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Low dietary folate intake has been implicated as a risk factor for depression. However, observational epidemiological studies are plagued by problems of confounding, reverse causality and measurement error. A common polymorphism (C677T) in MTHFR is associated with methyltetrahydrofolate reductase (MTHFR) activity and circulating folate and homocysteine levels and offers insights into whether the association between low folate and depression is causal. We genotyped this polymorphism in 3478 women in the British Women's Heart and Health Study. In these women, we looked at the association between genotype and three indicators of depression; ever diagnosed as depressed, currently taking antidepressants and the EuroQol mood question. We also carried out a systematic review and meta-analysis of all published studies which have looked at the association between MTHFR C677T genotype and depression. In the British Women's Heart and Health Study, we found evidence of an increased risk of ever being diagnosed as depressed in MTHFR C677T TT individuals compared with CC individuals, odds ratio (OR) 1.35(95% CI: 1.01, 1.80). Furthermore, we identified eight other studies, which have examined the association between depression and MTHFR C677T. We were able to include all of these studies in our meta-analysis together with our results, obtaining an overall summary OR of 1.36 (95% CI: 1.11, 1.67, P=0.003). Since this genotype influences the functioning of the folate metabolic pathway, these findings suggest that folate or its derivatives may be causally related to risk of depression.Molecular Psychiatry (2006) 11, 352–360. doi:10.1038/sj.mp.4001790; published online 10 January 2006 [ABSTRACT FROM AUTHOR]

To examine the association of milk consumption with insulin resistance and the metabolic syndrome.The association was examined in 4024 British women aged 60–79 who were randomly selected from primary care centres in 23 towns.Women who never drank milk had lower homeostasis model assessment insulin resistance (HOMA) scores, triglyceride concentrations and body mass indices, and higher high-density lipoprotein (HDL)-cholesterol concentrations, than those who drank milk. The age-adjusted odds ratio for the metabolic syndrome comparing non-milk drinkers with drinkers was 0.55 (0.33, 0.94), which did not attenuate with adjustment for potential confounders. Diabetes was less common in non-milk drinkers.Individuals who do not drink milk may be protected against insulin resistance and the metabolic syndrome. However, randomized controlled trials are required to establish whether milk avoidance is causally associated with these outcomes.Diabet. Med. 22, 808–811 (2005) [ABSTRACT FROM AUTHOR]

It has recently been suggested that there are substantial differences in mother–daughter and father–son associations of body mass index and obesity among contemporary UK children, but much larger studies of older cohorts have failed to find evidence of substantial sex-specific effects. We have tested this hypothesis using the Avon Longitudinal Study of Parents and Children, a large contemporary cohort. Our analyses are based on 4654 complete parent–offspring trios (2323 with male offspring and 2331 with female offspring, all aged approximately 7.5 years). We found maternal body mass index to be a little more strongly associated with female than with male offspring body mass index (β=0.18 (95% confidence interval 0.16–0.20) for females vs 0.13 (0.12, 0.15) for males). However, associations between paternal body mass index and male compared with female offspring were very similar (β=0.16 (0.14, 0.19) for females vs 0.15 (0.12, 0.17) for males). Hence, our study suggests that there is no compelling reason to integrate the belief that there are large differences in parent–offspring body mass index associations with obesity prevention strategies. [ABSTRACT FROM AUTHOR]

Objective To compare ordinary least squares (OLS) and instrumental variable (IV) estimates of the effects of COX-2 selective inhibitor non-steroidal anti-inflammatory drugs (COX-2s) relative to non-selective NSAIDs (non-selectives) on incidence of gastrointestinal (GI) bleeding, and acute myocardial infarction (MI). We test the validity of the IV estimates, and compare to estimates from randomised controlled trials (RCTs). Design Cohort study using administration data. Setting Primary care. Participants 93 562 patients aged over 65 years attending one of 104 general practices (GP) in the UK. Main outcomes GI bleeding and acute MI. Methods We use data from the UK general practice research database. Our outcomes are incident gastrointestinal bleeding and myocardial infarctions within 60, 120, 180 and 360 days of the first prescription. We estimate risk differences in outcomes using OLS and IVs, using physician prior prescribing as an IV, and compare them to RCT estimates. Results The OLS estimates suggested COX-2s were positively associated with GI bleeds, and were negatively associated with MI. Adjusted OLS estimates were attenuated. In contrast our IV estimates imply –0.43(–1.54,0.68) fewer GI bleeds per 100 people treated with COX-2s after 180 days. The IV estimates provide little evidence, −0.55(−1.2, 1.5), of a difference in MI between treatments. These are comparable to previously published IV estimates and RCT evidence. Conclusions Deriving causal treatment effects using observational health data has proven to be problematic. We demonstrate that in contrast to IV based estimates, conventional OLS methods fail to estimate casual effects as indicated by RCTs. [ABSTRACT FROM PUBLISHER]

Purpose Age‐related macular degeneration (AMD) is a progressive eye disease, with a pre‐clinical stage of age‐related maculopathy (ARM), and is the leading cause of blindness in the Western world. This study aimed to determine the population prevalence in a representative group of men (65‐83 years) and identify prospective risk factors for ARM/AMD. Methods 2348 men (45‐63 years from Speedwell, Bristol) were enlisted into a cohort study in 1979. At phase V (mean of 17.9 years follow‐up) they had retinal photographs taken which were assessed using the Wisconsin Age‐related Maculopathy Grading System. Results Data were obtained on 934 men from a potentially eligible sample of 1394 (67%). Early ARM was found in 9.2% of all men and late ARM in 0.5%; the rates increased with age. Baseline risk factors collected in 1979 that were associated with increased risk of AMD (ARM stage 2‐4) seen in 1997 were: diastolic blood pressure, C‐reactive protein, and increased consumption of lard, oils and fats whilst triglycerides were associated with a reduced risk. In multivariable analyses, elevated mean arterial pressure (OR per z‐score 1.37, 95% CI 1.04, 1.79) and fat consumption were significant predictors of increased risk, whilst triglycerides had reduced risk (OR 0.68, 95% CI 0.47, 0.99). Conclusion Whilst the prevalence of AMD was only 0.5%, almost 10% of elderly men in this UK sample were at high risk of developing AMD over the next 5 years. Our observation that elevated triglycerides is associated with reduced risk, if replicated, may provide insights into pathophysiological pathways. Early detection and possible risk factor modification should be explored to prevent ARM progression and blindness. [ABSTRACT FROM AUTHOR]

Population studies in Britain and elsewhere report deficiencies in quality of pulmonary function measurements. Methods were tested to improve the standardisation of spirometry in an epidemiological study. The spirometer provided visual feedback about acceptability and reproducibility to American Thoracic Society (ATS) standards. After 14 weeks technicians (research nurses) were given feedback and further training. Measurements were repeated in a 5% sample. Participant characteristics and technical factors (technician and technician feedback) predicted unacceptable forced expiratory volume in 1 second (FEV1) and excessively variable FEV1 and forced vital capacity (FVC). Only participant characteristics predicted unacceptable FVC. Feedback to technicians reduced test failure for FEV1 by half and excessive within-session variability by one-third. In the reproducibility study, coefficients of variation for FEV1 and FVC were 3%. Epidemiological studies can achieve standards of between-session reproducibility for spirometry comparable to levels reported by pulmonary function laboratories. Performance feedback to technicians improves the level of minimally acceptable spirometry, and within-session reproducibility. Public Health (2000) 114, 353–360 [ABSTRACT FROM AUTHOR]

Disordered eating and self-harm commonly co-occur in young people suggesting potential for shared underlying causes. Body image dissatisfaction (BID) has been recognised as a psychological correlate of body size, associated with both disordered eating and self-harm. However, the investigation into etiological pathways early in the lifecourse to provide detail on how body size and BID may foster disordered eating and self-harm remains largely unexplored. Employing data from two large population-based cohorts, the UK Biobank and the Avon Longitudinal Study of Parents And Children (ALSPAC), we conducted bidirectional Mendelian randomization (MR) to determine the causal direction of effect between genetically predicted prepubertal body size and two measures of BID indicating (i) desire to be smaller, and (ii) desire to be larger. We then used multivariable regression followed by counterfactual mediation analyses. Bidirectional MR indicated robust evidence that increased genetically predicted prepubertal body size increased desire to be smaller and decreased desire to be larger. Evidence for the reverse causal direction was negligible. These findings remained very similar across sensitivity analyses. In females and males, multivariable regression analyses demonstrated that being overweight increased the risk of disordered eating (risk ratio (RR), 95% confidence interval (CI): 1.19, 1.01 to 1.40 and 1.98, 1.28 to 3.05, respectively) and self-harm (RR, 95% CI: 1.35, 1.04 to 1.77 and 1.55, 0.86 to 2.81, respectively), while being underweight was protective against disordered eating (RR, 95% CI: 0.57, 0.40 to 0.81 and 0.81, 0.38 to 1.73, respectively). There was weak evidence of an increase in the risk of self-harm among underweight individuals. Mediation analyses indicated that the relationship between being overweight and subsequent disordered eating was largely mediated by the desire to be smaller. Our research carries important public health implications, suggesting distinct risk profiles for self-harm and disordered eating in relation to weight and body image. In addition, a better understanding of genetically predicted prepubertal BID may be valuable in the prevention and treatment of disordered eating and self-harm in adolescence., Competing Interests: Competing interests: TGR is an employee of GlaxoSmithKline outside of this research. All other authors declare no competing interests. Ethics approval and consent to participate: The UK Biobank study have obtained ethics approval from the Research Ethics Committee (REC; approval number: 11/NW/0382) and informed consent from all participants enrolled in UK Biobank. Estimates were derived using data from the UK Biobank (app #76538). Ethical approval for the study was obtained from the ALSPAC ethics and law committee and the local research ethics committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time., (© 2024. The Author(s).)

Background: The genetic and environmental aetiology of autistic and Attention Deficit Hyperactivity Disorder (ADHD) traits is known to vary spatially, but does this translate into variation in the association of specific common genetic variants?, Methods: We mapped associations between polygenic scores for autism and ADHD and their respective traits in the Avon Longitudinal Study of Parents and Children (N = 4,255-6,165) across the area surrounding Bristol, UK, and compared them to maps of environments associated with the prevalence of autism and ADHD., Results: Our results suggest genetic associations vary spatially, with consistent patterns for autistic traits across polygenic scores constructed at different p-value thresholds. Patterns for ADHD traits were more variable across thresholds. We found that the spatial distributions often correlated with known environmental influences., Conclusions: These findings shed light on the factors that contribute to the complex interplay between the environment and genetic influences in autistic and ADHD traits., (© 2024 The Author(s). Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Obese adults are often reported to have smaller brain volumes than their non-obese peers. Whether this represents evidence of accelerations in obesity-driven atrophy or is instead a legacy of developmental differences established earlier in the lifespan remains unclear. This study investigated whether early-life differences in adiposity explain differences in numerous adult brain traits commonly attributed to mid-life obesity. We used a two-sample life course Mendelian randomization study in 37 501 adults recruited to UK Biobank (UKB) imaging centres from 2014, with secondary analyses in 6996 children assessed in the Adolescent Brain Cognitive Development Study (ABCD) recruited from 2018. Exposures were genetic variants for childhood (266 variants) and adult (470 variants) adiposity derived from a genome-wide association study (GWAS) of 407 741 UKB participants. Primary outcomes were: adult total brain volume; grey matter volume, thickness and surface area; white matter volume and hyperintensities; and hippocampus, amygdala and thalamus volumes at mean age 55 in the UKB. Secondary outcomes were equivalent childhood measures collected at mean age 10 in ABCD. In the UKB, individuals who were genetically predicted to have had higher levels of adiposity in childhood were found to have multiple smaller adult brain volumes relative to intracranial volume [e.g. z-score difference in normalized brain volume per category increase in adiposity-95% confidence interval (CI) = -0.20 (-0.28, -0.12); P = 4 × 10-6]. These effect sizes remained essentially unchanged after accounting for birthweight or current adult obesity in multivariable models, whereas most observed adult effects attenuated towards null [e.g. adult z-score (95% CI) for total volume = 0.06 (-0.05, 0.17); P = 0.3]. Observational analyses in ABCD showed a similar pattern of changes already present in those with a high body mass index by age 10 [z-score (95% CI) = -0.10 (-0.13, -0.07); P = 8 × 10-13], with follow-up genetic risk score analyses providing some evidence for a causal effect already at this early age. Sensitivity analyses revealed that many of these effects were likely due to the persistence of larger head sizes established in those who gained excess weight in childhood [childhood z-score (95% CI) for intracranial volume = 0.14 (0.05, 0.23); P = 0.002], rather than smaller brain sizes per se. Our data suggest that the persistence of early-life developmental differences across the life course may underlie numerous neuroimaging traits commonly attributed to obesity-related atrophy in later life., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Genetic variants used as instruments for exposures in Mendelian randomisation (MR) analyses may have horizontal pleiotropic effects (i.e., influence outcomes via pathways other than through the exposure), which can undermine the validity of results. We examined the extent of this using smoking behaviours as an example. We first ran a phenome-wide association study in UK Biobank, using a smoking initiation genetic instrument. From the most strongly associated phenotypes, we selected those we considered could either plausibly or not plausibly be caused by smoking. We examined associations between genetic instruments for smoking initiation, smoking heaviness and lifetime smoking and these phenotypes in UK Biobank and the Avon Longitudinal Study of Parents and Children (ALSPAC). We conducted negative control analyses among never smokers, including children. We found evidence that smoking-related genetic instruments were associated with phenotypes not plausibly caused by smoking in UK Biobank and (to a lesser extent) ALSPAC. We observed associations with phenotypes among never smokers. Our results demonstrate that smoking-related genetic risk scores are associated with unexpected phenotypes that are less plausibly downstream of smoking. This may reflect horizontal pleiotropy in these genetic risk scores, and we would encourage researchers to exercise caution this when using these and genetic risk scores for other complex behavioural exposures. We outline approaches that could be taken to consider this and overcome issues caused by potential horizontal pleiotropy, for example, in genetically informed causal inference analyses (e.g., MR) it is important to consider negative control outcomes and triangulation approaches, to avoid arriving at incorrect conclusions., (© 2024 The Author(s). Genetic Epidemiology published by Wiley Periodicals LLC.)

Introduction: Knowledge of the impact of smoking on health care costs is important for establishing the external effects of smoking and for evaluating policies intended to modify this behavior. Conventional analysis of this association is difficult because of omitted variable bias, reverse causality, and measurement error., Aims and Methods: We approached these challenges using a Mendelian Randomization study design; genetic variants associated with smoking behaviors were used in instrumental variables models with inpatient hospital costs (calculated from electronic health records) as the outcome. We undertook genome-wide association studies to identify genetic variants associated with smoking initiation and a composite smoking index (reflecting cumulative health impacts of smoking) on up to 300 045 individuals (mean age: 57 years at baseline, range 39-72 years) in the UK Biobank. We followed individuals up for a mean of 6 years., Results: Genetic liability to initiate smoking (ever vs. never smoking) was estimated to increase mean per-patient annual inpatient hospital costs by £477 (95% confidence interval (CI): £187 to £766). A one-unit change in genetic liability to the composite smoking index (range: 0-4.0) increased inpatient hospital costs by £204 (95% CI: £105 to £303) per unit increase in this index. There was some evidence that the composite smoking index causal models violated the instrumental variable assumptions, and all Mendelian Randomization models were estimated with considerable uncertainty. Models conditioning on risk tolerance were not robust to weak instrument bias., Conclusions: Our findings have implications for the potential cost-effectiveness of smoking interventions., Implications: We report the first Mendelian Randomization analysis of the causal effect of smoking on health care costs. Using two smoking phenotypes, we identified substantial impacts of smoking on inpatient hospital costs, although the causal models were associated with considerable uncertainty. These results could be used alongside other evidence on the impact of smoking to evaluate the cost-effectiveness of antismoking interventions and to understand the scale of externalities associated with this behavior., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Background: Adiposity shows opposing associations with mortality within COVID-19 versus non-COVID-19 respiratory conditions. We assessed the likely causality of adiposity for mortality among intensive care patients with COVID-19 versus non-COVID-19 by examining the consistency of associations across temporal and geographical contexts where biases vary., Methods: We used data from 297 intensive care units (ICUs) in England, Wales, and Northern Ireland (Intensive Care National Audit and Research Centre Case Mix Programme). We examined associations of body mass index (BMI) with 30-day mortality, overall and by date and region of ICU admission, among patients admitted with COVID-19 (N = 34,701; February 2020-August 2021) and non-COVID-19 respiratory conditions (N = 25,205; February 2018-August 2019)., Results: Compared with non-COVID-19 patients, COVID-19 patients were younger, less often of a white ethnic group, and more often with extreme obesity. COVID-19 patients had fewer comorbidities but higher mortality. Socio-demographic and comorbidity factors and their associations with BMI and mortality varied more by date than region of ICU admission. Among COVID-19 patients, higher BMI was associated with excess mortality (hazard ratio (HR) per standard deviation (SD) = 1.05; 95% CI = 1.03-1.07). This was evident only for extreme obesity and only during February-April 2020 (HR = 1.52, 95% CI = 1.30-1.77 vs. recommended weight); this weakened thereafter. Among non-COVID-19 patients, higher BMI was associated with lower mortality (HR per SD = 0.83; 95% CI = 0.81-0.86), seen across all overweight/obesity groups and across dates and regions, albeit with a magnitude that varied over time., Conclusions: Obesity is associated with higher mortality among COVID-19 patients, but lower mortality among non-COVID-19 respiratory patients. These associations appear vulnerable to confounding/selection bias in both patient groups, questioning the existence or stability of causal effects., (© 2024. The Author(s).)

Background: Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke., Methods: We performed genome-wide association studies for subsequent major adverse cardiovascular events (MACE; n cases =51 929; n controls =39 980) and subsequent arterial ischemic stroke (AIS; n cases =45 120; n controls =46 789) after the first incident stroke within the Million Veteran Program and UK Biobank. We then used genetic variants associated with proteins (protein quantitative trait loci) to determine the effect of 1463 plasma protein abundances on subsequent MACE using Mendelian randomization., Results: Two variants were significantly associated with subsequent cardiovascular events: rs76472767 near gene RNF220 (odds ratio, 0.75 [95% CI, 0.64-0.85]; P =3.69×10 -8 ) with subsequent AIS and rs13294166 near gene LINC01492 (odds ratio, 1.52 [95% CI, 1.37-1.67]; P =3.77×10 -8 ) with subsequent MACE. Using Mendelian randomization, we identified 2 proteins with an effect on subsequent MACE after a stroke: CCL27 ([C-C motif chemokine 27], effect odds ratio, 0.77 [95% CI, 0.66-0.88]; adjusted P =0.05) and TNFRSF14 ([tumor necrosis factor receptor superfamily member 14], effect odds ratio, 1.42 [95% CI, 1.24-1.60]; adjusted P =0.006). These proteins are not associated with incident AIS and are implicated to have a role in inflammation., Conclusions: We found evidence that 2 proteins with little effect on incident stroke appear to influence subsequent MACE after incident AIS. These associations suggest that inflammation is a contributing factor to subsequent MACE outcomes after incident AIS and highlights potential novel targets., Competing Interests: Dr Tilling reports grants from the National Institute for Health and Care Research; grants from Wellcome Trust; and grants from Medical Research Council. Dr Gaunt reports grants from the National Institute for Health and Care Research (UK); grants from Biogen; grants from UK Medical Research Council; and grants from GlaxoSmithKline. Dr Gaziano reports grants from the US Department of Veterans Affairs. Dr Davey Smith reports grants from the Medical Research Council. Dr Peloso reports support from Veterans Health Administration; employment by Boston University; compensation from the American Heart Association for consultant services; and grants from the National Institutes of Health. Dr Hartley started working for Novo Nordisk after contributing to this article. The other authors report no conflicts.

Data within biobanks capture broad yet detailed indices of human variation, but biobank-wide insights can be difficult to extract due to complexity and scale. Here, using large-scale factor analysis, we distill hundreds of variables (diagnoses, assessments and survey items) into 35 latent constructs, using data from unrelated individuals with predominantly estimated European genetic ancestry in UK Biobank. These factors recapitulate known disease classifications, disentangle elements of socioeconomic status, highlight the relevance of psychiatric constructs to health and improve measurement of pro-health behaviours. We go on to demonstrate the power of this approach to clarify genetic signal, enhance discovery and identify associations between underlying phenotypic structure and health outcomes. In building a deeper understanding of ways in which constructs such as socioeconomic status, trauma, or physical activity are structured in the dataset, we emphasize the importance of considering the interwoven nature of the human phenome when evaluating public health patterns., (© 2024. The Author(s).)

Introduction: Although observational data suggest a relationship between headache and smoking, there remain questions about causality. Smoking may increase headache risk, individuals may smoke to alleviate headaches, or smoking and headache may share common risk factors. Mendelian randomization (MR) is a method that uses genetic variants as instruments for making causal inferences about an exposure and an outcome., Aims and Methods: First, we conducted logistic regression of observational data in UK Biobank assessing the association between smoking behaviors (smoking status, cigarettes per day amongst daily smokers, and lifetime smoking score) on the risk of self-reported headache (in the last month and for more than 3 months). Second, we used genetic instruments for smoking behaviors and headache (identified in independent genome-wide association studies [GWAS]) to perform bidirectional MR analysis., Results: Observationally, there is a weak association between smoking behavior and experiencing headache, with increased cigarettes per day associated with increased headache risk. In the MR analysis, genetic liability to smoking initiation and lifetime smoking increased odds of headache in the last month but not odds of headaches lasting more than 3 months. In the opposite direction, there was weak evidence for higher genetic liability to headaches decreasing the chance of quitting., Conclusions: There was weak evidence for a partially bidirectional causal relationship between smoking behaviors and headache in the last month. Given this relationship is distinct from smoking heaviness, it suggests headache and smoking may share common risk factors such as personality traits., Implications: Using MR, this study addresses the uncertainty regarding the observed relationship between headache and smoking. There was evidence for weak causal effects of smoking initiation and lifetime smoking (but not smoking heaviness) on likelihood of experiencing headache in the last month, but not over a prolonged period of more than 3 months. Those with higher genetic liability to headaches were also less likely to successfully stop smoking. This partially bidirectional causal relationship distinct from smoking heaviness suggests that observed associations are unlikely due to biological effects of tobacco smoke exposure and may be explained by shared personality traits., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Background: An increasing proportion of people have a body mass index (BMI) classified as overweight or obese and published studies disagree whether this will be beneficial or detrimental to health. We applied and evaluated two intergenerational instrumental variable methods to estimate the average causal effect of BMI on mortality in a cohort with many deaths: the parents of UK Biobank participants., Methods: In Cox regression models, parental BMI was instrumented by offspring BMI using an 'offspring as instrument' (OAI) estimation and by offspring BMI-related genetic variants in a 'proxy-genotype Mendelian randomization' (PGMR) estimation., Results: Complete-case analyses were performed in parents of 233 361 UK Biobank participants with full phenotypic, genotypic and covariate data. The PGMR method suggested that higher BMI increased mortality with hazard ratios per kg/m2 of 1.02 (95% CI: 1.01, 1.04) for mothers and 1.04 (95% CI: 1.02, 1.05) for fathers. The OAI method gave considerably higher estimates, which varied according to the parent-offspring pairing between 1.08 (95% CI: 1.06, 1.10; mother-son) and 1.23 (95% CI: 1.16, 1.29; father-daughter)., Conclusion: Both methods supported a causal role of higher BMI increasing mortality, although caution is required regarding the immediate causal interpretation of these exact values. Evidence of instrument invalidity from measured covariates was limited for the OAI method and minimal for the PGMR method. The methods are complementary for interrogating the average putative causal effects because the biases are expected to differ between them., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Ethnic differences in non-communicable disease risk have been described between individuals of South Asian and European ethnicity that are only partially explained by genetics and other known risk factors. DNA methylation is one underexplored mechanism that may explain differences in disease risk. Currently, there is little knowledge of how DNA methylation varies between South Asian and European ethnicities. This study characterised differences in blood DNA methylation between individuals of self-reported European and South Asian ethnicity from two UK-based cohorts: Southall and Brent Revisited and Born in Bradford. DNA methylation differences between ethnicities were widespread throughout the genome (n = 16,433 CpG sites, 3.4% sites tested). Specifically, 76% of associations were attributable to ethnic differences in cell composition with fewer effects attributable to smoking and genetic variation. Ethnicity-associated CpG sites were enriched for EWAS Catalog phenotypes including metabolites. This work highlights the need to consider ethnic diversity in epigenetic research., (© 2022. The Author(s).)

Objective: Conventional scoring methods for radiographic hip OA (rHOA) are subjective and show inconsistent relationships with clinical outcomes. To provide a more objective rHOA scoring method, we aimed to develop a semi-automated classifier based on DXA images and confirm its relationships with clinical outcomes., Methods: Hip DXAs in UK Biobank (UKB) were marked up for osteophyte area from which acetabular, superior and inferior femoral head osteophyte grades were derived. Joint space narrowing (JSN) grade was obtained automatically from minimum joint space width (mJSW) measures. Clinical outcomes related to rHOA comprised hip pain, hospital diagnosed OA (HES OA) and total hip replacement. Logistic regression and Cox proportional hazard modelling were used to examine associations between overall rHOA grade (0-4; derived from combining osteophyte and JSN grades) and the clinical outcomes., Results: A toal of 40 340 individuals were included in the study (mean age 63.7), of whom 81.2% had no evidence of rHOA, while 18.8% had grade ≥1 rHOA. Grade ≥1 osteophytes at each location and JSN were associated with hip pain, HES OA and total hip replacement. Associations with all three clinical outcomes increased progressively according to rHOA grade, with grade 4 rHOA and total hip replacement showing the strongest association [57.70 (38.08-87.44)]., Conclusions: Our novel semi-automated tool provides a useful means for classifying rHOA on hip DXAs, given its strong and progressive relationships with clinical outcomes. These findings suggest DXA scanning can be used to classify rHOA in large DXA-based cohort studies supporting further research, with the future potential for population-based screening., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years 1 . Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions 2,3 . Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank 4,5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation-proxies for these drivers-provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Despite early interest in the health effects of polyunsaturated fatty acids (PUFA), there is still substantial controversy and uncertainty on the evidence linking PUFA to cardiovascular diseases (CVDs). We investigated the effect of plasma concentration of omega-3 PUFA (i.e. docosahexaenoic acid (DHA) and total omega-3 PUFA) and omega-6 PUFA (i.e. linoleic acid and total omega-6 PUFA) on the risk of CVDs using Mendelian randomization., Methods: We conducted the largest genome-wide association study (GWAS) of circulating PUFA to date including a sample of 114,999 individuals and incorporated these data in a two-sample Mendelian randomization framework to investigate the involvement of circulating PUFA on a wide range of CVDs in up to 1,153,768 individuals of European ancestry (i.e. coronary artery disease, ischemic stroke, haemorrhagic stroke, heart failure, atrial fibrillation, peripheral arterial disease, aortic aneurysm, venous thromboembolism and aortic valve stenosis)., Results: GWAS identified between 46 and 64 SNPs for the four PUFA traits, explaining 4.8-7.9% of circulating PUFA variance and with mean F statistics >100. Higher genetically predicted DHA (and total omega-3 fatty acids) concentration was related to higher risk of some cardiovascular endpoints; however, these findings did not pass our criteria for multiple testing correction and were attenuated when accounting for LDL-cholesterol through multivariable Mendelian randomization or excluding SNPs in the vicinity of the FADS locus. Estimates for the relation between higher genetically predicted linoleic acid (and total omega-6) concentration were inconsistent across different cardiovascular endpoints and Mendelian randomization methods. There was weak evidence of higher genetically predicted linoleic acid being related to lower risk of ischemic stroke and peripheral artery disease when accounting by LDL-cholesterol., Conclusions: We have conducted the largest GWAS of circulating PUFA to date and the most comprehensive Mendelian randomization analyses. Overall, our Mendelian randomization findings do not support a protective role of circulating PUFA concentration on the risk of CVDs. However, horizontal pleiotropy via lipoprotein-related traits could be a key source of bias in our analyses., (© 2022. The Author(s).)

Background: Understanding the interplay between educational attainment and genetic predictors of cardiovascular risk may improve our understanding of the aetiology of educational inequalities in cardiovascular disease., Methods: In up to 320 120 UK Biobank participants of White British ancestry (mean age = 57 years, female 54%), we created polygenic scores for nine cardiovascular risk factors or diseases: alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and stroke. We estimated whether educational attainment modified genetic susceptibility to these risk factors and diseases., Results: On the additive scale, higher educational attainment reduced genetic susceptibility to higher body mass index, smoking, atrial fibrillation and type 2 diabetes, but increased genetic susceptibility to higher LDL-C and higher systolic blood pressure. On the multiplicative scale, there was evidence that higher educational attainment increased genetic susceptibility to atrial fibrillation and coronary heart disease, but little evidence of effect modification was found for all other traits considered., Conclusions: Educational attainment modifies the genetic susceptibility to some cardiovascular risk factors and diseases. The direction of this effect was mixed across traits considered and differences in associations between the effect of the polygenic score across strata of educational attainment was uniformly small. Therefore, any effect modification by education of genetic susceptibility to cardiovascular risk factors or diseases is unlikely to substantially explain the development of inequalities in cardiovascular risk., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objective: Identify whether participants with lower education are less likely to report taking statins for primary cardiovascular prevention than those with higher education, but an equivalent increase in underlying cardiovascular risk., Methods: Using data from a large prospective cohort study, UK Biobank, we calculated a QRISK3 cardiovascular risk score for 472 097 eligible participants with complete data on self-reported educational attainment and statin use (55% female participants; mean age 56 years). We used logistic regression to explore the association between (i) QRISK3 score and (ii) educational attainment on self-reported statin use. We then stratified the association between QRISK3 score and statin use, by educational attainment to test for interactions., Results: There was evidence of an interaction between QRISK3 score and educational attainment. Per unit increase in QRISK3 score, more educated individuals were more likely to report taking statins. In women with ≤7 years of schooling, a one unit increase in QRISK3 score was associated with a 7% higher odds of statin use (OR 1.07, 95% CI 1.07 to 1.07). In women with ≥20 years of schooling, a one unit increase in QRISK3 score was associated with an 14% higher odds of statin use (OR 1.14, 95% CI 1.14 to 1.15). Comparable ORs in men were 1.04 (95% CI 1.04 to 1.05) for ≤7 years of schooling and 1.08 (95% CI 1.08, 1.08) for ≥20 years of schooling., Conclusion: Per unit increase in QRISK3 score, individuals with lower educational attainment were less likely to report using statins, likely contributing to health inequalities., Competing Interests: Competing interests: DG is employed part-time by Novo Nordisk., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: 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.

Background: Preserved ratio impaired spirometry (PRISm) is defined as a FEV 1 of less than 80% predicted and a FEV 1 /forced vital capacity (FVC) ratio of 0·70 or higher. Previous research has indicated that PRISm is associated with respiratory symptoms and is a precursor of chronic obstructive pulmonary disease (COPD). However, these findings are based on relatively small selective cohorts with short follow-up. We aimed to determine the prevalence, risk factors, clinical implications, and mortality of PRISm in a large adult general population., Methods: For this cohort analysis, we used data from the UKBiobank to assess PRISm prevalence, risk factors and associated symptoms, and associated comorbidities in a large adult population. Participants with spirometry deemed acceptable by an investigator (best measure FEV 1 and FVC values) at baseline were included. Participants were excluded if they did not have acceptable spirometry or were missing data on body-mass index or smoking status. Control spirometry was defined as a FEV 1 of 80% or more predicted and a FEV 1 /FVC ratio of 0·70 or higher. Airflow obstruction was defined as a FEV 1 /FVC ratio of less than 0·70. We used multivariable regression to determine risk factors for PRISm and associated comorbidities. Individuals who lived within close proximity to an assessment centre were invited for follow-up, with repeat spirometry. Only participants who had been included at baseline were examined in follow-up. This allowed for a longitudinal analysis of PRISm over time and risk factors for transition to airflow obstruction. We also did the survival analysis for a 12-year period., Findings: Participants were recruited by UK Biobank between Dec 19, 2006, and Oct 10, 2010. We included 351 874 UK Biobank participants (189 247 women and 162 627 men) in our study, with a median follow-up of 9·0 years (IQR 8·0-10·0). 38 639 (11·0%) of 351 874 participants had PRISm at baseline. After adjustment, PRISm was strongly associated with obesity (odds ratio [OR] 2·40 [2·26-2·55], p<0·0001), current smoking (1·48 [1·36-1·62], p<0·0001), and patient reported doctor-diagnosed asthma (1·76 [1·66-1·88], p<0·0001). Other risk factors identified included female sex, being overweight, trunk fat mass, and trunk fat percentage. PRISm was strongly associated with symptoms and comorbidity including increased risk of breathlessness (adjusted OR 2·0 [95% CI 1·91-2·14], p<0·0001) and cardiovascular disease (adjusted OR 1·71 [1·64-1·83], p<0·0001 for heart attack). Longitudinal analysis showed that 241 (12·2%) of 1973 participants who had PRISm at baseline had transitioned to airflow obstruction consistent with COPD. PRISm was associated with increased all-cause mortality (adjusted hazard ratio 1·61 [95% CI 1·53-1·69], p<0·0001) versus control participants., Interpretation: PRISm was associated with breathlessness, multimorbidity, and increased risk of death, which does not seem to be explained by smoking, obesity, or existing lung disease. Although for many patients PRISm is transient, it is important to understand which individuals are at risk of progressive lung function abnormalities. Further research into the genetic, structural and functional pathophysiology of PRISm is warranted., Funding: UK Medical Research Council and University of Bristol., Competing Interests: Declaration of interests JWD declares personal fees from Chiesi, Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: High body mass index (BMI) is an important predictor of mortality but estimating underlying causality is hampered by confounding and pre-existing disease. Here, we use information from the offspring to approximate parental BMIs, with an aim to avoid biased estimation of mortality risk caused by reverse causality., Methods: The analyses were based on information on 9674 offspring-mother and 9096 offspring-father pairs obtained from the 1958 British birth cohort. Parental BMI-mortality associations were analysed using conventional methods and using offspring BMI as a proxy, or instrument, for their parents' BMI., Results: In the conventional analysis, associations between parental BMI and all-cause mortality were U-shaped (P curvature  < 0.001), while offspring BMI had linear associations with parental mortality (P trend  < 0.001, P curvature  > 0.46). Curvature was particularly pronounced for mortality from respiratory diseases and from lung cancer. Instrumental variable analyses suggested a positive association between BMI and mortality from all causes [mothers: HR per SD of BMI 1.43 (95% CI 1.21-1.69), fathers: HR 1.17 (1.00-1.36)] and from coronary heart disease [mothers: HR 1.65 (1.15-2.36), fathers: HR 1.51 (1.17-1.97)]. These were larger than HR from the equivalent conventional analyses, despite some attenuation by adjustment for social indicators and smoking., Conclusions: Analyses using offspring BMI as a proxy for parental BMI suggest that the apparent adverse consequences of low BMI are considerably overestimated and adverse consequences of overweight are underestimated in conventional epidemiological studies., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Noncognitive skills have been shown to associate with a range of health and socioeconomic outcomes. Many studies have relied on cross sectional data and have been unable to assess the longitudinal consistency of noncognitive skill measures. Using data from a UK birth cohort, we investigated a range of noncognitive skills: behavioural problems, social skills, communication, self-esteem, persistence, locus of control, empathy, impulsivity and personality. We assessed their consistency over a 17-year period throughout childhood and adolescence (age 6 months to 18 years), their genomic architecture, and their associations with socioeconomic outcomes. We found high longitudinal measurement consistency for behavioural and communication skills, but low consistency for other noncognitive skills, suggesting a high noise to signal ratio. We observed consistent non-zero heritability estimates and genetic correlations for only behavioural difficulties. Using aggregate measures of each skill over time, we found evidence of phenotypic correlations and heritability ([Formula: see text] = 0.1-0.2) for behaviour, communication, self-esteem and locus of control. Associations between noncognitive skills and educational outcomes were observed for skills measured in mid to late childhood but these were at most a third of the size of IQ-education associations. These results suggest that measures designed to capture noncognitive skills may be subject to considerable response heterogeneity or measurement error. Aggregate measures that leverage repeat responses from longitudinal data may offer researchers more reliable measures that better identify underlying noncognitive skills than cross sectional measures., (© 2021. The Author(s).)

Background: There is a wealth of literature on the observed association between childhood trauma and psychotic illness. However, the relationship between childhood trauma and psychosis is complex and could be explained, in part, by gene-environment correlation., Methods: The association between schizophrenia polygenic scores (PGS) and experiencing childhood trauma was investigated using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Norwegian Mother, Father and Child Cohort Study (MoBa). Schizophrenia PGS were derived in each cohort for children, mothers, and fathers where genetic data were available. Measures of trauma exposure were derived based on data collected throughout childhood and adolescence (0-17 years; ALSPAC) and at age 8 years (MoBa)., Results: Within ALSPAC, we found a positive association between schizophrenia PGS and exposure to trauma across childhood and adolescence; effect sizes were consistent for both child or maternal PGS. We found evidence of an association between the schizophrenia PGS and the majority of trauma subtypes investigated, with the exception of bullying. These results were comparable with those of MoBa. Within ALSPAC, genetic liability to a range of additional psychiatric traits was also associated with a greater trauma exposure., Conclusions: Results from two international birth cohorts indicate that genetic liability for a range of psychiatric traits is associated with experiencing childhood trauma. Genome-wide association study of psychiatric phenotypes may also reflect risk factors for these phenotypes. Our findings also suggest that youth at higher genetic risk might require greater resources/support to ensure they grow-up in a healthy environment.

Large studies such as UK Biobank are increasingly used for GWAS and Mendelian randomization (MR) studies. However, selection into and dropout from studies may bias genetic and phenotypic associations. We examine genetic factors affecting participation in four optional components in up to 451,306 UK Biobank participants. We used GWAS to identify genetic variants associated with participation, MR to estimate effects of phenotypes on participation, and genetic correlations to compare participation bias across different studies. 32 variants were associated with participation in one of the optional components (P < 6 × 10 -9 ), including loci with links to intelligence and Alzheimer's disease. Genetic correlations demonstrated that participation bias was common across studies. MR showed that longer educational duration, older menarche and taller stature increased participation, whilst higher levels of adiposity, dyslipidaemia, neuroticism, Alzheimer's and schizophrenia reduced participation. Our effect estimates can be used for sensitivity analysis to account for selective participation biases in genetic or non-genetic analyses.

Background: 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)., Methods: We conducted two-sample MR to explore the bi-directional effects of smoking on schizophrenia and depression. For smoking behaviour, we used (1) smoking initiation GWAS from the GSCAN consortium and (2) we conducted our own GWAS of lifetime smoking behaviour (which captures smoking duration, heaviness and cessation) in a sample of 462690 individuals from the UK Biobank. We validated this instrument using positive control outcomes (e.g. lung cancer). For schizophrenia and depression we used GWAS from the PGC consortium., Results: There was strong evidence to suggest smoking is a risk factor for both schizophrenia (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.67-3.08, p < 0.001) and depression (OR 1.99, 95% CI 1.71-2.32, p < 0.001). Results were consistent across both lifetime smoking and smoking initiation. We found some evidence that genetic liability to depression increases smoking (β = 0.091, 95% CI 0.027-0.155, p = 0.005) but evidence was mixed for schizophrenia (β = 0.022, 95% CI 0.005-0.038, p = 0.009) with very weak evidence for an effect on smoking initiation., Conclusions: These 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 on mental health.

Background and Aims: We hypothesized that a genetic risk score (GRS) for fatty liver disease influences the risk of cirrhosis and hepatocellular carcinoma (HCC). Three genetic variants (patatin-like phospholipase domain-containing protein 3 [PNPLA3] p.I148M; transmembrane 6, superfamily member 2 [TM6SF2] p.E167K; and hydroxysteroid 17-beta dehydrogenase 13 [HSD17B13] rs72613567) were combined into a risk score, ranging from 0 to 6 for risk-increasing alleles., Approach and Results: We examined the association of the risk score with plasma markers of liver disease and with cirrhosis and HCC in 110,761 individuals from Copenhagen, Denmark, and 334,691 individuals from the UK Biobank. The frequencies of risk scores of 0, 1, 2, 3, 4, and 5 or 6 were 5%, 25%, 41%, 23%, 5.5%, and 0.5%, respectively. A higher GRS was associated with an increase in plasma alanine aminotransferase (ALT) level of 26% in those with score 5 or 6 versus 0. In meta-analysis of the Copenhagen studies and the UK Biobank, individuals with scores 1, 2, 3, 4, and 5 or 6 had odds ratios (ORs) for cirrhosis of 1.6 (95% confidence interval [CI], 1.3, 1.9), 2.0 (95% CI, 1.8, 2.2), 3.1 (95% CI, 2.7, 3.5), 5.2 (95% CI, 4.2, 6.4), and 12 (95% CI, 7.7, 19), respectively, as compared with those with a score of 0. The corresponding ORs for HCC were 1.2 (95% CI, 0.9, 1.7), 1.0 (95% CI, 0.7, 1.3), 2.4 (95% CI, 1.9, 3.0), 3.3 (95% CI, 2.2, 5.0), and 29 (95% CI, 17, 51)., Conclusion: A GRS for fatty liver disease confers up to a 12-fold higher risk of cirrhosis and up to a 29-fold higher risk of HCC in individuals from the general population., (© 2020 by the American Association for the Study of Liver Diseases.)

Psychiatric disorders show phenotypic as well as genetic overlaps. There are however also marked developmental changes throughout childhood. We investigated the extent to which, for a full range of early childhood psychopathology, a general "p" factor was explained by genetic liability, as indexed by multiple different psychiatric polygenic risk scores (PRS) and whether these relationships altered with age. The sample was a UK, prospective, population-based cohort with psychopathology data at age 7 (N = 8161) and age 13 (N = 7017). PRS were generated from large published genome-wide association studies. At both ages, we found evidence for a childhood "p" factor as well as for specific factors. Schizophrenia and attention-deficit/hyperactivity disorder (ADHD) PRS were associated with this general "p" factor at both ages but depression and autism spectrum disorder (ASD) PRS were not. We also found some evidence of associations between schizophrenia, ADHD and depression PRS with specific factors, but these were less robust and there was evidence for developmental changes.

Psychiatric disorders are highly heritable and associated with a wide variety of social adversity and physical health problems. Using genetic liability (rather than phenotypic measures of disease) as a proxy for psychiatric disease risk can be a useful alternative for research questions that would traditionally require large cohort studies with long-term follow up. Here we conducted a hypothesis-free phenome-wide association study in about 330,000 participants from the UK Biobank to examine associations of polygenic risk scores (PRS) for five psychiatric disorders (major depression (MDD), bipolar disorder (BP), schizophrenia (SCZ), attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)) with 23,004 outcomes in UK Biobank, using the open-source PHESANT software package. There was evidence after multiple testing (p<2.55x10-06) for associations of PRSs with 294 outcomes, most of them attributed to associations of PRSMDD (n = 167) and PRSSCZ (n = 157) with mental health factors. Among others, we found strong evidence of association of higher PRSADHD with 1.1 months younger age at first sexual intercourse [95% confidence interval [CI]: -1.25,-0.92] and a history of physical maltreatment; PRSASD with 0.01% lower erythrocyte distribution width [95%CI: -0.013,-0.007]; PRSSCZ with 0.95 lower odds of playing computer games [95%CI:0.95,0.96]; PRSMDD with a 0.12 points higher neuroticism score [95%CI:0.111,0.135] and PRSBP with 1.03 higher odds of having a university degree [95%CI:1.02,1.03]. We were able to show that genetic liabilities for five major psychiatric disorders associate with long-term aspects of adult life, including socio-demographic factors, mental and physical health. This is evident even in individuals from the general population who do not necessarily present with a psychiatric disorder diagnosis., Competing Interests: The authors have declared that no competing interests exist.

Introduction : Susceptibility to amyotrophic lateral sclerosis (ALS) is associated with smoking in some studies, but it is not clear which aspect of smoking behavior is related. Using detailed records of lifetime smoking we investigated the relationship between smoking and ALS in a UK population. Methods : In this retrospective case-control study, smoking status was collected using environmental questionnaires from people diagnosed with ALS between 2008 and 2013 and from age, sex and geographically matched controls. Categorical measures of smoking behavior were: smoking at the time of survey and smoking initiation; continuous measures were intensity (cigarettes per day), duration (years from starting to stopping or time of survey), cigarette pack years, and comprehensive smoking index (CSI), a measure of lifetime smoking. We used logistic regression to assess the risk of ALS with different combinations of smoking variables adjusted for age at survey, gender, level of education, smoking status and alcohol initiation, selecting the best model using the Akaike Information Criterion. Results : There were 388 records with full smoking history. The best-fitting model used CSI and smoking status at the time of survey. We found a weak association between current smoking and risk of ALS, OR 3.63 (95% CI 1.02-13.9) p value 0.05. Increase in CSI score did not increase risk of ALS: OR 0.81 (95% CI 0.58-1.11) p value 0.2. Conclusion : There is weak evidence of a positive effect of current smoking on the risk of ALS which does not show dose-dependence with higher levels of lifetime smoking and maybe a false positive result.

Estimates of the marginal effect of measures of adiposity such as body mass index (BMI) on healthcare costs are important for the formulation and evaluation of policies targeting adverse weight profiles. Most estimates of this association are affected by endogeneity bias. We use a novel identification strategy exploiting Mendelian Randomization - random germline genetic variation modelled using instrumental variables - to identify the causal effect of BMI on inpatient hospital costs. Using data on over 300,000 individuals, the effect size per person per marginal unit of BMI per year varied according to specification, including £21.22 (95% confidence interval (CI): £14.35-£28.07) for conventional inverse variance weighted models to £18.85 (95% CI: £9.05-£28.65) for penalized weighted median models. Effect sizes from Mendelian Randomization models were larger in most cases than non-instrumental variable multivariable adjusted estimates (£13.47, 95% CI: £12.51-£14.43). There was little evidence of non-linearity. Within-family estimates, intended to address dynastic biases, were imprecise., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Several studies report a polygenic component of risk for Alzheimer's disease. Understanding whether this polygenic signal is associated with educational, cognitive and behavioural outcomes in children could provide an earlier window for intervention., Methods: We examined whether polygenic risk scores (PRS) at varying P-value thresholds in children from the Avon Longitudinal Study of Parents and Children were associated with academic achievement, cognitive and behavioural measures in childhood and adolescence., Results: We did not detect any evidence that the genome-wide significant PRS (5x10-8) were associated with these outcomes. PRS at the highest P-value threshold examined (P ≤ 5x10-1) were associated with lower academic achievement in adolescents (Key Stage 3; β: -0.03; 95% confidence interval: -0.05, -0.003) but the effect was attenuated when single nucleotide polymorphisms (SNPs) associated with educational attainment were removed. These PRS were associated with lower IQ (β: -0.04; 95% CI: -0.07, -0.02) at age 8 years with the effect remaining after removing SNPs associated with educational attainment., Conclusions: SNPs mediating the biological effects of Alzheimer's disease are unlikely to operate early in life. The evidence of association between PRS for Alzheimer's disease at liberal thresholds and cognitive measures suggest shared genetic pathways between Alzheimer's disease, academic achievement and cognition., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual's self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner's self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual's weekly alcohol consumption increases partner's alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10 -6 ). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.

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., Competing Interests: The authors have declared that no competing interests exist.

Background: Smoking is an important cause of mortality and recent studies have suggested that even low-intensity smoking might be associated with increased mortality. Still, smoking is associated with lower socio-economic status as well as other potential risk factors, and disease onset might motivate smoking cessation, thus residual confounding and reverse causality might bias results. We aimed to assess the evidence of a causal relationship between smoking intensity and cause-specific as well as all-cause-mortality using Mendelian randomization analyses., Methods: We included 56 019 participants from the Norwegian HUNT2 Study and 337 103 participants from UK Biobank, linked to national registry data on causes of death. We estimated associations of self-reported smoking as well as the genetic variant rs1051730 as an instrument for smoking intensity with all-cause and cause-specific mortality. We subsequently meta-analysed the results from the two cohorts., Results: Each effect allele of the rs1051730 was associated with a 9% increased hazard of all-cause mortality [95% confidence interval (CI) 6-11] among ever smokers. Effect alleles were also associated with death by neoplasms [hazard ratio (HR) 1.11, 95% CI 1.06-1.15], circulatory diseases (HR 1.06, 95% CI 1.01-1.11) and respiratory diseases (HR 1.15, 95% CI 1.05-1.26) among ever smokers. The association was stronger among ever than never smokers for all-cause mortality (p < 0.001), neoplasms (p = 0.001) and respiratory diseases (p = 0.038)., Conclusions: Our results indicate a causal effect of smoking intensity on all-cause mortality and death by neoplasms and respiratory diseases. There was weaker evidence of a causal effect of smoking intensity on death by circulatory diseases., (© The Author(s) 2019; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Despite the well-documented association between smoking and personality traits such as neuroticism and extraversion, little is known about the potential causal nature of these findings. If it were possible to unpick the association between personality and smoking, it may be possible to develop tailored smoking interventions that could lead to both improved uptake and efficacy., Methods: Recent genome-wide association studies (GWAS) have identified variants robustly associated with both smoking phenotypes and personality traits. Here we use publicly available GWAS summary statistics in addition to individual-level data from UK Biobank to investigate the link between smoking and personality. We first estimate genetic overlap between traits using LD score regression and then use bidirectional Mendelian randomisation methods to unpick the nature of this relationship., Results: We found clear evidence of a modest genetic correlation between smoking behaviours and both neuroticism and extraversion. We found some evidence that personality traits are causally linked to certain smoking phenotypes: among current smokers each additional neuroticism risk allele was associated with smoking an additional 0.07 cigarettes per day (95% CI 0.02-0.12, p = 0.009), and each additional extraversion effect allele was associated with an elevated odds of smoking initiation (OR 1.015, 95% CI 1.01-1.02, p = 9.6 × 10-7)., Conclusion: We found some evidence for specific causal pathways from personality to smoking phenotypes, and weaker evidence of an association from smoking initiation to personality. These findings could be used to inform future smoking interventions or to tailor existing schemes.

Intelligence and education are predictive of better physical and mental health, socioeconomic position (SEP), and longevity. However, these associations are insufficient to prove that intelligence and/or education cause these outcomes. Intelligence and education are phenotypically and genetically correlated, which makes it difficult to elucidate causal relationships. We used univariate and multivariable Mendelian randomization to estimate the total and direct effects of intelligence and educational attainment on mental and physical health, measures of socioeconomic position, and longevity. Both intelligence and education had beneficial total effects. Higher intelligence had positive direct effects on income and alcohol consumption, and negative direct effects on moderate and vigorous physical activity. Higher educational attainment had positive direct effects on income, alcohol consumption, and vigorous physical activity, and negative direct effects on smoking, BMI and sedentary behaviour. If the Mendelian randomization assumptions hold, these findings suggest that both intelligence and education affect health., Competing Interests: ND reports a grant for research unrelated to this work from the Global Research Awards for Nicotine Dependence (GRAND), an independent grant making body funded by Pfizer. DH, EA, ES, ID, GD No competing interests declared, (© 2019, Davies et al.)

Importance: Early-life exposures, such as prenatal maternal lifestyle, illnesses, nutritional deficiencies, toxin levels, and adverse birth events, have long been considered potential risk factors for neurodevelopmental disorders in offspring. However, maternal genetic factors could be confounding the association between early-life exposures and neurodevelopmental outcomes in offspring, which makes inferring a causal relationship problematic., Objective: To test whether maternal polygenic risk scores (PRSs) for neurodevelopmental disorders were associated with early-life exposures previously linked to the disorders., Design, Setting, and Participants: In this UK population-based cohort study, 7921 mothers with genotype data from the Avon Longitudinal Study of Parents and Children (ALSPAC) underwent testing for association of maternal PRS for attention-deficit/hyperactivity disorder (ADHD PRS), autism spectrum disorder (ASD PRS), and schizophrenia (SCZ PRS) with 32 early-life exposures. ALSPAC data collection began September 6, 1990, and is ongoing. Data were analyzed for the current study from April 1 to September 1, 2018., Exposures: Maternal ADHD PRS, ASD PRS, and SCZ PRS were calculated using discovery effect size estimates from the largest available genome-wide association study and a significance threshold of P < .05., Main Outcomes and Measures: Outcomes measured included questionnaire data on maternal lifestyle and behavior (eg, smoking, alcohol consumption, body mass index, and maternal age), maternal use of nutritional supplements and medications in pregnancy (eg, acetaminophen, iron, zinc, folic acid, and vitamins), maternal illnesses (eg, diabetes, hypertension, rheumatism, psoriasis, and depression), and perinatal factors (eg, birth weight, preterm birth, and cesarean delivery)., Results: Maternal PRSs were available from 7921 mothers (mean [SD] age, 28.5 [4.8] years). The ADHD PRS was associated with multiple prenatal factors, including infections (odds ratio [OR], 1.11; 95% CI, 1.04-1.18), use of acetaminophen during late pregnancy (OR, 1.11; 95% CI, 1.04-1.18), lower blood levels of mercury (β coefficient, -0.06; 95% CI, -0.11 to -0.02), and higher blood levels of cadmium (β coefficient, 0.07; 95% CI, 0.05-0.09). Little evidence of associations between ASD PRS or SCZ PRS and prenatal factors or of association between any of the PRSs and adverse birth events was found. Sensitivity analyses revealed consistent results., Conclusions and Relevance: These findings suggest that maternal risk alleles for neurodevelopmental disorders, primarily ADHD, are associated with some pregnancy-related exposures. These findings highlight the need to carefully account for potential genetic confounding and triangulate evidence from different approaches when assessing the effects of prenatal exposures on neurodevelopmental disorders in offspring.

Background: Children with neurodevelopmental disorders are at increased risk of developing depression. Irritability predicts depression in the general population and is common in children with neurodevelopmental disorders. Thus, it is possible that irritability in children with neurodevelopmental disorders contributes to the link with later depression. This study aimed to (a) examine the association between childhood neurodevelopmental difficulties and adolescent depression and (b) test whether irritability explains this association., Methods: Children with any neurodevelopmental difficulty at the age of 7-9 (n = 1,697) and a selected, comparison group without any neurodevelopmental difficulty (n = 3,177) were identified from a prospective, UK population-based cohort, the Avon Longitudinal Study of Parents and Children. Neurodevelopmental difficulties were defined as a score in the bottom 5% of the sample on at least one measure of cognitive ability, communication, autism spectrum symptoms, attention-deficit/hyperactivity symptoms, reading or motor coordination. The Development and Well-Being Assessment measured parent-reported child irritability at the age of 7, parent-reported adolescent depression at the age of 10 and 13, and self-reported depression at the age of 15. Depression measures were combined, deriving an outcome of major depressive disorder (MDD) in adolescence. Logistic regression examined the association between childhood neurodevelopmental difficulties and adolescent MDD, controlling for gender. Path analysis estimated the proportion of this association explained by irritability. Analyses were repeated for individual neurodevelopmental problems., Results: Childhood neurodevelopmental difficulties were associated with adolescent MDD (OR = 2.11, 95% CI = 1.24, 3.60, p = .006). Childhood irritability statistically accounted for 42% of this association. On examining each neurodevelopmental difficulty separately, autistic, communication and ADHD problems were each associated with depression, with irritability explaining 29%-51% of these links., Conclusions: Childhood irritability appears to be a key contributor to the link between childhood neurodevelopmental difficulties and adolescent MDD. High rates of irritability in children with autistic and ADHD difficulties may explain elevated rates of depression in the neurodevelopmental group., (© 2019 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: High adiposity is associated with higher risks for a variety of adverse health outcomes, including higher rates of age-adjusted mortality and increased morbidity. This has important implications for the management of healthcare systems, since the endocrinal, cardiometabolic and other changes associated with increased adiposity may be associated with substantial healthcare costs., Methods: We studied the association between various measures of adiposity and inpatient hospital costs through record linkage between UK Biobank and records of inpatient care in England and Wales. UK Biobank is a large prospective cohort study that aimed to recruit men and women aged between 40 and 69 from 2006 to 2010. We applied generalised linear models to cost per person year to estimate the marginal effect of adiposity, and average adjusted predicted costs of adiposity., Results: Valid cost and body mass index (BMI) data from 457,689 participants were available for inferential analysis. Some 54.4% of individuals included in the analysis sample had positive inpatient healthcare costs over the period of follow-up. Median hospital costs per person-year of follow-up were £89, compared to mean costs of £481. Mean BMI overall was 27.4 kg/m 2 (standard deviation 4.8). The marginal effect of a unit increase in BMI was £13.61 (99% confidence interval £12.60-£14.63) per person-year of follow up. The marginal effect of a standard deviation increase in BMI was £69.20 (99% confidence interval £64.98-£73.42). The marginal effect of becoming obese was £136.35 (99% confidence interval £124.62-£148.08). Average adjusted predicted inpatient hospital costs increased almost linearly when modelled using continuous measure of adiposity. Sensitivity analysis of different scenarios did not substantially change these conclusions, although there was some evidence of attenuation of the effects of adiposity when controlling for waist-hip ratios, and when individuals who self-reported any pre-existing conditions were excluded from analysis., Conclusions: Higher adiposity is associated with higher inpatient hospital costs. Further scrutiny using causal inferential methods is warranted to establish if further public health investments are required to manage the large healthcare costs observationally associated with overweight and obesity.

Background: There is mounting evidence that our environment and lifestyle has an impact on epigenetic regulatory mechanisms, such as DNA methylation. It has been suggested that these molecular processes may mediate the effect of risk factors on disease susceptibility, although evidence in this regard has been challenging to uncover. Using genetic variants as surrogate variables, we have used two-sample Mendelian randomization (2SMR) to investigate the potential implications of putative changes to DNA methylation levels on disease susceptibility., Methods: To illustrate our approach, we identified 412 CpG sites where DNA methylation was associated with prenatal smoking. We then applied 2SMR to investigate potential downstream effects of these putative changes on 643 complex traits using findings from large-scale genome-wide association studies. To strengthen evidence of mediatory mechanisms, we used multiple-trait colocalization to assess whether DNA methylation, nearby gene expression and complex trait variation were all influenced by the same causal genetic variant., Results: We identified 22 associations that survived multiple testing (P < 1.89 × 10-7). In-depth follow-up analyses of particular note suggested that the associations between DNA methylation at the ASPSCR1 and REST/POL2RB gene regions, both linked with reduced lung function, may be mediated by changes in gene expression. We validated associations between DNA methylation and traits using independent samples from different stages across the life course., Conclusion: Our approach should prove valuable in prioritizing CpG sites that may mediate the effect of causal risk factors on disease. In-depth evaluations of findings are necessary to robustly disentangle causality from alternative explanations such as horizontal pleiotropy., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.)

The age of large-scale genome-wide association studies (GWAS) has provided us with an unprecedented opportunity to evaluate the genetic liability of complex disease using polygenic risk scores (PRS). In this study, we have analysed 162 PRS (p<5×10 -05 ) derived from GWAS and 551 heritable traits from the UK Biobank study (N = 334,398). Findings can be investigated using a web application (http:‌//‌mrcieu.‌mrsoftware.org/‌PRS‌&#95;atlas/), which we envisage will help uncover both known and novel mechanisms which contribute towards disease susceptibility. To demonstrate this, we have investigated the results from a phenome-wide evaluation of schizophrenia genetic liability. Amongst findings were inverse associations with measures of cognitive function which extensive follow-up analyses using Mendelian randomization (MR) provided evidence of a causal relationship. We have also investigated the effect of multiple risk factors on disease using mediation and multivariable MR frameworks. Our atlas provides a resource for future endeavours seeking to unravel the causal determinants of complex disease., Competing Interests: TR, SH, GH, GD No competing interests declared, (© 2019, Richardson et al.)

Mendelian randomization (MR) has been used to estimate the causal effect of body mass index (BMI) on particular traits thought to be affected by BMI. However, BMI may also be a modifiable, causal risk factor for outcomes where there is no prior reason to suggest that a causal effect exists. We performed a MR phenome-wide association study (MR-pheWAS) to search for the causal effects of BMI in UK Biobank (n = 334 968), using the PHESANT open-source phenome scan tool. A subset of identified associations were followed up with a formal two-stage instrumental variable analysis in UK Biobank, to estimate the causal effect of BMI on these phenotypes. Of the 22 922 tests performed, our MR-pheWAS identified 587 associations below a stringent P value threshold corresponding to a 5% estimated false discovery rate. These included many previously identified causal effects, for instance, an adverse effect of higher BMI on risk of diabetes and hypertension. We also identified several novel effects, including protective effects of higher BMI on a set of psychosocial traits, identified initially in our preliminary MR-pheWAS in circa 115,000 UK Biobank participants and replicated in a different subset of circa 223,000 UK Biobank participants. Our comprehensive MR-pheWAS identified potential causal effects of BMI on a large and diverse set of phenotypes. This included both previously identified causal effects, and novel effects such as a protective effect of higher BMI on feelings of nervousness., Competing Interests: Dr Gaunt is currently conducting unrelated precompetitive research sponsored by GlaxoSmithKline and Biogen. All other authors have declared that no competing interests exist.

Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10 -8 ), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10 -5 ). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10 -6 ), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.