Metabolomics datasets in the Born in Bradford cohort [version 2; peer review: 1 approved, 1 approved with reservations].

Metabolomics is the quantification of small molecules, commonly known as metabolites. Collectively, these metabolites and their interactions within a biological system are known as the metabolome. The metabolome is a unique area of study, capturing influences from both genotype and environment. The availability of high-throughput technologies for quantifying large numbers of metabolites, as well as lipids and lipoprotein particles, has enabled detailed investigation of human metabolism in large-scale epidemiological studies. The Born in Bradford (BiB) cohort includes 12,453 women who experienced 13,776 pregnancies recruited between 2007-2011, their partners and their offspring. In this data note, we describe the metabolomic data available in BiB, profiled during pregnancy, in cord blood and during early life in the offspring. These include two platforms of metabolomic profiling: nuclear magnetic resonance and mass spectrometry. The maternal measures, taken at 26-28 weeks’ gestation, can provide insight into the metabolome during pregnancy and how it relates to maternal and offspring health. The offspring cord blood measurements provide information on the fetal metabolome. These measures, alongside maternal pregnancy measures, can be used to explore how they may influence outcomes. The infant measures (taken around ages 12 and 24 months) provide a snapshot of the early life metabolome during a key phase of nutrition, environmental exposures, growth, and development. These metabolomic data can be examined alongside the BiB cohorts’ extensive phenotype data from questionnaires, medical, educational and social record linkage, and other ‘omics data

Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk:a Mendelian randomization study

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required

Maternal alcohol consumption and offspring DNA methylation: Findings from six general population-based birth cohorts

Aim: Alcohol consumption during pregnancy is sometimes associated with adverse outcomes in offspring, potentially mediated by epigenetic modifications. We aimed to investigate genome-wide DNA methylation in cord blood of newborns exposed to alcohol in utero. Materials & methods: We meta-analyzed information from six population-based birth cohorts within the Pregnancy and Childhood Epigenetics consortium. Results: We found no strong evidence of association at either individual CpGs or across larger regions of the genome. Conclusion: Our findings suggest no association between maternal alcohol consumption and offspring cord blood DNA methylation. This is in stark contrast to the multiple strong associations previous studies have found for maternal smoking, which is similarly socially patterned. However, it is possible that a combination of a larger sample size, higher doses, different timings of exposure, exploration of a different tissue and a more global assessment of genomic DNA methylation might show evidence of association

Investigating the effect of sexual behaviour on oropharyngeal cancer risk:a methodological assessment of Mendelian randomization

BACKGROUND: Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS: Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS: In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76). CONCLUSIONS: Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02233-3

Epigenome-wide association study of asthma- and wheeze characterizes loci within HK1

Background:To identify novel epigenetic markers of adolescent asthma and replicate findings in an independent cohort, then explore whether such markers are detectable at birth, predictive of early-life wheeze, and associated with gene expression in cord blood.Methods:We performed epigenome-wide screening with recursive random forest feature selection and internal validation in the IOW birth cohort. We then tested whether we could replicate these findings in the independent cohort ALSPAC and followed-up our top finding with children of the IOW cohort.Results:We identified 10 CpG sites associated with adolescent asthma at a 5% false discovery rate (IOW, n = 370), five of which exhibited evidence of associations in the replication study (ALSPAC, n = 720). One site, cg16658191, within HK1 displayed particularly strong associations after cellular heterogeneity adjustments in both cohorts (ORIOW = 0.17, 95% CI 0.04–0.57) (ORALSPAC = 0.57, 95% CI 0.38–0.87). Additionally, higher expression of HK1 (OR = 3.81, 95% CI 1.41–11.77) in cord blood was predictive of wheezing in infancy (n = 82).Conclusion:We identified novel associations between asthma and wheeze with methylation at cg16658191 and the expression of HK1, which may serve as markers of, predictors of, and potentially etiologic factors involved in asthma and early life wheeze

Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course

Rationale: We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. Methods: We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7-13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. Results: We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. Interpretation: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course