Biology subjects

Wootton, R. E.

Publications and source records attributed to Wootton, R. E..

5 recordsLinked to original sources

bioRxiv2018

MR-pheWAS with stratification and interaction: Searching for the causal effects of smoking heaviness identified an effect on facial aging

Mendelian randomization (MR) is an established approach for estimating the causal effect of an environmental exposure on a downstream outcome. The gene x environment (GxE) study design can be used within an MR framework to determine whether MR estimates may be biased if the genetic instrument affects the outcome through pathways other than via the exposure of interest (known as horizontal pleiotropy). MR phenome-wide association studies (MR-pheWAS) search for the effects of an exposure, and a recently published tool (PHESANT) means that it is now possible to do this comprehensively, across thousands of traits in UK Biobank. In this study, we introduce the GxE MR-pheWAS approach, and search for the 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. If this effect is entirely mediated by tobacco intake, we would expect to see an effect in ever smokers but not never smokers. We used PHESANT to search for the causal effects of smoking heaviness, instrumented by genetic variant rs16969968, among never and ever smokers respectively, in UK Biobank. We ranked results by: 1) strength of effect of rs16969968 among ever smokers, and 2) strength of interaction between ever and never smokers. We replicated previously established causal effects of smoking heaviness, including a detrimental effect on lung function and pulse rate. Novel results included a detrimental effect of heavier smoking on facial aging. We have demonstrated how GxE MR-pheWAS can be used to identify causal effects of an exposure, while simultaneously assessing the extent that results may be biased by horizontal pleiotropy.\n\nAuthor summaryMendelian randomization uses genetic variants associated with an exposure to investigate causality. For instance, a genetic variant that relates to how heavily a person smokes has been used to test whether smoking causally affects health outcomes. Mendelian randomization is biased if the genetic variant also affects the outcome via other pathways. We exploit additional information - that the effect of heavy smoking only occurs in people who actually smoke - to overcome this problem. By testing associations in ever and never smokers separately we can assess whether the genetic variant affects an outcome via smoking or another pathway. If the effect is entirely via smoking heaviness, we would expect to see an effect in ever but not never smokers, and this would suggest that smoking causally influences the outcome. Previous Mendelian randomization studies of smoking heaviness focused on specific outcomes - here we searched for the causal effects of smoking heaviness across over 18,000 traits. We identified previously established effects (e.g. a detrimental effect on lung function) and novel results including a detrimental effect of heavier smoking on facial aging. Our approach can be used to search for the causal effects of other exposures, where the exposure only occurs in known subsets of the population.

epidemiology↗

bioRxiv2018

The effects of age at menarche and first sexual intercourse on reproductive and behavioural outcomes: a Mendelian randomization study

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 the developmental environment. In environments characterized by harsh conditions, adopting a fast life history strategy may increase fitness. In line with this, there is evidence demonstrating that greater childhood adversity is associated with earlier age at menarche. 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 on outcomes related to reproduction, education and risky behaviour in UK Biobank (N = 114883-181,255). 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 < 0.0001). 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 results should be treated with caution. 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.

evolutionary biology↗

bioRxiv2018

Causal effects of lifetime smoking on risk for depression and schizophrenia: Evidence from a Mendelian randomisation study

BackgroundSmoking prevalence is higher amongst individuals with schizophrenia and depression compared to the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS).\n\nMethodsWe conducted a GWAS of lifetime smoking behaviour (capturing smoking duration, heaviness and cessation) in a sample of 462,690 individuals from the UK Biobank, and validated the findings via two-sample MR analyses of positive control outcomes (e.g., lung cancer). Having established the validity of our instrument, we used bi-directional two-sample Mendelian randomisation to explore its effects on schizophrenia and depression.\n\nOutcomesThere was strong evidence to suggest smoking is a causal risk factor for both schizophrenia (OR = 2.27, 95% CI = 1.67 - 3.08, P < 0.001) and depression (OR = 1.99, 95% CI = 1.71 - 2.32, P < 0.001). We also found some evidence that genetic risk for both schizophrenia and depression cause increased lifetime smoking ({beta} = 0.022, 95% CI = 0.005 - 0.038, P = 0.009; {beta}= 0.091, 95% CI = 0.027 - 0.155, P = 0.005).\n\nInterpretationThese findings suggest that the association between smoking, schizophrenia and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking for mental health.\n\nFundingThis work was supported by the Medical Research Council Integrative Epidemiology Unit, the NIHR Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSThe association between smoking and mental health (especially schizophrenia and depression) is often assumed to be the result of self-medication (for example, to alleviate symptoms). However, more recent evidence has suggested that smoking might also be a risk factor for schizophrenia and depression. This alternative direction of effect is supported by meta-analyses and previous prospective observational evidence using related individuals to control for genetic and environmental confounding. However, observational evidence cannot completely account for confounding or the possibility of reverse causation. One way to get around these problems is Mendelian randomisation (MR). Previous MR studies of smoking and mental health have not shown an effect of smoking on depression and are inconclusive for the effects of smoking on schizophrenia. However, these studies have only looked at individual aspects of smoking behaviour and some studies required stratifying participants into smokers and non-smokers, reducing power.\n\nAdded value of this studyWe have developed a novel genetic instrument for lifetime smoking exposure which can be used within a two-sample MR framework, using publicly-available GWAS summary statistics. We were therefore able to test the bi-directional association between smoking with schizophrenia and depression to see if the effects are causal. We found strong evidence to suggest that smoking is a causal risk factor for both schizophrenia and depression. There was some evidence to suggest that risk of schizophrenia and depression increases lifetime smoking (consistent with the self-medication hypothesis) but the effects were stronger for depression than schizophrenia.\n\nImplications of all the available evidenceThis study was the first to demonstrate evidence for an effect of lifetime smoking exposure on risk of schizophrenia and depression within a causal inference framework. This emphasises the detrimental public health consequences of smoking, not just for physical health, but also to mental illness.

epidemiology↗

bioRxiv2018

Schizophrenia risk and reproductive success: A Mendelian randomization study.

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 and age at first birth 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 (rg=0.002, p=0.84) or age at first birth (rg=-0.007, p=0.45). 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% 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). These results suggest that increased genetic liability for schizophrenia does not confer a reproductive advantage.

evolutionary biology↗

bioRxiv2018

Testing the causal effects between subjective wellbeing and physical health using Mendelian randomisation

ObjectivesTo investigate whether the association between subjective wellbeing (subjective happiness and life satisfaction) and physical health is causal.\n\nDesignWe conducted two-sample bidirectional Mendelian randomisation between subjective wellbeing and six measures of physical health: coronary artery disease, myocardial infarction, total cholesterol, HDL cholesterol, LDL cholesterol and body mass index (BMI).\n\nParticipantsWe used summary data from four large genome-wide association study consortia: CARDIoGRAMplusC4D for coronary artery disease and myocardial infarction; the Global Lipids Genetics Consortium for cholesterol measures; the Genetic Investigation of Anthropometric Traits consortium for BMI; and the Social Science Genetics Association Consortium for subjective wellbeing. A replication analysis was conducted using 337,112 individuals from the UK Biobank (54% female, mean age =56.87, SD=8.00 years at recruitment).\n\nMain outcome measuresCoronary artery disease, myocardial infarction, total cholesterol, HDL cholesterol, LDL cholesterol, BMI and subjective wellbeing.\n\nResultsThere was evidence of a causal effect of BMI on subjective wellbeing such that each 1 kg/m2 increase in BMI caused a 0.045 (95%CI 0.006 to 0.084, p=0.023) SD reduction in subjective wellbeing. Replication analyses provided strong evidence of an effect of BMI on satisfaction with health ({beta}=0.034 (95% CI: -0.042 to -0.026) unit decrease in health satisfaction per SD increase in BMI, p<2-16). There was no clear evidence of a causal effect between subjective wellbeing and the other physical health measures in either direction.\n\nConclusionsOur results suggest that a higher BMI lowers subjective wellbeing. Our replication analysis confirmed this finding, suggesting the effect in middle-age is driven by satisfaction with health. BMI is a modifiable determinant and therefore, our study provides further motivation to tackle the obesity epidemic because of the knock-on effects of higher BMI on subjective wellbeing.

epidemiology↗