Bidirectional Mendelian randomization highlights causal relationships between circulating INHBC and multiple cardiometabolic diseases and traits.

Human genetic and transgenic mouse studies have highlighted a potential liver-adipose tissue endocrine axis, involving activin C (Act-C) and/or Act-E and ALK7, influencing fat distribution and systemic metabolism. We investigated the bidirectional effects between circulating INHBC, which homodimerizes into Act-C, and adiposity traits, insulin resistance, inflammation, and cardiometabolic disease risk. Additionally, we examined if Act-C is an ALK7 ligand in human adipocytes. We used Mendelian randomization and in vitro studies in immortalized human abdominal and gluteal adipocytes. Circulating INHBC was causally linked to reduced lower-body fat, dyslipidaemia, and increased risks of coronary artery disease (CAD) and non-alcoholic fatty liver disease (NAFLD). Conversely, upper-body fat distribution, obesity, hypertriglyceridemia, subclinical inflammation, and type 2 diabetes positively impacted plasma INHBC levels. Mechanistically, an atherogenic lipid profile may partly explain the INHBC-CAD link, while inflammation and hypertriglyceridemia may partly explain how adiposity traits affect circulating INHBC. Phenome-wide Mendelian randomization showed weak causal relationships between higher plasma INHBC and impaired kidney function and higher gout risk. In human adipocytes, recombinant Act-C activated SMAD2/3 signaling via ALK7 and suppressed lipolysis. In summary, INHBC influences systemic metabolism by activating ALK7 in adipose tissue and may serve as a drug target for atherogenic dyslipidemia, CAD, and NAFLD.

The role of accelerometer-derived sleep traits on glycated haemoglobin and glucose levels: a Mendelian randomization study.

Self-reported shorter/longer sleep duration, insomnia, and evening preference are associated with hyperglycaemia in observational analyses, with similar observations in small studies using accelerometer-derived sleep traits. Mendelian randomization (MR) studies support an effect of self-reported insomnia, but not others, on glycated haemoglobin (HbA1c). To explore potential effects, we used MR methods to assess effects of accelerometer-derived sleep traits (duration, mid-point least active 5-h, mid-point most active 10-h, sleep fragmentation, and efficiency) on HbA1c/glucose in European adults from the UK Biobank (UKB) (n = 73,797) and the MAGIC consortium (n = 146,806). Cross-trait linkage disequilibrium score regression was applied to determine genetic correlations across accelerometer-derived, self-reported sleep traits, and HbA1c/glucose. We found no causal effect of any accelerometer-derived sleep trait on HbA1c or glucose. Similar MR results for self-reported sleep traits in the UKB sub-sample with accelerometer-derived measures suggested our results were not explained by selection bias. Phenotypic and genetic correlation analyses suggested complex relationships between self-reported and accelerometer-derived traits indicating that they may reflect different types of exposure. These findings suggested accelerometer-derived sleep traits do not affect HbA1c. Accelerometer-derived measures of sleep duration and quality might not simply be 'objective' measures of self-reported sleep duration and insomnia, but rather captured different sleep characteristics.

Impact of insomnia on ovarian cancer risk and survival: a Mendelian randomization study.

BACKGROUND: Insomnia is the most common sleep disorder in patients with epithelial ovarian cancer (EOC). We investigated the causal association between genetically predicted insomnia and EOC risk and survival through a two-sample Mendelian randomization (MR) study. METHODS: Insomnia was proxied using genetic variants identified in a genome-wide association study (GWAS) meta-analysis of UK Biobank and 23andMe. Using genetic associations with EOC risk and overall survival from the Ovarian Cancer Association Consortium (OCAC) GWAS in 66,450 women (over 11,000 cases with clinical follow-up), we performed Iterative Mendelian Randomization and Pleiotropy (IMRP) analysis followed by a set of sensitivity analyses. Genetic associations with survival and response to treatment in ovarian cancer study of The Cancer Genome Atlas (TCGA) were estimated controlling for chemotherapy and clinical factors. FINDINGS: Insomnia was associated with higher risk of endometrioid EOC (OR = 1.60, 95% CI 1.05-2.45) and lower risk of high-grade serous EOC (HGSOC) and clear cell EOC (OR = 0.79 and 0.48, 95% CI 0.63-1.00 and 0.27-0.86, respectively). In survival analysis, insomnia was associated with shorter survival of invasive EOC (OR = 1.45, 95% CI 1.13-1.87) and HGSOC (OR = 1.4, 95% CI 1.04-1.89), which was attenuated after adjustment for body mass index and reproductive age. Insomnia was associated with reduced survival in TCGA HGSOC cases who received standard chemotherapy (OR = 2.48, 95% CI 1.13-5.42), but was attenuated after adjustment for clinical factors. INTERPRETATION: This study supports the impact of insomnia on EOC risk and survival, suggesting treatments targeting insomnia could be pivotal for prevention and improving patient survival. FUNDING: National Institutes of Health, National Cancer Institute. Full funding details are provided in acknowledgments.

Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10-8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

Insomnia symptom prevalence in England: a comparison of cross-sectional self-reported data and primary care records in the UK Biobank.

OBJECTIVES: We aimed to use a large dataset to compare self-reported and primary care measures of insomnia symptom prevalence in England and establish whether they identify participants with similar characteristics. DESIGN: Cross-sectional study with linked electronic health records (EHRs). SETTING: Primary care in England. PARTICIPANTS: 163 748 UK Biobank participants in England (aged 38-71 at baseline) with linked primary care EHRs. OUTCOME MEASURES: We compared the percentage of those self-reporting 'usually' having insomnia symptoms at UK Biobank baseline assessment (2006-2010) to those with a Read code for insomnia symptoms in their primary care records prior to baseline. We stratified prevalence in both groups by sociodemographic, lifestyle, sleep and health characteristics. RESULTS: We found that 29% of the sample self-reported having insomnia symptoms, while only 6% had a Read code for insomnia symptoms in their primary care records. Only 10% of self-reported cases had an insomnia symptom Read code, while 49% of primary care cases self-reported having insomnia symptoms. In both primary care and self-reported data, prevalence of insomnia symptom cases was highest in females, older participants and those with the lowest household incomes. However, while snorers and risk takers were more likely to be a primary care case, they were less likely to self-report insomnia symptoms than non-snorers and non-risk takers. CONCLUSIONS: Only a small proportion of individuals experiencing insomnia symptoms have an insomnia symptom Read code in their primary care record. However, primary care data do provide a clinically meaningful measure of insomnia prevalence. In addition, the sociodemographic characteristics of people attending primary care with insomnia were consistent with those with self-reported insomnia, thus primary care records are a valuable data source for studying risk factors for insomnia. Further studies should replicate our findings in other populations and examine ways to increase discussions about sleep health in primary care.

Mammographic density mediates the protective effect of early-life body size on breast cancer risk.

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%-79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.

Adolescent chronic sleep restriction promotes alcohol drinking in adulthood: evidence from epidemiological and preclinical data.

Epidemiological investigations have indicated that insufficient sleep is prevalent among adolescents, posing a globally underestimated health risk. Sleep fragmentation and sleep loss during adolescence have been linked to concurrent emotional dysregulation and an increase in impulsive, risk-taking behaviors, including a higher likelihood of substance abuse. Among the most widely used substances, alcohol stands as the primary risk factor for deaths and disability among individuals aged 15-49 worldwide. While the association between sleep loss and alcohol consumption during adolescence is well documented, the extent to which prior exposure to sleep loss in adolescence contributes to heightened alcohol use later in adulthood remains less clearly delineated. Here, we analyzed longitudinal epidemiological data spanning 9 years, from adolescence to adulthood, including 5497 participants of the Avon Longitudinal Study of Parents And Children cohort. Sleep and alcohol measures collected from interviews and questionnaires at 15 and 24 years of age were analyzed with multivariable linear regression and a cross-lagged autoregressive path model. Additionally, we employed a controlled preclinical experimental setting to investigate the causal relationship underlying the associations found in the human study and to assess comorbid behavioral alterations. Preclinical data were collected by sleep restricting Marchigian Sardinian alcohol preferring rats (msP, n=40) during adolescence and measuring voluntary alcohol drinking concurrently and in adulthood. Polysomnography was used to validate the efficacy of the sleep restriction procedure. Behavioral tests were used to assess anxiety, risky behavior, and despair. In humans, after adjusting for covariates, we found a cross-sectional association between all sleep parameters and alcohol consumption at 15 years of age but not at 24 years. Notably, alcohol consumption (Alcohol Use Disorder Identification Test for Consumption) at 24 years was predicted by insufficient sleep at 15 years whilst alcohol drinking at 15 years could not predict sleep problems at 24. In msP rats, adolescent chronic sleep restriction escalated alcohol consumption and led to increased propensity for risk-taking behavior in adolescence and adulthood. Our findings demonstrate that adolescent insufficient sleep causally contributes to higher adult alcohol consumption, potentially by promoting risky behavior.

Cigarette Smoking and E-cigarette Use Induce Shared DNA Methylation Changes Linked to Carcinogenesis.

Tobacco use is a major modifiable risk factor for adverse health outcomes, including cancer, and elicits profound epigenetic changes thought to be associated with long-term cancer risk. While electronic cigarettes (e-cigarettes) have been advocated as harm reduction alternatives to tobacco products, recent studies have revealed potential detrimental effects, highlighting the urgent need for further research into the molecular and health impacts of e-cigarettes. Here, we applied computational deconvolution methods to dissect the cell- and tissue-specific epigenetic effects of tobacco or e-cigarette use on DNA methylation (DNAme) in over 3,500 buccal/saliva, cervical, or blood samples, spanning epithelial and immune cells at directly and indirectly exposed sites. The 535 identified smoking-related DNAme loci [cytosine-phosphate-guanine sites (CpG)] clustered into four functional groups, including detoxification or growth signaling, based on cell type and anatomic site. Loci hypermethylated in buccal epithelial cells of smokers associated with NOTCH1/RUNX3/growth factor receptor signaling also exhibited elevated methylation in cancer tissue and progressing lung carcinoma in situ lesions, and hypermethylation of these sites predicted lung cancer development in buccal samples collected from smokers up to 22 years prior to diagnosis, suggesting a potential role in driving carcinogenesis. Alarmingly, these CpGs were also hypermethylated in e-cigarette users with a limited smoking history. This study sheds light on the cell type-specific changes to the epigenetic landscape induced by smoking-related products. SIGNIFICANCE: The use of both cigarettes and e-cigarettes elicits cell- and exposure-specific epigenetic effects that are predictive of carcinogenesis, suggesting caution when broadly recommending e-cigarettes as aids for smoking cessation.

Estimating the health impact of nicotine exposure by dissecting the effects of nicotine versus non-nicotine constituents of tobacco smoke: A multivariable Mendelian randomisation study.

The detrimental health effects of smoking are well-known, but the impact of regular nicotine use without exposure to the other constituents of tobacco is less clear. Given the increasing daily use of alternative nicotine delivery systems, such as e-cigarettes, it is increasingly important to understand and separate the effects of nicotine use from the impact of tobacco smoke exposure. Using a multivariable Mendelian randomisation framework, we explored the direct effects of nicotine compared with the non-nicotine constituents of tobacco smoke on health outcomes (lung cancer, chronic obstructive pulmonary disease [COPD], forced expiratory volume in one second [FEV-1], forced vital capacity [FVC], coronary heart disease [CHD], and heart rate [HR]). We used Genome-Wide Association Study (GWAS) summary statistics from Buchwald and colleagues, the GWAS and Sequencing Consortium of Alcohol and Nicotine, the International Lung Cancer Consortium, and UK Biobank. Increased nicotine metabolism increased the risk of COPD, lung cancer, and lung function in the univariable analysis. However, when accounting for smoking heaviness in the multivariable analysis, we found that increased nicotine metabolite ratio (indicative of decreased nicotine exposure per cigarette smoked) decreases heart rate (b = -0.30, 95% CI -0.50 to -0.10) and lung function (b = -33.33, 95% CI -41.76 to -24.90). There was no clear evidence of an effect on the remaining outcomes. The results suggest that these smoking-related outcomes are not due to nicotine exposure but are caused by the other components of tobacco smoke; however, there are multiple potential sources of bias, and the results should be triangulated using evidence from a range of methodologies.

Comprehensive evaluation of smoking exposures and their interactions on DNA methylation.

BACKGROUND: Smoking impacts DNA methylation, but data are lacking on smoking-related differential methylation by sex or dietary intake, recent smoking cessation (<1 year), persistence of differential methylation from in utero smoking exposure, and effects of environmental tobacco smoke (ETS). METHODS: We meta-analysed data from up to 15,014 adults across 5 cohorts with DNA methylation measured in blood using Illumina's EPIC array for current smoking (2560 exposed), quit < 1 year (500 exposed), in utero (286 exposed), and ETS exposure (676 exposed). We also evaluated the interaction of current smoking with sex or diet (fibre, folate, and vitamin C). FINDINGS: Using false discovery rate (FDR < 0.05), 65,857 CpGs were differentially methylated in relation to current smoking, 4025 with recent quitting, 594 with in utero exposure, and 6 with ETS. Most current smoking CpGs attenuated within a year of quitting. CpGs related to in utero exposure in adults were enriched for those previously observed in newborns. Differential methylation by current smoking at 4-71 CpGs may be modified by sex or dietary intake. Nearly half (35-50%) of differentially methylated CpGs on the 450 K array were associated with blood gene expression. Current smoking and in utero smoking CpGs implicated 3049 and 1067 druggable targets, including chemotherapy drugs. INTERPRETATION: Many smoking-related methylation sites were identified with Illumina's EPIC array. Most signals revert to levels observed in never smokers within a year of cessation. Many in utero smoking CpGs persist into adulthood. Smoking-related druggable targets may provide insights into cancer treatment response and shared mechanisms across smoking-related diseases. FUNDING: Intramural Research Program of the National Institutes of Health, Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, Chief Scientist Office of the Scottish Government Health Directorates and the Scottish Funding Council, Medical Research Council UK and the Wellcome Trust.

Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes.

BACKGROUND: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. METHODS: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. RESULTS: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. CONCLUSIONS: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. FUNDING: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust.

Ultra-processed foods, adiposity and risk of head and neck cancer and oesophageal adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition study: a mediation analysis.

PURPOSE: To investigate the role of adiposity in the associations between ultra-processed food (UPF) consumption and head and neck cancer (HNC) and oesophageal adenocarcinoma (OAC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: Our study included 450,111 EPIC participants. We used Cox regressions to investigate the associations between the consumption of UPFs and HNC and OAC risk. A mediation analysis was performed to assess the role of body mass index (BMI) and waist-to-hip ratio (WHR) in these associations. In sensitivity analyses, we investigated accidental death as a negative control outcome. RESULTS: During a mean follow-up of 14.13 ± 3.98 years, 910 and 215 participants developed HNC and OAC, respectively. A 10% g/d higher consumption of UPFs was associated with an increased risk of HNC (hazard ratio [HR] = 1.23, 95% confidence interval [CI] 1.14-1.34) and OAC (HR = 1.24, 95% CI 1.05-1.47). WHR mediated 5% (95% CI 3-10%) of the association between the consumption of UPFs and HNC risk, while BMI and WHR, respectively, mediated 13% (95% CI 6-53%) and 15% (95% CI 8-72%) of the association between the consumption of UPFs and OAC risk. UPF consumption was positively associated with accidental death in the negative control analysis. CONCLUSIONS: We reaffirmed that higher UPF consumption is associated with greater risk of HNC and OAC in EPIC. The proportion mediated via adiposity was small. Further research is required to investigate other mechanisms that may be at play (if there is indeed any causal effect of UPF consumption on these cancers).

Correlations in sleeping patterns and circadian preference between spouses.

Spouses may affect each other's sleeping behaviour. In 47,420 spouse-pairs from the UK Biobank, we found a weak positive phenotypic correlation between spouses for self-reported sleep duration (r = 0.11; 95% CI = 0.10, 0.12) and a weak inverse correlation for chronotype (diurnal preference) (r = -0.11; -0.12, -0.10), which replicated in up to 127,035 23andMe spouse-pairs. Using accelerometer data on 3454 UK Biobank spouse-pairs, the correlation for derived sleep duration was similar to self-report (r = 0.12; 0.09, 0.15). Timing of diurnal activity was positively correlated (r = 0.24; 0.21, 0.27) in contrast to the inverse correlation for chronotype. In Mendelian randomization analysis, positive effects of sleep duration (mean difference=0.13; 0.04, 0.23 SD per SD) and diurnal activity (0.49; 0.03, 0.94) were observed, as were inverse effects of chronotype (-0.15; -0.26, -0.04) and snoring (-0.15; -0.27, -0.04). Findings support the notion that an individual's sleep may impact that of their partner, promoting opportunities for sleep interventions at the family-level.

Methodological approaches, challenges, and opportunities in the application of Mendelian randomisation to lifecourse epidemiology: A systematic literature review.

Diseases diagnosed in adulthood may have antecedents throughout (including prenatal) life. Gaining a better understanding of how exposures at different stages in the lifecourse influence health outcomes is key to elucidating the potential benefits of disease prevention strategies. Mendelian randomisation (MR) is increasingly used to estimate causal effects of exposures across the lifecourse on later life outcomes. This systematic literature review explores MR methods used to perform lifecourse investigations and reviews previous work that has utilised MR to elucidate the effects of factors acting at different stages of the lifecourse. We conducted searches in PubMed, Embase, Medline and MedRXiv databases. Thirteen methodological studies were identified. Four studies focused on the impact of time-varying exposures in the interpretation of "standard" MR techniques, five presented methods for repeat measures of the same exposure, and four described methodological approaches to handling multigenerational exposures. A further 127 studies presented the results of an applied research question. Over half of these estimated effects in a single generation and were largely confined to the exploration of questions regarding body composition. The remaining mostly estimated maternal effects. There is a growing body of research focused on the development and application of MR methods to address lifecourse research questions. The underlying assumptions require careful consideration and the interpretation of results rely on select conditions. Whilst we do not advocate for a particular strategy, we encourage practitioners to make informed decisions on how to approach a research question in this field with a solid understanding of the limitations present and how these may be affected by the research question, modelling approach, instrument selection, and data availability.

Investigating the causal interplay between sleep traits and risk of acute myocardial infarction: a Mendelian randomization study.

BACKGROUND: Few studies have investigated the joint effects of sleep traits on the risk of acute myocardial infarction (AMI). No previous study has used factorial Mendelian randomization (MR) which may reduce confounding, reverse causation, and measurement error. Thus, it is prudent to study joint effects using robust methods to propose sleep-targeted interventions which lower the risk of AMI. METHODS: The causal interplay between combinations of two sleep traits (including insomnia symptoms, sleep duration, or chronotype) on the risk of AMI was investigated using factorial MR. Genetic risk scores for each sleep trait were dichotomized at their median in UK Biobank (UKBB) and the second survey of the Trøndelag Health Study (HUNT2). A combination of two sleep traits constituting 4 groups were analyzed to estimate the risk of AMI in each group using a 2×2 factorial MR design. RESULTS: In UKBB, participants with high genetic risk for both insomnia symptoms and short sleep had the highest risk of AMI (hazard ratio (HR) 1.10; 95% confidence interval (CI) 1.03, 1.18), although there was no evidence of interaction (relative excess risk due to interaction (RERI) 0.03; 95% CI -0.07, 0.12). These estimates were less precise in HUNT2 (HR 1.02; 95% CI 0.93, 1.13), possibly due to weak instruments and/or small sample size. Participants with high genetic risk for both a morning chronotype and insomnia symptoms (HR 1.09; 95% CI 1.03, 1.17) and a morning chronotype and short sleep (HR 1.11; 95% CI 1.04, 1.19) had the highest risk of AMI in UKBB, although there was no evidence of interaction (RERI 0.03; 95% CI -0.06, 0.12; and RERI 0.05; 95% CI -0.05, 0.14, respectively). Chronotype was not available in HUNT2. CONCLUSIONS: This study reveals no interaction effects between sleep traits on the risk of AMI, but all combinations of sleep traits increased the risk of AMI except those with long sleep. This indicates that the main effects of sleep traits on AMI are likely to be independent of each other.

Establishing the relationships between adiposity and reproductive factors: a multivariable Mendelian randomization analysis.

BACKGROUND: Few studies have investigated associations between adiposity and reproductive factors using causal methods, both of which have a number of consequences on women's health. Here we assess whether adiposity at different points in the lifecourse affects reproductive factors differently and independently, and the plausibility of the impact of reproductive factors on adiposity. METHODS: We used genetic data from UK Biobank (273,238 women) and other consortia (EGG, GIANT, ReproGen and SSGAC) for eight reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age first had sexual intercourse and lifetime number of sexual partners, and two adiposity traits: childhood and adulthood body size. We applied multivariable Mendelian randomization to account for genetic correlation and to estimate the causal effects of childhood and adulthood adiposity, independently of each other, on reproductive factors. Additionally, we estimated the effects of reproductive factors, independently of other relevant reproductive factors, on adulthood adiposity. RESULTS: We found a higher childhood body size leads to an earlier age at menarche, and an earlier age at menarche leads to a higher adulthood body size. Furthermore, we find contrasting and independent effects of childhood and adulthood body size on age at first birth (beta 0.22 SD (95% confidence interval: 0.14, 0.31) vs - 2.49 (- 2.93, - 2.06) per 1 SD increase), age at last birth (0.13 (0.06,0.21) vs - 1.86 (- 2.23, - 1.48) per 1 SD increase), age at menopause (0.17 (0.09, 0.25) vs - 0.99 (- 1.39, - 0.59) per 1 SD increase), and likelihood of having children (Odds ratio 0.97 (0.95, 1.00) vs 1.20 (1.06, 1.37) per 1 SD increase). CONCLUSIONS: Our findings demonstrate the importance of considering a lifecourse approach when investigating the inter-relationships between adiposity measures and reproductive events, as well as the use of 'age specific' genetic instruments when evaluating lifecourse hypotheses in a Mendelian randomization framework.

The mediating role of mammographic density in the protective effect of early-life adiposity on breast cancer risk: a multivariable Mendelian randomization study.

Observational studies suggest that mammographic density (MD) may have a role in the unexplained protective effect of childhood adiposity on breast cancer risk. Here, we investigated a complex and interlinked relationship between puberty onset, adiposity, MD, and their effects on breast cancer using Mendelian randomization (MR). We estimated the effects of childhood and adulthood adiposity, and age at menarche on MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)) using MR and multivariable MR (MVMR), allowing us to disentangle their total and direct effects. Next, we examined the effect of MD on breast cancer risk, including risk of molecular subtypes, and accounting for genetic pleiotropy. Finally, we used MVMR to evaluate whether the protective effect of childhood adiposity on breast cancer was mediated by MD. Childhood adiposity had a strong inverse effect on mammographic DA, while adulthood adiposity increased NDA. Later menarche had an effect of increasing DA and PD, but when accounting for childhood adiposity, this effect attenuated to the null. DA and PD had a risk-increasing effect on breast cancer across all subtypes. The MD single-nucleotide polymorphism (SNP) estimates were extremely heterogeneous, and examination of the SNPs suggested different mechanisms may be linking MD and breast cancer. Finally, MR mediation analysis estimated that 56% (95% CIs [32% - 79%]) of the childhood adiposity effect on breast cancer risk was mediated via DA. In this work, we sought to disentangle the relationship between factors affecting MD and breast cancer. We showed that higher childhood adiposity decreases mammographic DA, which subsequently leads to reduced breast cancer risk. Understanding this mechanism is of great importance for identifying potential targets of intervention, since advocating weight gain in childhood would not be recommended.

Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization.

A recent World Health Organization report states that at least 40% of all cancer cases may be preventable, with smoking, alcohol consumption, and obesity identified as three of the most important modifiable lifestyle factors. Given the significant decline in smoking rates, particularly within developed countries, other potentially modifiable risk factors for head and neck cancer warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes (T2D) and hypertension have been associated with head and neck cancer risk in multiple observational studies. However, adiposity has also been correlated with smoking, with bias, confounding or reverse causality possibly explaining these findings. To overcome the challenges of observational studies, we conducted two-sample Mendelian randomization (inverse variance weighted [IVW] method) using genetic variants which were robustly associated with adiposity, glycaemic and blood pressure traits in genome-wide association studies (GWAS). Outcome data were taken from the largest available GWAS of 6034 oral and oropharyngeal cases, with 6585 controls. We found limited evidence of a causal effect of genetically proxied body mass index (BMI; OR IVW = 0.89, 95% CI 0.72-1.09, p = 0.26 per 1 standard deviation in BMI [4.81kg/m2]) on oral and oropharyngeal cancer risk. Similarly, there was limited evidence for related traits including T2D and hypertension. Small effects cannot be excluded given the lack of power to detect them in currently available GWAS.

Self-reported insomnia symptoms, sleep duration, chronotype and the risk of acute myocardial infarction (AMI): a prospective study in the UK Biobank and the HUNT Study.

Insomnia and short/long sleep duration increase the risk of AMI, but their interaction with each other or with chronotype is not well known. We investigated the prospective joint associations of any two of these sleep traits on risk of AMI. We included 302 456 and 31 091 participants without past AMI episodes from UK Biobank (UKBB; 2006-10) and the Trøndelag Health Study (HUNT2; 1995-97), respectively. A total of 6 833 and 2 540 incident AMIs were identified during an average 11.7 and 21.0 years follow-up, in UKBB and HUNT2, respectively. Compared to those who reported normal sleep duration (7-8 h) without insomnia symptoms, the Cox proportional hazard ratios (HRs) for incident AMI in UKBB among participants who reported normal, short and long sleep duration with insomnia symptoms were 1.07 (95% CI 0.99, 1.15), 1.16 (95% CI 1.07, 1.25) and 1.40 (95% CI 1.21, 1.63), respectively. The corresponding HRs in HUNT2 were 1.09 (95% CI 0.95, 1.25), 1.17 (95% CI 0.87, 1.58) and 1.02 (95% CI 0.85, 1.23). The HRs for incident AMI in UKBB among evening chronotypes were 1.19 (95% CI 1.10, 1.29) for those who had insomnia symptoms, 1.18 (95% CI 1.08, 1.29) for those with short sleep duration, and 1.21 (95% CI 1.07, 1.37) for those with long sleep duration, compared to morning chronotypes without another sleep symptom. The relative excess risk for incident AMI in UKBB due to interaction between insomnia symptoms and long sleep duration was 0.25 (95% CI 0.01, 0.48). Insomnia symptoms with long sleep duration may contribute more than just an additive effect of these sleep traits on the risk of AMI.