Publications by authors named "George Davey Smith"

1,330 Publications

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Role of inflammation in depression and anxiety: Tests for disorder specificity, linearity and potential causality of association in the UK Biobank.

EClinicalMedicine 2021 Aug 26;38:100992. Epub 2021 Jun 26.

Department of Psychiatry, University of Cambridge, Cambridge, UK.

Background: Concentrations of C-reactive protein (CRP), interleukin 6 (IL-6) and other inflammatory markers are elevated in people with depression and anxiety compared to controls, but evidence for disorder-specificity, linearity and potential causality is sparse.

Methods: Using population-based data from up to 144,890 UK Biobank cohort participants, we tested associations of circulating CRP concentrations with depression and anxiety symptom scores and probable diagnosis, including tests for linearity, disorder-specificity and sex difference. We examined potential causality using 1-sample and 2-sample Mendelian randomisation (MR) analyses testing associations of genetically-predicted CRP concentration and IL-6 activity with depression and anxiety. The study was conducted from June 2019 to February 2021.

Findings: CRP concentration was associated with depressive and anxiety symptom scores and with probable diagnoses of depression and generalised anxiety disorder (GAD) in a dose-response fashion. These associations were stronger for depression than for anxiety, and for women than for men although less consistently. MR analyses provided consistent results suggesting that genetically predicted higher IL-6 activity was associated with increased risk for depressive symptoms, while genetically-predicted higher CRP concentration was associated with decreased risks of depressive and anxiety symptoms.

Interpretation: Altered activity of the IL-6/IL-6R pathway could be a risk factor for depression. The field now requires experimental studies of IL-6 modulation in humans and animal models to further examine causality, mechanisms and treatment potential. Such studies are also needed to elucidate mechanisms for divergent associations of genetically-predicted higher IL-6 activity (risk increasing) and higher CRP concentrations (protective) with depression/anxiety.

Funding: This research was funded in whole, or in part, by the Wellcome Trust (grant code: 201486/Z/16/Z). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This work was supported by a Data Science Award from the MQ: Transforming Mental Health (grant code: MQDS17/40) to GMK and PBJ, which also supported ZY. GMK also acknowledges funding support from the Wellcome Trust (grant code: 201486/Z/16/Z), the Medical Research Council UK (grant code: MC_PC_17213 and MR/S037675/1), and the BMA Foundation (J Moulton grant 2019). NK and SM are supported by the International Max Planck Research School of Translational Psychiatry (IMPRS-TP). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1).
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http://dx.doi.org/10.1016/j.eclinm.2021.100992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413248PMC
August 2021

Body muscle gain and markers of cardiovascular disease susceptibility in young adulthood: A cohort study.

PLoS Med 2021 Sep 9;18(9):e1003751. Epub 2021 Sep 9.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

Background: The potential benefits of gaining body muscle for cardiovascular disease (CVD) susceptibility, and how these compare with the potential harms of gaining body fat, are unknown. We compared associations of early life changes in body lean mass and handgrip strength versus body fat mass with atherogenic traits measured in young adulthood.

Methods And Findings: Data were from 3,227 offspring of the Avon Longitudinal Study of Parents and Children (39% male; recruited in 1991-1992). Limb lean and total fat mass indices (kg/m2) were measured using dual-energy X-ray absorptiometry scans performed at age 10, 13, 18, and 25 y (across clinics occurring from 2001-2003 to 2015-2017). Handgrip strength was measured at 12 and 25 y, expressed as maximum grip (kg or lb/in2) and relative grip (maximum grip/weight in kilograms). Linear regression models were used to examine associations of change in standardised measures of these exposures across different stages of body development with 228 cardiometabolic traits measured at age 25 y including blood pressure, fasting insulin, and metabolomics-derived apolipoprotein B lipids. SD-unit gain in limb lean mass index from 10 to 25 y was positively associated with atherogenic traits including very-low-density lipoprotein (VLDL) triglycerides. This pattern was limited to lean gain in legs, whereas lean gain in arms was inversely associated with traits including VLDL triglycerides, insulin, and glycoprotein acetyls, and was also positively associated with creatinine (a muscle product and positive control). Furthermore, this pattern for arm lean mass index was specific to SD-unit gains occurring between 13 and 18 y, e.g., -0.13 SD (95% CI -0.22, -0.04) for VLDL triglycerides. Changes in maximum and relative grip from 12 to 25 y were both positively associated with creatinine, but only change in relative grip was also inversely associated with atherogenic traits, e.g., -0.12 SD (95% CI -0.18, -0.06) for VLDL triglycerides per SD-unit gain. Change in fat mass index from 10 to 25 y was more strongly associated with atherogenic traits including VLDL triglycerides, at 0.45 SD (95% CI 0.39, 0.52); these estimates were directionally consistent across sub-periods, with larger effect sizes with more recent gains. Associations of lean, grip, and fat measures with traits were more pronounced among males. Study limitations include potential residual confounding of observational estimates, including by ectopic fat within muscle, and the absence of grip measures in adolescence for estimates of grip change over sub-periods.

Conclusions: In this study, we found that muscle strengthening, as indicated by grip strength gain, was weakly associated with lower atherogenic trait levels in young adulthood, at a smaller magnitude than unfavourable associations of fat mass gain. Associations of muscle mass gain with such traits appear to be smaller and limited to gains occurring in adolescence. These results suggest that body muscle is less robustly associated with markers of CVD susceptibility than body fat and may therefore be a lower-priority intervention target.
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http://dx.doi.org/10.1371/journal.pmed.1003751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428664PMC
September 2021

Estimating the influence of body mass index (BMI) on mortality using offspring BMI as an instrumental variable.

Int J Obes (Lond) 2021 Sep 8. Epub 2021 Sep 8.

MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.

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 < 0.001), while offspring BMI had linear associations with parental mortality (P < 0.001, P > 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.
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http://dx.doi.org/10.1038/s41366-021-00962-8DOI Listing
September 2021

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 Sep 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
September 2021

Mendelian Randomization Analyses Suggest Childhood Body Size Indirectly Influences End Points From Across the Cardiovascular Disease Spectrum Through Adult Body Size.

J Am Heart Assoc 2021 Sep 1;10(17):e021503. Epub 2021 Sep 1.

MRC Integrative Epidemiology Unit Population Health Sciences Bristol Medical School University of Bristol United Kingdom.

Background Obesity is associated with long-term health consequences including cardiovascular disease. Separating the independent effects of childhood and adulthood obesity on cardiovascular disease risk is challenging as children with obesity typically remain overweight throughout the lifecourse. Methods and Results This study used 2-sample univariable and multivariable Mendelian randomization to estimate the effect of childhood body size both independently and after accounting for adult body size on 12 endpoints across the cardiovascular disease disease spectrum. Univariable analyses identified strong evidence of a total effect between genetically predicted childhood body size and increased risk of atherosclerosis, atrial fibrillation, coronary artery disease, heart failure, hypertension, myocardial infarction, peripheral artery disease, and varicose veins. However, evidence of a direct effect was weak after accounting for adult body size using multivariable Mendelian randomization, suggesting that childhood body size indirectly increases risk of these 8 disease outcomes via the pathway involving adult body size. Conclusions These findings suggest that the effect of genetically predicted childhood body size on the cardiovascular disease outcomes analyzed in this study are a result of larger body size persisting into adulthood. Further research is necessary to ascertain the critical timepoints where, if ever, the detrimental impact of obesity initiated in early life begins to become immutable.
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http://dx.doi.org/10.1161/JAHA.121.021503DOI Listing
September 2021

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.

Cell 2021 Sep 26;184(18):4784-4818.e17. Epub 2021 Aug 26.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan; Department of Orthopedic Surgery, Shimane University, Shimane 693-8501, Japan.

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.
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http://dx.doi.org/10.1016/j.cell.2021.07.038DOI Listing
September 2021

Detecting heterogeneity of intervention effects using analysis and meta-analysis of differences in variance between trial arms.

Epidemiology 2021 Aug 20. Epub 2021 Aug 20.

Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol.

Background: Randomized controlled trials (RCTs) with continuous outcomes usually only examine mean differences in response between trial arms. If the intervention has heterogeneous effects, then outcome variances will also differ between arms. Power of an individual trial to assess heterogeneity is lower than the power to detect the same size of main effect.

Methods: We describe several methods for assessing differences in variance in trial arms and apply them to a single trial with individual patient data and to meta-analyses using summary data. Where individual data are available, we use regression-based methods to examine the effects of covariates on variation. We present an additional method to meta-analyze differences in variances with summary data.

Results: In the single trial there was agreement between methods, and the difference in variance was largely due to differences in prevalence of depression at baseline. In two meta-analyses, most individual trials did not show strong evidence of a difference in variance between arms, with wide confidence intervals. However, both meta-analyses showed evidence of greater variance in the control arm, and in one example this was perhaps because mean outcome in the control arm was higher.

Conclusions: Using meta-analysis, we overcame low power of individual trials to examine differences in variance using meta-analysis. Evidence of differences in variance should be followed up to identify potential effect modifiers and explore other possible causes such as varying compliance.
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http://dx.doi.org/10.1097/EDE.0000000000001401DOI Listing
August 2021

Mendelian Randomization: Concepts and Scope.

Cold Spring Harb Perspect Med 2021 Aug 23. Epub 2021 Aug 23.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, United Kingdom.

Mendelian randomization (MR) is a method of studying the causal effects of modifiable exposures (i.e., potential risk factors) on health, social, and economic outcomes using genetic variants associated with the specific exposures of interest. MR provides a more robust understanding of the influence of these exposures on outcomes because germline genetic variants are randomly inherited from parents to offspring and, as a result, should not be related to potential confounding factors that influence exposure-outcome associations. The genetic variant can therefore be used as a tool to link the proposed risk factor and outcome, and to estimate this effect with less confounding and bias than conventional epidemiological approaches. We describe the scope of MR, highlighting the range of applications being made possible as genetic data sets and resources become larger and more freely available. We outline the MR approach in detail, covering concepts, assumptions, and estimation methods. We cover some common misconceptions, provide strategies for overcoming violation of assumptions, and discuss future prospects for extending the clinical applicability, methodological innovations, robustness, and generalizability of MR findings.
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http://dx.doi.org/10.1101/cshperspect.a040501DOI Listing
August 2021

Multivariate genome-wide covariance analyses of literacy, language and working memory skills reveal distinct etiologies.

NPJ Sci Learn 2021 Aug 19;6(1):23. Epub 2021 Aug 19.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Several abilities outside literacy proper are associated with reading and spelling, both phenotypically and genetically, though our knowledge of multivariate genomic covariance structures is incomplete. Here, we introduce structural models describing genetic and residual influences between traits to study multivariate links across measures of literacy, phonological awareness, oral language, and phonological working memory (PWM) in unrelated UK youth (8-13 years, N = 6453). We find that all phenotypes share a large proportion of underlying genetic variation, although especially oral language and PWM reveal substantial differences in their genetic variance composition with substantial trait-specific genetic influences. Multivariate genetic and residual trait covariance showed concordant patterns, except for marked differences between oral language and literacy/phonological awareness, where strong genetic links contrasted near-zero residual overlap. These findings suggest differences in etiological mechanisms, acting beyond a pleiotropic set of genetic variants, and implicate variation in trait modifiability even among phenotypes that have high genetic correlations.
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http://dx.doi.org/10.1038/s41539-021-00101-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377061PMC
August 2021

Joint associations of depression, genetic susceptibility and the area of residence for coronary heart disease incidence.

J Epidemiol Community Health 2021 Aug 18. Epub 2021 Aug 18.

Department of Social Research, Population Research Unit, University of Helsinki, Helsinki, Finland.

Background: Depression is a risk factor for coronary heart disease (CHD), but less is known whether genetic susceptibility to CHD or regional-level social indicators modify this association.

Methods: Risk factors of CHD including a Polygenic Risk Score (PRS) were measured for 19 999 individuals residing in Finland in 1997, 2002, 2007 and 2012 (response rates 60%-75%). During the register-based follow-up until 2015, there were 1381 fatal and non-fatal incident CHD events. Unemployment rate, degree of urbanisation and crime rate of the municipality of residence were used as regional level social indicators. HRs were calculated using register-based antidepressant purchases as a non-reversible time-dependent covariate.

Results: Those having depression and in the highest quartile of PRS had somewhat higher CHD risk than predicted only by the main effects of depression and PRS (HR for interaction 1.53, 95% CI 0.95 to 2.45). Depression was moderately associated with CHD in high crime (HR 1.51, 95% CI 1.20 to 1.90) and weakly in low crime regions (HR 1.07, 95% CI 0.86 to 1.33; p value of interaction=0.087). Otherwise, we did not found evidence for interactions.

Conclusions: Those having both depression and high genetic susceptibility need a special attention in healthcare for CHD.
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http://dx.doi.org/10.1136/jech-2021-216451DOI Listing
August 2021

Osteophyte size and location on hip DXA scans are associated with hip pain: Findings from a cross sectional study in UK Biobank.

Bone 2021 Aug 11;153:116146. Epub 2021 Aug 11.

Musculoskeletal Research Unit, University of Bristol, UK; Medical Research Council Integrative Epidemiology Unit, University of Bristol, UK.

Objective: It remains unclear how the different features of radiographic hip osteoarthritis (rHOA) contribute to hip pain. We examined the relationship between rHOA, including its individual components, and hip pain using a novel dual-energy x-ray absorptiometry (DXA)-based method.

Methods: Hip DXAs were obtained from UK Biobank. A novel automated method obtained minimum joint space width (mJSW) from points placed around the femoral head and acetabulum. Osteophyte areas at the lateral acetabulum, superior and inferior femoral head were derived manually. Semi-quantitative measures of osteophytes and joint space narrowing (JSN) were combined to define rHOA. Logistic regression was used to examine the relationships between these variables and hip pain, obtained via questionnaires.

Results: 6807 hip DXAs were examined. rHOA was present in 353 (5.2%) individuals and was associated with hip pain [OR 2.42 (1.78-3.29)] and hospital diagnosed OA [6.01 (2.98-12.16)]. Total osteophyte area but not mJSW was associated with hip pain in mutually adjusted models [1.31 (1.23-1.39), 0.95 (0.87-1.04) respectively]. On the other hand, JSN as a categorical variable showed weak associations between grade ≥ 1 and grade ≥ 2 JSN with hip pain [1.30 (1.06-1.60), 1.80 (1.34-2.42) respectively]. Acetabular, superior and inferior femoral osteophyte areas were all independently associated with hip pain [1.13 (1.06-1.20), 1.13 (1.05-1.24), 1.10 (1.03-1.17) respectively].

Conclusion: In this cohort, the relationship between rHOA and prevalent hip pain was explained by 2-dimensional osteophyte area, but not by the apparent mJSW. Osteophytes at different locations showed important, potentially independent, associations with hip pain, possibly reflecting the contribution of distinct biomechanical pathways.
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http://dx.doi.org/10.1016/j.bone.2021.116146DOI Listing
August 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 Aug 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
August 2021

Genetic association study of childhood aggression across raters, instruments, and age.

Transl Psychiatry 2021 07 30;11(1):413. Epub 2021 Jul 30.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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http://dx.doi.org/10.1038/s41398-021-01480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324785PMC
July 2021

Cross-sectional analysis of educational inequalities in primary prevention statin use in UK Biobank.

Heart 2021 Jul 27. Epub 2021 Jul 27.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

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.
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http://dx.doi.org/10.1136/heartjnl-2021-319238DOI Listing
July 2021

Lung function, COPD and cognitive function: a multivariable and two sample Mendelian randomization study.

BMC Pulm Med 2021 Jul 22;21(1):246. Epub 2021 Jul 22.

MRC Integrative Epidemiology Unit (IEU), University of Bristol, Oakfield Grove, Bristol, BS8 2BN, UK.

Background: Observational studies show an association between reduced lung function and impaired cognition. Cognitive dysfunction influences important health outcomes and is a precursor to dementia, but treatments options are currently very limited. Attention has therefore focused on identifying modifiable risk factors to prevent cognitive decline and preserve cognition. Our objective was to determine if lung function or risk of COPD causes reduced cognitive function using Mendelian randomization (MR).

Methods: Single nucleotide polymorphisms from genome wide association studies of lung function and COPD were used as exposures. We examined their effect on general cognitive function in a sample of 132,452 individuals. We then performed multivariable MR (MVMR), examining the effect of lung function before and after conditioning for covariates.

Results: We found only weak evidence that reduced lung function (Beta - 0.002 (SE 0.02), p-value 0.86) or increased liability to COPD (- 0.008 (0.008), p-value 0.35) causes lower cognitive function. MVMR found both reduced FEV and FVC do cause lower cognitive function, but that after conditioning for height (- 0.03 (0.03), p-value 0.29 and - 0.01 (0.03) p-value 0.62, for FEV1 and FVC respectively) and educational attainment (- 0.03 (0.03) p-value 0.33 and - 0.01 (0.02), p-value 0.35) the evidence became weak.

Conclusion: We did not find evidence that reduced lung function or COPD causes reduced cognitive function. Previous observational studies are probably affected by residual confounding. Research efforts should focus on shared risk factors for reduced lung function and cognition, rather than lung function alone as a modifiable risk factor.
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http://dx.doi.org/10.1186/s12890-021-01611-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296721PMC
July 2021

Interrogating structural inequalities in COVID-19 mortality in England and Wales.

J Epidemiol Community Health 2021 Jul 20. Epub 2021 Jul 20.

Department of Public Health and Policy, University of Liverpool, Liverpool, UK.

Background: Numerous observational studies have highlighted structural inequalities in COVID-19 mortality in the UK. Such studies often fail to consider the hierarchical, spatial nature of such inequalities in their analysis, leading to the potential for bias and an inability to reach conclusions about the most appropriate structural levels for policy intervention.

Methods: We use publicly available population data on COVID-19-related mortality and all-cause mortality between March and July 2020 in England and Wales to investigate the spatial scale of such inequalities. We propose a multiscale approach to simultaneously consider three spatial scales at which processes driving inequality may act and apportion inequality between these.

Results: Adjusting for population age structure and number of local care homes we find highest regional inequality in March and June/July. We find finer grained within region inequality increased steadily from March until July. The importance of spatial context increases over the study period. No analogous pattern is visible for non-COVID-19 mortality. Higher relative deprivation is associated with increased COVID-19 mortality at all stages of the pandemic but does not explain structural inequalities.

Conclusions: Results support initial stochastic viral introduction in the South, with initially high inequality decreasing before the establishment of regional trends by June and July, prior to reported regionality of the 'second-wave'. We outline how this framework can help identify structural factors driving such processes, and offer suggestions for a long-term, locally targeted model of pandemic relief in tandem with regional support to buffer the social context of the area.
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http://dx.doi.org/10.1136/jech-2021-216666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295019PMC
July 2021

Unhealthy Behaviours and Risk of Parkinson's Disease: A Mendelian Randomisation Study.

J Parkinsons Dis 2021 Jul 15. Epub 2021 Jul 15.

Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.

Background: Tobacco smoking and alcohol intake have been identified in observational studies as potentially protective factors against developing Parkinson's disease (PD); the impact of body mass index (BMI) on PD risk is debated. Whether such epidemiological associations are causal remains unclear. Mendelian randomsation (MR) uses genetic variants to explore the effects of exposures on outcomes; potentially reducing bias from residual confounding and reverse causation.

Objective: Using MR, we examined relationships between PD risk and three unhealthy behaviours: tobacco smoking, alcohol intake, and higher BMI.

Methods: 19,924 PD cases and 2,413,087 controls were included in the analysis. We performed genome-wide association studies to identify single nucleotide polymorphisms associated with tobacco smoking, alcohol intake, and BMI. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design.

Results: Ever-smoking reduced the risk of PD (OR 0.955; 95%confidence interval [CI] 0.921-0.991; p = 0.013). Higher daily alcohol intake increased the risk of PD (OR 1.125, 95%CI 1.025-1.235; p = 0.013) and a 1 kg/m2 higher BMI reduced the risk of PD (OR 0.988, 95%CI 0.979-0.997; p = 0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments.

Conclusion: Using split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD. In contrast to observational data, alcohol consumption appeared to increase the risk of PD. Higher BMI had a protective effect on PD, but the effect was small.
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http://dx.doi.org/10.3233/JPD-202487DOI Listing
July 2021

Examining the possible causal relationship between lung function, COPD and Alzheimer's disease: a Mendelian randomisation study.

BMJ Open Respir Res 2021 Jul;8(1)

Academic Respiratory Unit, Southmead Hospital, Bristol, UK

Rationale: Large retrospective case-control studies have reported an association between chronic obstructive pulmonary disease (COPD), reduced lung function and an increased risk of Alzheimer's disease. However, it remains unclear if these diseases are causally linked, or due to shared risk factors. Conventional observational epidemiology suffers from unmeasured confounding and reverse causation. Additional analyses addressing causality are required.

Objectives: To examine a causal relationship between COPD, lung function and Alzheimer's disease.

Methods: Using two-sample Mendelian randomisation, we used single nucleotide polymorphisms (SNPs) identified in a genome wide association study (GWAS) for lung function as instrumental variables (exposure). Additionally, we used SNPs discovered in a GWAS for COPD in those with moderate to very severe obstruction. The effect of these SNPs on Alzheimer's disease (outcome) was taken from a GWAS based on a sample of 24 807 patients and 55 058 controls.

Results: We found minimal evidence for an effect of either lung function (OR: 1.02 per SD; 95% CI 0.91 to 1.13; p value 0.68) or liability for COPD on Alzheimer's disease (OR: 0.97 per SD; 95% CI 0.92 to 1.03; p value 0.40).

Conclusion: Neither reduced lung function nor liability COPD are likely to be causally associated with an increased risk of Alzheimer's, any observed association is likely due to unmeasured confounding. Scientific attention and health prevention policy may be better focused on overlapping risk factors, rather than attempts to reduce risk of Alzheimer's disease by targeting impaired lung function or COPD directly.
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http://dx.doi.org/10.1136/bmjresp-2020-000759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264898PMC
July 2021

Effects of adiposity on the human plasma proteome: observational and Mendelian randomisation estimates.

Int J Obes (Lond) 2021 Jul 5. Epub 2021 Jul 5.

Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

Background: Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins.

Methods: We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI.

Results: Observationally, BMI was associated with 1576 proteins (P < 1.4 × 10), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48-0.79, P = 1.6 × 10), FABP4 (0.64 SD per SD BMI, 95% CI 0.46-0.83, P = 6.7 × 10) and SHBG (-0.45 SD per SD BMI, 95% CI -0.65 to -0.25, P = 1.4 × 10). There was agreement in the magnitude of observational and MR estimates (R = 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease.

Conclusions: This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease.
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http://dx.doi.org/10.1038/s41366-021-00896-1DOI Listing
July 2021

Piloting the objective measurement of eating behaviour at a population scale: a nested study within the Avon Longitudinal Study of Parents and Children.

Wellcome Open Res 2020 4;5:185. Epub 2020 Aug 4.

Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.

Effective measurement and adaption of eating behaviours, such as eating speed, may improve weight loss and weight over time. We assessed whether the Mandometer, a portable weighing scale connected to a computer that generates a graph of food removal rate from the plate to which it is connected, together with photo-imaging of food, might prove an effective approach to measuring eating behaviours at large scale. We deployed the Mandometer in the home environment to measure main meals over three days of 95 21-year-old participants of the Avon Longitudinal Study of Parents and Children. We used multi-level models to describe food weight and eating speed and, as exemplar analyses, examined the relationship of eating behaviours with body mass index (BMI), dietary composition (fat content) and genotypic variation (the rs9939609 variant). Using this pilot data, we calculated the sample size required to detect differences in food weight and eating speed between groups of an exposure variable. All participants were able to use the Mandometer effectively after brief training. In exemplar analyses, evidence suggested that obese participants consumed more food than those of "normal" weight (i.e., BMI 19 to <25 kg/m ) and that A/A homozygotes (an indicator of higher weight) ate at a faster rate compared to T/T homozygotes. There was also some evidence that those with a high-fat diet consumed less food than those with a low-fat diet, but no strong evidence that individuals with medium- or high-fat diets ate at a faster rate. We demonstrated the potential for assessing eating behaviour in a short-term home setting and combining this with information in a research setting. This study may offer the opportunity to design interventions tailored for at-risk eating behaviours, offering advantages over the "one size fits all" approach of current failing obesity interventions.
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http://dx.doi.org/10.12688/wellcomeopenres.16091.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215563PMC
August 2020

Causal inference for heritable phenotypic risk factors using heterogeneous genetic instruments.

PLoS Genet 2021 Jun 22;17(6):e1009575. Epub 2021 Jun 22.

Department of Statistics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Over a decade of genome-wide association studies (GWAS) have led to the finding of extreme polygenicity of complex traits. The phenomenon that "all genes affect every complex trait" complicates Mendelian Randomization (MR) studies, where natural genetic variations are used as instruments to infer the causal effect of heritable risk factors. We reexamine the assumptions of existing MR methods and show how they need to be clarified to allow for pervasive horizontal pleiotropy and heterogeneous effect sizes. We propose a comprehensive framework GRAPPLE to analyze the causal effect of target risk factors with heterogeneous genetic instruments and identify possible pleiotropic patterns from data. By using GWAS summary statistics, GRAPPLE can efficiently use both strong and weak genetic instruments, detect the existence of multiple pleiotropic pathways, determine the causal direction and perform multivariable MR to adjust for confounding risk factors. With GRAPPLE, we analyze the effect of blood lipids, body mass index, and systolic blood pressure on 25 disease outcomes, gaining new information on their causal relationships and potential pleiotropic pathways involved.
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http://dx.doi.org/10.1371/journal.pgen.1009575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301661PMC
June 2021

The causal effects of serum lipids and apolipoproteins on kidney function: multivariable and bidirectional Mendelian-randomization analyses.

Int J Epidemiol 2021 Jun 21. Epub 2021 Jun 21.

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

Background: The causal nature of the observed associations between serum lipids and apolipoproteins and kidney function are unclear.

Methods: Using two-sample and multivariable Mendelian randomization (MR), we examined the causal effects of serum lipids and apolipoproteins on kidney function, indicated by the glomerular-filtration rate estimated using creatinine (eGFRcrea) or cystatin C (eGFRcys) and the urinary albumin-to-creatinine ratio (UACR). We obtained lipid- and apolipoprotein-associated genetic variants from the Global Lipids Genetics Consortium (n = 331 368) and UK Biobank (n = 441 016), respectively, and kidney-function markers from the Trøndelag Health Study (HUNT; n = 69 736) and UK Biobank (n = 464 207). The reverse causal direction was examined using variants associated with kidney-function markers selected from recent genome-wide association studies.

Results: There were no strong associations between genetically predicted lipid and apolipoprotein levels with kidney-function markers. Some, but inconsistent, evidence suggested a weak association of higher genetically predicted atherogenic lipid levels [indicated by low-density lipoprotein cholesterol (LDL-C), triglycerides and apolipoprotein B] with increased eGFR and UACR. For high-density lipoprotein cholesterol (HDL-C), results differed between eGFRcrea and eGFRcys, but neither analysis suggested substantial effects. We found no clear evidence of a reverse causal effect of eGFR on lipid or apolipoprotein traits, but higher UACR was associated with higher LDL-C, triglyceride and apolipoprotein B levels.

Conclusion: Our MR estimates suggest that serum lipid and apolipoprotein levels do not cause substantial changes in kidney function. A possible weak effect of higher atherogenic lipids on increased eGFR and UACR warrants further investigation. Processes leading to higher UACR may lead to more atherogenic lipid levels.
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http://dx.doi.org/10.1093/ije/dyab014DOI Listing
June 2021

Blood pressure variability and night-time dipping assessed by 24-hour ambulatory monitoring: Cross-sectional association with cardiac structure in adolescents.

PLoS One 2021 16;16(6):e0253196. Epub 2021 Jun 16.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.

Greater blood pressure (BP) is associated with greater left ventricular mass indexed to height2.7 (LVMi2.7) in adolescents. This study examined whether greater BP variability and reduced night-time dipping are associated with cardiac remodeling in a general population of adolescents. A cross-sectional analysis was undertaken in 587 UK adolescents (mean age 17.7 years; 43.1% male). BP was measured in a research clinic and using 24-hour ambulatory monitoring. We examined associations (for both systolic and diastolic BP) of: 1) clinic and 24-hour mean BP; 2) measures of 24-hour BP variability: standard deviation weighted for day/night (SDdn), variability independent of the mean (VIM) and average real variability (ARV); and 3) night-time dipping with cardiac structures. Cardiac structures were assessed by echocardiography: 1) LVMi2.7; 2) relative wall thickness (RWT); 3) left atrial diameter indexed to height (LADi) and 4) left ventricular internal diameter in diastole (LVIDD). Higher systolic BP was associated with greater LVMi2.7. Systolic and diastolic BP were associated with greater RWT. Associations were inconsistent for LADi and LVIDD. There was evidence for associations between both greater SDdn and ARV and higher RWT (per 1 SD higher diastolic ARV, mean difference in RWT was 0.13 SDs, 95% CI 0.045 to 0.21); these associations with RWT remained after adjustment for mean BP. There was no consistent evidence of associations between night-time dipping and cardiac structure. Measurement of BP variability, even in adolescents with blood pressure in the physiologic range, might benefit risk of cardiovascular remodeling assessment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253196PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208567PMC
June 2021

Associations between school enjoyment at age 6 and later educational achievement: evidence from a UK cohort study.

NPJ Sci Learn 2021 Jun 15;6(1):18. Epub 2021 Jun 15.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

Education is influenced by a broad range of factors but there has been limited research into the role that early school enjoyment plays in pupil's educational achievement. Here we used data from a UK cohort to answer three research questions. What is the association between early school enjoyment and later academic achievement? To what extent do family background factors underlie this association? Do sex differences in school enjoyment underlie sex differences in achievement? School enjoyment was self-reported in two questionnaires completed at age 6. We used multiple imputation to account for missing covariates in this study, giving an imputed sample size of 12,135. Children's school enjoyment at age 6 associated with sex and cognitive ability but not family socioeconomic background. For example, girls were twice as likely to report enjoying school than boys (OR: 1.97; 95% CI: 1.56, 2.48). School enjoyment strongly associated with later achievement in age 16 compulsory GCSE exams even after adjustment for socioeconomic background and cognitive ability; pupils who reported enjoying school scored on average 14.4 (95% CI: 6.9, 21.9) more points (equivalent to almost a 3-grade increase across all subjects) and were 29% more likely to obtain 5 + A*-C GCSE's including Maths and English (OR: 1.29; 95% CI: 0.99, 1.7) than those who did not enjoy school. These results highlight the importance of school enjoyment for educational achievement. As a potentially more modifiable factor than socioeconomic background, cognitive ability or sex, school enjoyment may represent a promising intervention target for improving educational outcomes.
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http://dx.doi.org/10.1038/s41539-021-00092-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206254PMC
June 2021

Is genetic liability to ADHD and ASD causally linked to educational attainment?

Int J Epidemiol 2021 Jun 7. Epub 2021 Jun 7.

Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK.

Background: The association patterns of Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) with educational attainment (EA) are complex; children with ADHD and ASD are at risk of poor academic outcomes, and parental EA has been associated with risk of ADHD/ASD in the offspring. Little is known on the causal links between ADHD, ASD, EA and the potential contribution of cognitive ability.

Methods: Using the latest genome-wide association studies (GWAS) summary data on ADHD, ASD and EA, we applied two-sample Mendelian randomization (MR) to assess the effects of genetic liability to ADHD and ASD on EA. Reverse direction analyses were additionally performed. Multivariable MR was performed to estimate any effects independent of cognitive ability.

Results: Genetic liability to ADHD had a negative effect on EA, independently of cognitive ability (MVMRIVW: -1.7 months of education per doubling of genetic liability to ADHD; 95% CI: -2.8 to -0.7), whereas genetic liability to ASD a positive effect (MVMRIVW: 30 days per doubling of the genetic liability to ASD; 95% CI: 2 to 53). Reverse direction analyses suggested that genetic liability to higher EA had an effect on lower risk of ADHD, independently of cognitive ability (MVMRIVWOR: 0.33 per SD increase; 95% CI: 0.26 to 0.43) and increased risk of ASD (MRIVWOR: 1.51 per SD increase; 95% CI: 1.29 to 1.77), which was partly explained by cognitive ability (MVMRIVWOR per SD increase: 1.24; 95%CI: 0.96 to 1.60).

Conclusions: Genetic liability to ADHD and ASD is likely to affect educational attainment, independently of underlying cognitive ability.
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http://dx.doi.org/10.1093/ije/dyab107DOI Listing
June 2021

Author Correction: Investigating causality in the association between vitamin D status and self-reported tiredness.

Sci Rep 2021 May 7;11(1):10243. Epub 2021 May 7.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, United Kingdom.

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http://dx.doi.org/10.1038/s41598-021-89274-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105336PMC
May 2021

Mendelian randomisation for mediation analysis: current methods and challenges for implementation.

Eur J Epidemiol 2021 May 7;36(5):465-478. Epub 2021 May 7.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Mediation analysis seeks to explain the pathway(s) through which an exposure affects an outcome. Traditional, non-instrumental variable methods for mediation analysis experience a number of methodological difficulties, including bias due to confounding between an exposure, mediator and outcome and measurement error. Mendelian randomisation (MR) can be used to improve causal inference for mediation analysis. We describe two approaches that can be used for estimating mediation analysis with MR: multivariable MR (MVMR) and two-step MR. We outline the approaches and provide code to demonstrate how they can be used in mediation analysis. We review issues that can affect analyses, including confounding, measurement error, weak instrument bias, interactions between exposures and mediators and analysis of multiple mediators. Description of the methods is supplemented by simulated and real data examples. Although MR relies on large sample sizes and strong assumptions, such as having strong instruments and no horizontally pleiotropic pathways, our simulations demonstrate that these methods are unaffected by confounders of the exposure or mediator and the outcome and non-differential measurement error of the exposure or mediator. Both MVMR and two-step MR can be implemented in both individual-level MR and summary data MR. MR mediation methods require different assumptions to be made, compared with non-instrumental variable mediation methods. Where these assumptions are more plausible, MR can be used to improve causal inference in mediation analysis.
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http://dx.doi.org/10.1007/s10654-021-00757-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159796PMC
May 2021

Genome-wide association study of cardiac troponin I in the general population.

Hum Mol Genet 2021 May 7. Epub 2021 May 7.

Division of Research and Innovation, Akershus University Hospital, 1478 Lørenskog, Norway.

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes is unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI and HF development in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.
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http://dx.doi.org/10.1093/hmg/ddab124DOI Listing
May 2021

Variable Emergence of Autism Spectrum Disorder Symptoms From Childhood to Early Adulthood.

Am J Psychiatry 2021 08 26;178(8):752-760. Epub 2021 Apr 26.

Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics (Riglin, A.K. Thapar, Langley, Collishaw, Tagg, A. Thapar), and School of Psychology (Livingston, Langley), Cardiff University, Cardiff, U.K.; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. (Wootton, Davey Smith, Stergiakouli, Tilling).

Objective: Autism spectrum disorder (ASD) is currently considered an early-onset neurodevelopmental condition. Follow-up studies of clinic-ascertained autism suggest that autistic symptoms typically decline with age, although symptom improvement is limited for some. To date there have been no population-based prospective studies investigating the natural history of autistic symptoms from childhood to adulthood. The aim of this study was to characterize the development and heterogeneity of autistic symptoms in a population-based cohort from childhood to age 25.

Methods: Data were analyzed in a prospective U.K. population-based cohort (ALSPAC). Trajectories were derived using five assessments of the parent-rated Social and Communication Disorders Checklist (SCDC) spanning ages 7-25. Additional measures were used to validate symptom trajectories.

Results: Three distinct SCDC symptom trajectory classes were identified: low (88.5%), declining (5.0%), and late-emerging (6.5%). Both the declining and late-emerging trajectory classes were associated with child and adult ASD measures, low IQ, communication problems, peer problems, and worse adult functioning compared with the low trajectory class. Male sex was associated with a higher likelihood of being in the declining trajectory class (odds ratio=2.84, 95% CI=2.19, 3.69). This sex difference was not observed in the late-emerging class (odds ratio=1.00, 95% CI=0.80, 1.24) compared with the low trajectory class.

Conclusions: ASD symptom levels that emerged early tended to decline across development, although impairment was still present in adulthood for some. For others, autistic symptoms emerged across adolescence and adulthood. This challenges our current understanding that ASD symptoms inevitably first manifest early in development.
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http://dx.doi.org/10.1176/appi.ajp.2020.20071119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611492PMC
August 2021
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