Motivation Ageing is a biological and psychosocial process related to diseases and mortality. It correlates with changes in DNA methylation (DNAm) in all human tissues. Therefore, epigenetic markers can be used to estimate biological age using DNA methylation profiling across tissues. Results We developed a Bioconductor package that allows computation of several existing DNAm adult/childhood and gestational age clocks. Functions to visualize the DNAm age prediction versus chronological age and the correlation between DNAm clocks are also available as well as other features such as missing data imputation of cell types estimates that are required for DNAm age clocks. Availability https://github.com/isglobal-brge/methylclock Supplementary information Supplementary data are available at Bioinformatics online.

Common variants of human fat mass- and obesity-associated gene Fto have been linked with higher body mass index, but the biological explanation for the link has remained obscure. Recent findings suggest that these variants affect the homeobox protein IRX3. Here we report that FTO has a role in white adipose tissue which modifies its response to high-fat feeding. Wild type and Fto-deficient mice were exposed to standard or high-fat diet for 16 weeks after which metabolism, behavior and white adipose tissue morphology were analyzed together with adipokine levels and relative expression of genes regulating white adipose tissue adipogenesis and Irx3. Our results indicate that Fto deficiency increases the expression of genes related to adipogenesis preventing adipocytes from becoming hypertrophic after high-fat diet. In addition, we report a novel finding of increased Irx3 expression in Fto-deficient mice after high-fat feeding indicating a complex link between FTO, IRX3 and fat metabolism.

The Horizon2020 LifeCycle Project is a cross-cohort collaboration which brings together data from multiple birth cohorts from across Europe and Australia to facilitate studies on the influence of early-life exposures on later health outcomes. A major product of this collaboration has been the establishment of a FAIR (findable, accessible, interoperable and reusable) data resource known as the EU Child Cohort Network. Here we focus on the EU Child Cohort Network’s core variables. These are a set of basic variables, derivable by the majority of participating cohorts and frequently used as covariates or exposures in lifecourse research. First, we describe the process by which the list of core variables was established. Second, we explain the protocol according to which these variables were harmonised in order to make them interoperable. Third, we describe the catalogue developed to ensure that the network’s data are findable and reusable. Finally, we describe the core data, including the proportion of variables harmonised by each cohort and the number of children for whom harmonised core data are available. EU Child Cohort Network data will be analysed using a federated analysis platform, removing the need to physically transfer data and thus making the data more accessible to researchers. The network will add value to participating cohorts by increasing statistical power and exposure heterogeneity, as well as facilitating cross-cohort comparisons, cross-validation and replication. Our aim is to motivate other cohorts to join the network and encourage the use of the EU Child Cohort Network by the wider research community.

Objectives Type 2 diabetes (T2D) and comorbid depression challenges clinical management particularly in individuals with overweight. We aim to explore the shared etiology, via lifecourse adiposity, between T2D and depression. Methods We used data from birth until 46years from Northern Finland Birth Cohort 1966 (n = 6,372; 53.8% females). We conducted multivariate analyses on three outcomes: T2D (4.2%), depression (19.2%) and as comorbidity (1.8%). We conducted (i) Path analysis to clarify time-dependent body mass index (BMI) related pathways, including BMI polygenic risk scores (PRS); and (ii) Cox regression models to assess whether reduction of overweight between 7years and 31years influence T2D, depression and/or comorbidity. The models were tested for covariation with sex, education, smoking, physical activity, and diet score. Results The odd ratios (OR) of T2D in individuals with depression was 1.68 [95% confidence interval (CI): 1.34–2.11], and no change in estimate was observed when adjusted for covariates. T2D and comorbidity showed similar patterns of relationships in the path analyses (P < 0.001). The genetic risk for obesity (PRS BMI) did not show direct effect on T2D or comorbidity in adulthood but indirectly through measures of adiposity in early childhood and mid-adulthood in the path analysis (P < 0.001). Having early-onset of overweight at 7years and 31years showed highest risk of T2D (OR 3.8, 95%CI 2.4–6.1) and comorbidity (OR 5.0, 95%CI 2.7–9.5), with mild-to-moderate attenuation with adjustments. Depression showed no significant associations. Conclusions We found evidence for overweight since childhood as a risk factor for T2D and co-morbidity between T2D and depression, influenced moderately by lifestyle factors in later life. However, no shared early life adiposity related risk factors were observed between T2D and depression when assessed independently in this Finnish setting.

OBJECTIVE Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] = 0.013 [2.1 × 10−3], P value corrected for false discovery rate [PFDR] = 5.1 × 10−3) and cg02988288 (β [SE]−0.013 [2.3 × 10−3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSIONS Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.

Activation of pregnane X receptor (PXR) elevates circulating 4b-hydroxycholesterol (4bHC), an agonist of liver X receptor (LXR). PXR may also regulate 25-hydroxycholesterol and 27hydroxycholesterol. Our aim was to elucidate the roles of PXR and oxysterols in the regulation of cholesterol transporters. We measured oxysterols in serum of volunteers dosed with PXR agonist rifampicin 600 mg/day versus placebo for a week and analyzed the expression of cholesterol transporters in mononuclear cells. The effect of 4bHC on the transport of cholesterol and the expression of cholesterol transporters was studied in human primary monocyte-derived macrophages and foam cells in vitro. The expression of cholesterol transporters was measured also in rat tissues after dosing with a PXR agonist. The levels of 4bHC were elevated, while 25-hydroxycholesterol and 27-hydroxycholesterol remained unchanged in volunteers dosed with rifampicin. The expression of ATP binding cassette transporter A1 (ABCA1) was induced in human mononuclear cells in vivo. The influx of cholesterol was repressed by 4bHC, as was the expression of influx transporter lectin-like oxidized LDL receptor-1 in vitro. The cholesterol efflux and the expression of efflux transporters ABCA1 and ABCG1 were induced. The expression of inducible degrader of the LDL receptor was induced. In rats, PXR agonist increased circulating 4bHC and expression of LXR targets in peripheral tissues, especially ABCA1 and ABCG1 in heart. In conclusion, PXR activation-elevated 4bHC is a signaling molecule that represses cholesterol influx and induces efflux. The PXR-4bHC-LXR pathway could link the hepatic xenobiotic exposure and the regulation of cholesterol transport in peripheral tissues.

Recent evidence indicates consistent association of low socioeconomic status with epigenetic age acceleration, measured from DNA methylation. As work characteristics and job stressors are crucial components of socioeconomic status, we investigated their association with various measures of epigenetic age acceleration. The study population included employed and unemployed men and women (n=604) from the Northern Finland Birth Cohort 1966. We investigated the association of job strain, effort-reward imbalance and work characteristics with five biomarkers of epigenetic aging (Hannum, Horvath, PhenoAge, GrimAge, and DunedinPoAm). Our results indicate few significant associations between work stress indicators and epigenetic age acceleration, limited to a range of ±2 years, and smoking recording the highest effect on GrimAge age acceleration biomarker between current and no smokers (median difference 4.73 years (IQR 1.18, 8.41). PhenoAgeAA was associated with job strain active work (β=-1.301 95%CI -2.391, -0.212), slowing aging of less than 1.5 years, and working as white-collar slowed aging six months (GrimAgeAA β=-0.683, 95%CI -1.264, -0.102) when compared to blue collars. Association was found for working for more than 40 hours per week that increased the aging over 1.5 years, (HorvathAA β =2.058 95%CI 0.517,3.599, HannumAA β=1.567, 95%CI 0.415,2.719). The pattern of associations was different between women and men and some of the estimated effects are inconsistent with current literature. Our results provide the first evidence of association of work conditions with epigenetic aging biomarkers. However, further epidemiological research is needed to fully understand how work-related stress affects epigenetic age acceleration in men and women in different societies.

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