Whether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We first investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in 1 s (FEV1) in UK Biobank (n = 321,047) by using two-sample Mendelian randomization (MR) and then replicated this investigation in the SpiroMeta Consortium (n = 79,055). Second, we used two-step MR to investigate whether DNA methylation mediates the effect of smoking on FEV1. Lastly, we evaluated the presence of horizontal pleiotropy and assessed whether there is any evidence for shared causal genetic variants between lung function, DNA methylation, and gene expression by using a multiple-trait colocalization ("moloc") framework. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p < 1.2 × 10-4). Replication analysis supported a causal effect at three CpGs (cg21201401 [LIME1 and ZGPAT], cg19758448 [PGAP3], and cg12616487 [EML3 and AHNAK] [p < 0.0028]). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites might influence lung function via effects on smoking. By using "moloc", we found evidence of shared causal variants between lung function, gene expression, and DNA methylation. These findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although larger, tissue-specific datasets are required to confirm these results.

Heavy alcohol consumption often co-occurs with mental health problems; this could be due to confounding, shared biological mechanisms, or causal effects. Polygenic risk scores (PRS) for alcohol use can be used to explore this association at critical life stages.

Coffee consumption has been associated with several adverse pregnancy outcomes, although data from randomized-controlled trials are lacking. We investigate whether there is a causal relationship between coffee consumption and miscarriage, stillbirth, birthweight, gestational age and pre-term birth using Mendelian randomization (MR).

Multimorbidity, typically defined as having two or more long-term health conditions, is associated with reduced wellbeing and life expectancy. Understanding the determinants of multimorbidity, including whether they are causal, may help with the design and prioritisation of prevention interventions. This study seeks to assess the causality of education, BMI, smoking and alcohol as determinants of multimorbidity, and the degree to which BMI, smoking and alcohol mediate differences in multimorbidity by level of education.

There is substantial variation in the timing of significant reproductive life events such as menarche and first sexual intercourse. Life history theory explains this variation as an adaptive response to an individual's environment and it is important to examine how traits within life history strategies affect each other. Here we applied Mendelian randomization (MR) methods to investigate whether there is a causal effect of variation in age at menarche and age at first sexual intercourse (markers or results of exposure to early life adversity) on outcomes related to reproduction, education and risky behaviour in UK Biobank (N = 114 883-181 255). Our results suggest that earlier age at menarche affects some traits that characterize life history strategies including earlier age at first and last birth, decreased educational attainment, and decreased age at leaving education (for example, we found evidence for a 0.26 year decrease in age at first birth per year decrease in age at menarche, 95% confidence interval: -0.34 to -0.17; p < 0.001). We find no clear evidence of effects of age at menarche on other outcomes, such as risk taking behaviour. Age at first sexual intercourse was also related to many life history outcomes, although there was evidence of horizontal pleiotropy which violates an assumption of MR and we therefore cannot infer causality from this analysis. Taken together, these results highlight how MR can be applied to test predictions of life history theory and to better understand determinants of health and social behaviour.

Previous literature has demonstrated a strong association between cigarette smoking, suicidal ideation and suicide attempts. This association has not previously been examined in a causal inference framework and could have important implications for suicide prevention strategies.

Previous studies have found increased smoking prevalence amongst adults with anorexia nervosa (AN) compared to the general population. The current investigation explored bidirectional associations between AN and smoking behaviour (initiation and heaviness), to address questions surrounding causation. In Study One, logistic regression models with variance robust standard errors assessed longitudinal associations between AN and smoking, using data from adolescent participants of the Avon Longitudinal Study of Parents and Children (N = 5100). In Study Two, two-sample Mendelian randomisation (MR) tested possible causal effects using summary statistics from publicly available genome-wide association studies (GWAS). Study One provided no clear evidence for a predictive effect of AN on subsequent smoking behaviour, or for smoking heaviness/initiation predicting later AN. MR findings did not support causal effects between AN and smoking behaviour, in either direction. Findings do not support predictive or causal effects between AN and smoking behaviour. Previously reported associations may have been vulnerable to confounding, highlighting the possibility of smoking and AN sharing causal risk factors.

Mercury is highly toxic metal found in trace quantities in common foods. There is concern that exposure during pregnancy could impair infant development. Epidemiological evidence is mixed, but few studies have examined postnatal growth. Differences in nutrition, exposures, and the living environment after birth may make it easier to detect a negative impact from mercury toxicity on infant growth. This study includes 544 mother-child pairs from the Avon Longitudinal Study of Parents and Children. Blood mercury was measured in early pregnancy and infant weight at 10 intervals between 4 and 61 months. Mixed-effect models were used to estimate the change in infant weight associated with prenatal mercury exposure. The estimated difference in monthly weight gain was -0.02 kg per 1 standard deviation increase in Hg (95% confidence intervals: -0.10 to 0.06 kg). When restricted to the 10th decile of Hg, the association with weight at each age level was consistently negative but with wide confidence intervals. The lack of evidence for an association may indicate that at Hg levels in this cohort (median 1.9 µg/L) there is minimal biological impact, and the effect is too small to be either clinically relevant or detectable.

Harmful alcohol use is a leading cause of premature death and is associated with age-related disease. Biological ageing is highly variable between individuals and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (derived from DNA methylation or brain structural measures) may be clinically relevant. Here, we investigated the relationships between alcohol phenotypes and both brain and DNA methylation age estimates. First, using data from UK Biobank and Generation Scotland, we tested the association between alcohol consumption (units/week) or hazardous use (Alcohol Use Disorders Identification Test [AUDIT] scores) and accelerated brain and epigenetic ageing in 20,258 and 8051 individuals, respectively. Second, we used Mendelian randomisation (MR) to test for a causal effect of alcohol consumption levels and alcohol use disorder (AUD) on biological ageing. Alcohol use showed a consistent positive association with higher predicted brain age (AUDIT-C: β = 0.053, p = 3.16 × 10-13 ; AUDIT-P: β = 0.052, p = 1.6 × 10-13 ; total AUDIT score: β = 0.062, p = 5.52 × 10-16 ; units/week: β = 0.078, p = 2.20 × 10-16 ), and two DNA methylation-based estimates of ageing, GrimAge (units/week: β = 0.053, p = 1.48 × 10-7 ) and PhenoAge (units/week: β = 0.077, p = 2.18x10-10 ). MR analyses revealed limited evidence for a causal effect of AUD on accelerated brain ageing (β = 0.118, p = 0.044). However, this result should be interpreted cautiously as the significant effect was driven by a single genetic variant. We found no evidence for a causal effect of alcohol consumption levels on accelerated biological ageing. Future studies investigating the mechanisms associating alcohol use with accelerated biological ageing are warranted.

Background Education is inversely associated with cardiovascular disease (CVD). Several mediators of this have been established; however, a proportion of the protective effect remains unaccounted for. Mental health is a proposed mediator, but current evidence is mixed and subject to bias from confounding factors and reverse causation. Mendelian randomization is an instrumental variable technique that uses genetic proxies for exposures and mediators to reduce such bias. Methods and Results We performed logistic regression and 2-step Mendelian randomization analyses using UK Biobank data and genetic summary statistics to investigate whether educational attainment affects risk of mental health disorders. We then performed mediation analyses to explore whether mental health disorders mediate the association between educational attainment and cardiovascular risk. Higher levels of educational attainment were associated with reduced depression, anxiety, and CVD in observational analyses (odds ratio [OR], 0.79 [95% CI, 0.77-0.81], 0.76 [95% CI, 0.73-0.79], and 0.75 [95% CI, 0.74-0.76], respectively), and Mendelian randomization analyses provided evidence of causality (OR, 0.72 [95% CI, 0.67-0.77], 0.50 [95% CI, 0.42-0.59], and 0.62 [95% CI, 0.58-0.66], respectively). Both anxiety and depression were associated with CVD in observational analyses (OR, 1.63 [95% CI, 1.49-1.79] and 1.70 [95% CI, 1.59-1.82], respectively) but only depression showed evidence of causality in the Mendelian randomization analyses (OR, 1.09; 95% CI, 1.03-1.15). An estimated 2% of the total protective effect of education on CVD was mediated by depression. Conclusions Higher levels of educational attainment protect against mental health disorders, and reduced depression accounts for a small proportion of the total protective effect of education on CVD.

Higher body mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits, and smoking is not fully understood.

To investigate the association between smoking and infertility.

Previous studies suggest an association between maternal tobacco and caffeine consumption during and outside of pregnancy and offspring mental health. We aimed to separate effects of the maternal environment (intrauterine or postnatal) from pleiotropic genetic effects.

Mendelian randomization (MR) is an established approach to evaluate the effect of an exposure on an outcome. The gene-by-environment (GxE) study design can be used to determine whether the genetic instrument affects the outcome through pathways other than via the exposure of interest (horizontal pleiotropy). MR phenome-wide association studies (MR-pheWAS) search for the effects of an exposure, and can be conducted in UK Biobank using the PHESANT package. In this proof-of-principle study, we introduce the novel GxE MR-pheWAS approach, that combines MR-pheWAS with the use of GxE interactions. This method aims to identify the presence of effects of an exposure while simultaneously investigating horizontal pleiotropy. We systematically test for the presence of causal effects of smoking heaviness-stratifying on smoking status (ever versus never)-as an exemplar. If a genetic variant is associated with smoking heaviness (but not smoking initiation), and this variant affects an outcome (at least partially) via tobacco intake, we would expect the effect of the variant on the outcome to differ in ever versus never smokers. We used PHESANT to test for the presence of effects of smoking heaviness, instrumented by genetic variant rs16969968, among never and ever smokers respectively, in UK Biobank. We ranked results by the strength of interaction between ever and never smokers. We replicated previously established effects of smoking heaviness, including detrimental effects on lung function. Novel results included a detrimental effect of heavier smoking on facial aging. We have demonstrated how GxE MR-pheWAS can be used to identify potential effects of an exposure, while simultaneously assessing whether results may be biased by horizontal pleiotropy.

Schizophrenia is a debilitating and heritable mental disorder associated with lower reproductive success. However, the prevalence of schizophrenia is stable over populations and time, resulting in an evolutionary puzzle: how is schizophrenia maintained in the population, given its apparent fitness costs? One possibility is that increased genetic liability for schizophrenia, in the absence of the disorder itself, may confer some reproductive advantage. We assessed the correlation and causal effect of genetic liability for schizophrenia with number of children, age at first birth and number of sexual partners using data from the Psychiatric Genomics Consortium and UK Biobank. Linkage disequilibrium score regression showed little evidence of genetic correlation between genetic liability for schizophrenia and number of children (r g = 0.002, p = 0.84), age at first birth (r g = -0.007, p = 0.45) or number of sexual partners (r g = 0.007, p = 0.42). Mendelian randomization indicated no robust evidence of a causal effect of genetic liability for schizophrenia on number of children (mean difference: 0.003 increase in number of children per doubling in the natural log odds ratio of schizophrenia risk, 95% confidence interval (CI): -0.003 to 0.009, p = 0.39) or age at first birth (-0.004 years lower age at first birth, 95% CI: -0.043 to 0.034, p = 0.82). We find some evidence of a positive effect of genetic liability for schizophrenia on number of sexual partners (0.165 increase in the number of sexual partners, 95% CI: 0.117-0.212, p = 5.30×10-10). These results suggest that increased genetic liability for schizophrenia does not confer a fitness advantage but does increase mating success.

Smoking prevalence is higher amongst individuals with schizophrenia and depression compared with the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS).

Initial use of drugs such as tobacco and alcohol may lead to subsequent more problematic drug use-the 'gateway' hypothesis. However, observed associations may be due to a shared underlying risk factor, such as trait impulsivity. We used bidirectional Mendelian randomization (MR) to test the gateway hypothesis.

Depression often onsets in adolescence and is associated with recurrence in adulthood. There is a need to identify and monitor depression symptoms across adolescence and into young adulthood. The short Mood and Feelings Questionnaire (sMFQ) is commonly used to measure depression symptoms in adolescence but has not been validated in young adulthood. This study aimed to (1) examine whether the sMFQ is valid in young adulthood, and (2) identify cut-points best capturing DSM-5 depression diagnosis at age 25 METHODS: The sample included participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 25 (n = 4098). Receiver Operating Characteristic analyses examined how well the self-rated sMFQ discriminates between cases and non-cases of DSM-5 Major Depressive Disorder (MDD) classified using the self-rated Development and Well Being Assessment. Sensitivity and specificity values were used to identify cut-points on the sMFQ RESULTS: The sMFQ had high accuracy for discriminating MDD cases from non-cases at age 25. The commonly used cut-point in adolescence (≥12) performed well at this age, best balancing sensitivity and specificity. However, a lower cut-point (≥10) may be appropriate when favouring sensitivity over specificity e.g., in context of screening. Sensitivity analyses suggested similar results for males and females LIMITATIONS: ALSPAC is a longitudinal population cohort that suffers from non-random attrition CONCLUSIONS: The sMFQ is a valid measure of depression in young adults in the general population. It can be used to screen for and monitor depression across adolescence and early adulthood.

This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization.

Previous observational evidence has suggested an association between smoking and inflammatory bowel disease (IBD).