylation in adipose tissue.
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| 70. |
- Frkatović-Hodžić, Azra, et al.
(författare)
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Mapping of the gene network that regulates glycan clock of ageing
- 2023
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Ingår i: Aging. - 1945-4589. ; 15:24, s. 14509-14552
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Tidskriftsartikel (refereegranskat)abstract
- Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. We performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system we manipulated gene expression of candidate genes in the in vitro IgG expression system. Upregulation of three genes, EEF1A1, MANBA and TNFRSF13B, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this in vitro expression system.
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