Sex steroid hormones and risk of breast cancer:a two-sample Mendelian randomization study

BACKGROUND: Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association. METHODS: Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses. RESULTS: We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09–1.21, OR 1.19, 95% CI 1.07–1.33 and OR 1.03, 95% CI 1.01–1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12–1.27, OR 1.25, 95% CI 1.11–1.40 and OR 1.06, 95% CI 1.03–1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03–1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC. CONCLUSIONS: TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-022-01553-9

Harnessing Whole Genome Polygenic Risk Scores to Stratify Individuals Based on Cardiometabolic Risk Factors and Biomarkers at Age 10 in the Lifecourse - Brief Report

In this study, we investigated the capability of polygenic risk scores to stratify a cohort of young individuals into risk deciles based on 10 different cardiovascular traits and circulating biomarkers. METHODS: We first conducted large-scale genome-wide association studies using data on adults (mean age 56.5 years) enrolled in the UK Biobank study (n=393 193 to n=461 460). Traits and biomarkers analyzed were body mass index, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, apolipoprotein A-I, C-reactive protein and vitamin D. Findings were then leveraged to build whole genome polygenic risk scores in participants from the Avon Longitudinal Study of Parents and Children (mean age, 9.9 years) which were used to stratify this cohort into deciles in turn and analyzed against their respective traits. RESULTS: For each of the 10 different traits assessed, we found strong evidence of an incremental trend across deciles (all P<0.0001). Large differences were identified when comparing top and bottom deciles; for example, using the apolipoprotein B polygenic risk scores there was a mean difference of 13.2 mg/dL for this established risk factor of coronary heart disease in later life. CONCLUSIONS: Although the use of polygenic prediction in a clinical setting may currently be premature, our findings suggest they are becoming increasingly powerful as a means of predicting complex trait variation at an early stage in the lifecourse

Using Openly Accessible Resources to Strengthen Causal Inference in Epigenetic Epidemiology of Neurodevelopment and Mental Health

The recent focus on the role of epigenetic mechanisms in mental health has led to several studies examining the association of epigenetic processes with psychiatric conditions and neurodevelopmental traits. Some studies suggest that epigenetic changes might be causal in the development of the psychiatric condition under investigation. However, other scenarios are possible, e.g., statistical confounding or reverse causation, making it particularly challenging to derive conclusions on causality. In the present review, we examine the evidence from human population studies for a possible role of epigenetic mechanisms in neurodevelopment and mental health and discuss methodological approaches on how to strengthen causal inference, including the need for replication, (quasi-)experimental approaches and Mendelian randomization. We signpost openly accessible resources (e.g., &ldquo;MR-Base&rdquo; &ldquo;EWAS catalog&rdquo; as well as tissue-specific methylation and gene expression databases) to aid the application of these approaches

Epigenetic modelling of former, current and never smokers

BACKGROUND: DNA methylation (DNAm) performs excellently in the discrimination of current and former smokers from never smokers, where AUCs > 0.9 are regularly reported using a single CpG site (cg05575921; AHRR). However, there is a paucity of DNAm models which attempt to distinguish current, former and never smokers as individual classes. Derivation of a robust DNAm model that accurately distinguishes between current, former and never smokers would be particularly valuable to epidemiological research (as a more accurate smoking definition vs. self-report) and could potentially translate to clinical settings. Therefore, we appraise 4 DNAm models of ternary smoking status (that is, current, former and never smokers): methylation at cg05575921 (AHRR model), weighted scores from 13 CpGs created by Maas et al. (Maas model), weighted scores from a LASSO model of candidate smoking CpGs from the literature (candidate CpG LASSO model), and weighted scores from a LASSO model supplied with genome-wide 450K data (agnostic LASSO model). Discrimination is assessed by AUC, whilst classification accuracy is assessed by accuracy and kappa, derived from confusion matrices. RESULTS: We find that DNAm can classify ternary smoking status with reasonable accuracy, including when applied to external data. Ternary classification using only DNAm far exceeds the classification accuracy of simply assigning all classes as the most prevalent class (63.7% vs. 36.4%). Further, we develop a DNAm classifier which performs well in discriminating current from former smokers (agnostic LASSO model AUC in external validation data: 0.744). Finally, across our DNAm models, we show evidence of enrichment for biological pathways and human phenotype ontologies relevant to smoking, such as haemostasis, molybdenum cofactor synthesis, body fatness and social behaviours, providing evidence of the generalisability of our classifiers. CONCLUSIONS: Our findings suggest that DNAm can classify ternary smoking status with close to 65% accuracy. Both the ternary smoking status classifiers and current versus former smoking status classifiers address the present lack of former smoker classification in epigenetic literature; essential if DNAm classifiers are to adequately relate to real-world populations. To improve performance further, additional focus on improving discrimination of current from former smokers is necessary. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-021-01191-6

Assessment of Offspring DNA Methylation across the Lifecourse Associated with Prenatal Maternal Smoking Using Bayesian Mixture Modelling

A growing body of research has implicated DNA methylation as a potential mediator of the effects of maternal smoking in pregnancy on offspring ill-health. Data were available from a UK birth cohort of children with DNA methylation measured at birth, age 7 and 17. One issue when analysing genome-wide DNA methylation data is the correlation of methylation levels between CpG sites, though this can be crudely bypassed using a data reduction method. In this manuscript we investigate the effect of sustained maternal smoking in pregnancy on longitudinal DNA methylation in their offspring using a Bayesian hierarchical mixture model. This model avoids the data reduction used in previous analyses. Four of the 28 previously identified, smoking related CpG sites were shown to have offspring methylation related to maternal smoking using this method, replicating findings in well-known smoking related genes MYO1G and GFI1. Further weak associations were found at the AHRR and CYP1A1 loci. In conclusion, we have demonstrated the utility of the Bayesian mixture model method for investigation of longitudinal DNA methylation data and this method should be considered for use in whole genome applications

The long-term impact of folic acid in pregnancy on offspring DNA methylation : follow-up of the Aberdeen folic acid supplementation trial (AFAST)

Funding This work was supported by the NIHR Bristol Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. R.C.R., G.C.S., N.K., T.G., G.D.S. and C.L.R. work in a unit that receives funds from the University of Bristol and the UK Medical Research Council (MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8). This work was also supported by CRUK (grant number C18281/A19169) and the ESRC (grant number ES/N000498/1). C.M.T. is supported by a Wellcome Trust Career Re-entry Fellowship (grant number 104077/Z/14/Z).Peer reviewedPublisher PD