Publications
180 results found
Colicino S, Minelli C, Lewin A, et al., 2018, Using a Bayesian approach and external validation to predict persistent asthma at the age of 10 and 20 years in general and high-risk populations, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
van der Plaat D, Pereira M, Pesce G, et al., 2018, Age at menopause and lung function: A Mendelian randomization study, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Minelli C, Van der Plaat D, Leynaert B, et al., 2018, The effect of early puberty on asthma in women and men: A Mendelian randomization study, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wielscher M, Minelli C, Amaral A, et al., 2018, Cardio metabolic traits and lung function: A Mendelian Randomization study, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Burney P, Patel J, Minelli C, 2018, Late Breaking Abstract - The population attributable risks (PAR) for chronic airflow obstruction (CAO) in 40 BOLD study centres worldwide., 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Accordini S, Calciano L, Marcon A, et al., 2018, Incidence of airflow obstruction over 20 years in Europe, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Amaral AFS, Imboden M, Wielscher M, et al., 2018, Body mass index and lung function: A two-step epigenetic Mendelian randomization study, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Marcon A, Pesce G, Calciano L, et al., 2018, Trends in smoking initiation in Europe over 40 years: a retrospective cohort study, PLoS ONE, Vol: 13, ISSN: 1932-6203
Background:Tobacco consumption is the largest avoidable health risk. Understanding changes of smoking over time and across populations is crucial to implementing health policies. We evaluated trends in smoking initiation between 1970 and 2009 in random samples of European populations.Methods:We pooled data from six multicentre studies involved in the Ageing Lungs in European Cohorts consortium, including overall 119,104 subjects from 17 countries (range of median ages across studies: 33–52 years). We estimated retrospectively trends in the rates of smoking initiation (uptake of regular smoking) by age group, and tested birth cohort effects using Age-Period-Cohort (APC) modelling. We stratified all analyses by sex and region (North, East, South, West Europe).Results:Smoking initiation during late adolescence (16–20 years) declined for both sexes and in all regions (except for South Europe, where decline levelled off after 1990). By the late 2000s, rates of initiation during late adolescence were still high (40–80 per 1000/year) in East, South, and West Europe compared to North Europe (20 per 1000/year). Smoking initiation rates during early adolescence (11–15 years) showed a marked increase after 1990 in all regions (except for North European males) but especially in West Europe, where they reached 40 per 1000/year around 2005. APC models supported birth cohort effects in the youngest cohorts.Conclusion:Smoking initiation is still unacceptably high among European adolescents, and increasing rates among those aged 15 or less deserve attention. Reducing initiation in adolescents is fundamental, since youngsters are particularly vulnerable to nicotine addiction and tobacco adverse effects.
Minelli C, van der Plaat DA, Leynaert B, et al., 2018, Age at puberty and risk of asthma: A Mendelian randomisation study, PLoS Medicine, Vol: 15, ISSN: 1549-1277
BackgroundObservational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males.Methods and findingsMR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12–14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average). In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10−5) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10−4), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking.ConclusionsThis large MR stud
Bowden J, Spiller W, Del Greco M F, et al., 2018, Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression., International Journal of Epidemiology, Vol: 47, Pages: 1264-1278, ISSN: 0300-5771
Background: data furnishing a two-sample Mendelian randomization (MR) study are often visualized with the aid of a scatter plot, in which single-nucleotide polymorphism (SNP)-outcome associations are plotted against the SNP-exposure associations to provide an immediate picture of the causal-effect estimate for each individual variant. It is also convenient to overlay the standard inverse-variance weighted (IVW) estimate of causal effect as a fitted slope, to see whether an individual SNP provides evidence that supports, or conflicts with, the overall consensus. Unfortunately, the traditional scatter plot is not the most appropriate means to achieve this aim whenever SNP-outcome associations are estimated with varying degrees of precision and this is reflected in the analysis. Methods: We propose instead to use a small modification of the scatter plot-the Galbraith Radial plot-for the presentation of data and results from an MR study, which enjoys many advantages over the original method. On a practical level, it removes the need to recode the genetic data and enables a more straightforward detection of outliers and influential data points. Its use extends beyond the purely aesthetic, however, to suggest a more general modelling framework to operate within when conducting an MR study, including a new form of MR-Egger regression. Results: We illustrate the methods using data from a two-sample MR study to probe the causal effect of systolic blood pressure on coronary heart disease risk, allowing for the possible effects of pleiotropy. The Radial plot is shown to aid the detection of a single outlying variant that is responsible for large differences between IVW and MR-Egger regression estimates. Several additional plots are also proposed for informative data visualization. Conclusions: The Radial plot should be considered in place of the scatter plot for visualizing, analysing and interpreting data from a two-sample summary data MR study. Software is provided to help f
Gill DPS, Brewer C, Del Greco M F, et al., 2018, Age at menarche and adult body mass index: a Mendelian randomization study, International Journal of Obesity, Vol: 42, Pages: 1574-1581, ISSN: 0307-0565
BackgroundPubertal timing has psychological and physical sequelae. While observational studies have demonstrated an association between age at menarche and adult body mass index (BMI), confounding makes it difficult to infer causality.MethodsThe Mendelian randomization (MR) technique is not limited by traditional confounding and was used to investigate the presence of a causal effect of age at menarche on adult BMI. MR uses genetic variants as instruments under the assumption that they act on BMI only through age at menarche (no pleiotropy). Using a two-sample MR approach, heterogeneity between the MR estimates from individual instruments was used as a proxy for pleiotropy, with sensitivity analyses performed if detected. Genetic instruments and estimates of their association with age at menarche were obtained from a genome-wide association meta-analysis on 182,416 women. The genetic effects on adult BMI were estimated using data on 80,465 women from the UK Biobank. The presence of a causal effect of age at menarche on adult BMI was further investigated using data on 70,692 women from the GIANT Consortium.ResultsThere was evidence of pleiotropy among instruments. Using the UK Biobank data, after removing instruments associated with childhood BMI that were likely exerting pleiotropy, fixed-effect meta-analysis across instruments demonstrated that a 1 year increase in age at menarche reduces adult BMI by 0.38 kg/m2 (95% CI 0.25–0.51 kg/m2). However, evidence of pleiotropy remained. MR-Egger regression did not suggest directional bias, and similar estimates to the fixed-effect meta-analysis were obtained in sensitivity analyses when using a random-effect model, multivariable MR, MR-Egger regression, a weighted median estimator and a weighted mode-based estimator. The direction and significance of the causal effect were replicated using GIANT Consortium data.ConclusionMR provides evidence to support the hypothesis that earlier age at menarche causes
Burney PGJ, Minelli C, 2017, Using reference values to define disease based on the lower limit of normal biases the population attributable fraction, but not the population excess risk: the example of chronic airflow obstruction, Journal of Clinical Epidemiology, Vol: 93, Pages: 76-78, ISSN: 0895-4356
Background: The impact of disease on population health is most commonly estimated by the population attributable fraction (PAF), or less commonly by the excess risk, an alternative measure that estimates the absolute risk of disease in the population that can be ascribed to the exposure. Using chronic airflow obstruction as an example, we examined the impact on these estimates of defining disease based on different “normal” values.Method: We estimated PAF and the excess risk in scenarios in which the true rate of disease was 10% in the exposed and 5% in the unexposed, and where either 50% or 20% of the population was exposed. Disease definition was based on a “lower limit of normal”, using the 5th, 1st and 0.2nd centile of values in a “normal” population as thresholds to define normality. Results: Where normality is defined by centiles of values in a “normal” population, PAF is strongly influenced by which centile is selected to define normality. This is not true for the population excess risk. Conclusion: Care should be taken when interpreting estimates of PAF when disease is defined from a centile of a normal population.
Latronico N, Minelli C, Eikermann M, 2017, Prediction of long-term outcome subtypes in ARDS: first steps towards personalised medicine in critical care, Thorax, Vol: 72, Pages: 1067-1068, ISSN: 1468-3296
Bennett DA, Landry D, Little J, et al., 2017, Systematic review of statistical approaches to quantify, or correct for, measurement error in a continuous exposure in nutritional epidemiology., BMC Medical Research Methodology, Vol: 17, ISSN: 1471-2288
BACKGROUND: Several statistical approaches have been proposed to assess and correct for exposure measurement error. We aimed to provide a critical overview of the most common approaches used in nutritional epidemiology. METHODS: MEDLINE, EMBASE, BIOSIS and CINAHL were searched for reports published in English up to May 2016 in order to ascertain studies that described methods aimed to quantify and/or correct for measurement error for a continuous exposure in nutritional epidemiology using a calibration study. RESULTS: We identified 126 studies, 43 of which described statistical methods and 83 that applied any of these methods to a real dataset. The statistical approaches in the eligible studies were grouped into: a) approaches to quantify the relationship between different dietary assessment instruments and "true intake", which were mostly based on correlation analysis and the method of triads; b) approaches to adjust point and interval estimates of diet-disease associations for measurement error, mostly based on regression calibration analysis and its extensions. Two approaches (multiple imputation and moment reconstruction) were identified that can deal with differential measurement error. CONCLUSIONS: For regression calibration, the most common approach to correct for measurement error used in nutritional epidemiology, it is crucial to ensure that its assumptions and requirements are fully met. Analyses that investigate the impact of departures from the classical measurement error model on regression calibration estimates can be helpful to researchers in interpreting their findings. With regard to the possible use of alternative methods when regression calibration is not appropriate, the choice of method should depend on the measurement error model assumed, the availability of suitable calibration study data and the potential for bias due to violation of the classical measurement error model assumptions. On the basis of this review, we provide some prac
Thompson JR, Minelli C, Bowden J, et al., 2017, Mendelian randomization incorporating uncertainty about pleiotropy., Statistics in Medicine, Vol: 36, Pages: 4627-4645, ISSN: 0277-6715
Mendelian randomization (MR) requires strong assumptions about the genetic instruments, of which the most difficult to justify relate to pleiotropy. In a two-sample MR, different methods of analysis are available if we are able to assume, M1 : no pleiotropy (fixed effects meta-analysis), M2 : that there may be pleiotropy but that the average pleiotropic effect is zero (random effects meta-analysis), and M3 : that the average pleiotropic effect is nonzero (MR-Egger). In the latter 2 cases, we also require that the size of the pleiotropy is independent of the size of the effect on the exposure. Selecting one of these models without good reason would run the risk of misrepresenting the evidence for causality. The most conservative strategy would be to use M3 in all analyses as this makes the weakest assumptions, but such an analysis gives much less precise estimates and so should be avoided whenever stronger assumptions are credible. We consider the situation of a two-sample design when we are unsure which of these 3 pleiotropy models is appropriate. The analysis is placed within a Bayesian framework and Bayesian model averaging is used. We demonstrate that even large samples of the scale used in genome-wide meta-analysis may be insufficient to distinguish the pleiotropy models based on the data alone. Our simulations show that Bayesian model averaging provides a reasonable trade-off between bias and precision. Bayesian model averaging is recommended whenever there is uncertainty about the nature of the pleiotropy.
Gill DPS, Del Greco M F, Rawson TM, et al., 2017, Age at Menarche and Time Spent in Education: A Mendelian Randomization Study, Behavior Genetics, Vol: 47, Pages: 480-485, ISSN: 0001-8244
Menarche signifies the primary event in female puberty and is associated with changes in self-identity. It is not clear whether earlier puberty causes girls to spend less time in education. Observational studies on this topic are likely to be affected by confounding environmental factors. The Mendelian randomization (MR) approach addresses these issues by using genetic variants (such as single nucleotide polymorphisms, SNPs) as proxies for the risk factor of interest. We use this technique to explore whether there is a causal effect of age at menarche on time spent in education. Instruments and SNP-age at menarche estimates are identified from a Genome Wide Association Study (GWAS) meta-analysis of 182,416 women of European descent. The effects of instruments on time spent in education are estimated using a GWAS meta-analysis of 118,443 women performed by the Social Science Genetic Association Consortium (SSGAC). In our main analysis, we demonstrate a small but statistically significant causal effect of age at menarche on time spent in education: a 1 year increase in age at menarche is associated with 0.14 years (53 days) increase in time spent in education (95% CI 0.10–0.21 years, p = 3.5 × 10−8). The causal effect is confirmed in sensitivity analyses. In identifying this positive causal effect of age at menarche on time spent in education, we offer further insight into the social effects of puberty in girls.
Gill D, Del Greco M F, Walker AP, et al., 2017, The effect of iron status on risk of coronary artery disease: a Mendelian randomization study, Arteriosclerosis, Thrombosis, and Vascular Biology, Vol: 37, Pages: 1788-1792, ISSN: 1079-5642
Objective—Iron status is a modifiable trait that has been implicated in cardiovascular disease. This study uses the Mendelian randomization technique to investigate whether there is any causal effect of iron status on risk of coronary artery disease (CAD).Approach and Results—A 2-sample Mendelian randomization approach is used to estimate the effect of iron status on CAD risk. Three loci (rs1800562 and rs1799945 in the HFE gene and rs855791 in TMPRSS6) that are each associated with serum iron, transferrin saturation, ferritin, and transferrin in a pattern suggestive of an association with systemic iron status are used as instruments. SNP (single-nucleotide polymorphism)-iron status association estimates are based on a genome-wide association study meta-analysis of 48 972 individuals. SNP-CAD estimates are derived by combining the results of a genome-wide association study meta-analysis of 60 801 CAD cases and 123 504 controls with those of a meta-analysis of 63 746 CAD cases and 130 681 controls obtained from Metabochip and genome-wide association studies. Combined Mendelian randomization estimates are obtained for each marker by pooling results across the 3 instruments. We find evidence of a protective effect of higher iron status on CAD risk (iron odds ratio, 0.94 per SD unit increase; 95% confidence interval, 0.88–1.00; P=0.039; transferrin saturation odds ratio, 0.95 per SD unit increase; 95% confidence interval, 0.91–0.99; P=0.027; log-transformed ferritin odds ratio, 0.85 per SD unit increase; 95% confidence interval, 0.73–0.98; P=0.024; and transferrin odds ratio, 1.08 per SD unit increase; 95% confidence interval, 1.01–1.16; P=0.034).Conclusions—This Mendelian randomization study supports the hypothesis that higher iron status reduces CAD risk. These findings may highlight a therapeutic target.
Gill D, Sheehan NA, Wielscher M, et al., 2017, Age at menarche and lung function: a Mendelian randomization study., European Journal of Epidemiology, Vol: 32, Pages: 701-710, ISSN: 0393-2990
A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age at menarche, since genetic associations are not affected by classical confounding. We estimated the effects of age at menarche on forced vital capacity (FVC), a proxy for restrictive lung impairment, and ratio of forced expiratory volume in one second to FVC (FEV1/FVC), a measure of airway obstruction, in both adulthood and adolescence. We derived SNP-age at menarche association estimates for 122 variants from a published genome-wide meta-analysis (N = 182,416), with SNP-lung function estimates obtained by meta-analysing three studies of adult women (N = 46,944) and two of adolescent girls (N = 3025). We investigated the impact of departures from the assumption of no pleiotropy through sensitivity analyses. In adult women, in line with previous evidence, we found an effect on restrictive lung impairment with a 24.8 mL increase in FVC per year increase in age at menarche (95% CI 1.8-47.9; p = 0.035); evidence was stronger after excluding potential pleiotropic variants (43.6 mL; 17.2-69.9; p = 0.001). In adolescent girls we found an opposite effect (-56.5 mL; -108.3 to -4.7; p = 0.033), suggesting that the detrimental effect in adulthood may be preceded by a short-term post-pubertal benefit. Our secondary analyses showing results in the same direction in men and boys, in whom age at menarche SNPs have also shown association with sexual development, suggest a role for pubertal timing in general rather than me
Saad N, Patel JH, Minelli C, et al., 2017, Explaining ethnic disparities in lung function among young adults: a pilot investigation, PLOS One, Vol: 12, ISSN: 1932-6203
BackgroundEthnic disparities in lung function have been linked mainly to anthropometric factors but have not been fully explained. We conducted a cross-sectional pilot study to investigate how best to study ethnic differences in lung function in young adults and evaluate whether these could be explained by birth weight and socio-economic factors.MethodsWe recruited 112 university students of White and South Asian British ethnicity, measured post-bronchodilator lung function, obtained information on respiratory symptoms and socio-economic factors through questionnaires, and acquired birth weight through data linkage. We regressed lung function against ethnicity and candidate predictors defined a priori using linear regression, and used penalised regression to examine a wider range of factors. We reviewed the implications of our findings for the feasibility of a larger study.ResultsThere was a similar parental socio-economic environment and no difference in birth weight between the two ethnic groups, but the ethnic difference in FVC adjusted for sex, age, height, demi-span, father’s occupation, birth weight, maternal educational attainment and maternal upbringing was 0.81L (95%CI: -1.01 to -0.54L). Difference in body proportions did not explain the ethnic differences although parental immigration was an important predictor of FVC independent of ethnic group. Participants were comfortable with study procedures and we were able to link birth weight data to clinical measurements.ConclusionStudies of ethnic disparities in lung function among young adults are feasible. Future studies should recruit a socially more diverse sample and investigate the role of markers of acculturation in explaining such differences.
Saad NJ, Patel J, Burney P, et al., 2017, Birth Weight and Lung Function in Adulthood: A Systematic Review and Meta-analysis., Annals of the American Thoracic Society, Vol: 14, Pages: 994-1004, ISSN: 2329-6933
RATIONALE: There is evidence suggesting that birth weight may influence lung function in adulthood, but it is unclear whether it might differentially affect restrictive (FVC) and obstructive (FEV1/FVC) patterns. OBJECTIVES: To summarize evidence available on the association of birth weight, weight at 1 year, and weight gain in the first year of life with FVC and FEV1/FVC in adulthood. METHODS: We performed a systematic review of the literature by searching MEDLINE, EMBASE, and Web of Science through January 2015. Data were combined using inverse-variance weighted meta-analysis with random effects models and between-study heterogeneity evaluated. We conducted a priori subgroup or sensitivity analyses by age, country wealth, ethnicity, sex, and smoking. We evaluated risk of bias using the Newcastle Ottawa Scale and reporting bias using funnel plots. RESULTS: Eighteen articles were included in the review and 13 in the meta-analyses. Most studies were from high-income countries, and all had a low risk of bias. We found strong evidence of an association of birth weight with adult FVC, a 59.4 ml higher FVC in adulthood per kilogram increase in birth weight (95% confidence interval, 43.3-75.5), with no evidence of heterogeneity. Evidence of an association of birth weight with FEV1/FVC was weaker and showed some inconsistency across studies. Only one study investigated weight at 1 year, and another one reported weight gain in the first year. CONCLUSIONS: Our meta-analyses show strong and consistent evidence of an association of birth weight with adult FVC, a measure of restrictive impairment, with much weaker evidence for airflow obstruction.
Townend J, Minelli C, Mortimer K, et al., 2017, The association between chronic airflow obstruction and poverty in 12 sites from the multinational BOLD study, European Respiratory Journal, Vol: 49, ISSN: 1399-3003
Poverty is strongly associated with mortality from COPD, but little is known of its relation to airflow obstruction.In a cross-sectional study of adults aged ≥40 years from 12 sites (N=9255), participating in the Burden of Obstructive Lung Disease (BOLD) study, poverty was evaluated using a wealth score (0–10) based on household assets. Obstruction, measured as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) (%) after administration of 200 μg salbutamol, and prevalence of FEV1/FVC<lower limit of normal were tested for association with poverty for each site, and the results were combined by meta-analysis.Mean wealth scores ranged from 4 in Blantyre (Malawi) and Kashmir (India) to 10 in Riyadh (Saudi Arabia), and the prevalence of obstruction, from 16% in Kashmir to 3% in Riyadh and Penang (Malaysia). Following adjustments for age and sex, FEV1/FVC increased by 0.36% (absolute change) (95%CI: 0.22, 0.49; p<0.001) per unit increase in wealth score. Adjustments for other confounders reduced this effect to 0.23% (0.11, 0.34), but even this value remained highly significant (p<0.001). Results were consistent across sites (I2=1%; phet=0.44). Mean wealth scores explained 38% of the variation in mean FEV1/FVC between sites (r2=0.385, p=0.031).Airflow obstruction is consistently associated with poverty at individual and community levels across several countries.
Wild PS, Felix JF, Schillert A, et al., 2017, Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function, JOURNAL OF CLINICAL INVESTIGATION, Vol: 127, Pages: 1798-1812, ISSN: 0021-9738
BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.
Pereira M, Thompson JR, Weichenberger CX, et al., 2017, Inclusion of biological knowledge in a Bayesian shrinkage model for joint estimation of SNP effects, GENETIC EPIDEMIOLOGY, Vol: 41, Pages: 320-331, ISSN: 0741-0395
With the aim of improving detection of novel single-nucleotide polymorphisms (SNPs) in genetic association studies, we propose a method of including prior biological information in a Bayesian shrinkage model that jointly estimates SNP effects. We assume that the SNP effects follow a normal distribution centered at zero with variance controlled by a shrinkage hyperparameter. We use biological information to define the amount of shrinkage applied on the SNP effects distribution, so that the effects of SNPs with more biological support are less shrunk toward zero, thus being more likely detected. The performance of the method was tested in a simulation study (1,000 datasets, 500 subjects with ∼200 SNPs in 10 linkage disequilibrium (LD) blocks) using a continuous and a binary outcome. It was further tested in an empirical example on body mass index (continuous) and overweight (binary) in a dataset of 1,829 subjects and 2,614 SNPs from 30 blocks. Biological knowledge was retrieved using the bioinformatics tool Dintor, which queried various databases. The joint Bayesian model with inclusion of prior information outperformed the standard analysis: in the simulation study, the mean ranking of the true LD block was 2.8 for the Bayesian model versus 3.6 for the standard analysis of individual SNPs; in the empirical example, the mean ranking of the six true blocks was 8.5 versus 9.3 in the standard analysis. These results suggest that our method is more powerful than the standard analysis. We expect its performance to improve further as more biological information about SNPs becomes available.
Poobalasingam T, Yates LL, Walker SA, et al., 2017, Heterozygous Vangl2 looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair, Disease Models & Mechanisms, Vol: 10, Pages: 409-423, ISSN: 1754-8403
Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as Idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive pulmonary Disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising.The Planar Cell Polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly due to the perinatal lethality of many PCP mouse mutant lines.Here we have investigated heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in the lung disease, emphysema.In vitro, VANGL2 disruption impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking (a tissue damaging insult) on lung function. Finally, we show that that PCP genes VANGL2 and SCRIBBLE (SC
Fedorova OS, Janse JJ, Ogorodova LM, et al., 2017, Opisthorchis felineus negatively associates with skin test reactivity in Russia-EuroPrevall-International Cooperation study, Allergy, Vol: 72, Pages: 1096-1104, ISSN: 0105-4538
BACKGROUND: Most studies on the relationship between helminth infections and atopic disorders have been conducted in (sub)tropical developing countries where exposure to multiple parasites and lifestyle can confound the relationship. We aimed to study the relationship between infection with the fish-borne helminth Opishorchis felineus and specific IgE, skin prick testing, and atopic symptoms in Western Siberia, with lifestyle and hygiene standards of a developed country. METHODS: Schoolchildren aged 7-11 years were sampled from one urban and two rural regions. Skin prick tests (SPT) and specific IgE (sIgE) against food and aeroallergens were measured, and data on allergic symptoms and on demographic and socioeconomic factors were collected by questionnaire. Diagnosis of opisthorchiasis was based on PCR performed on stool samples. RESULTS: Of the 732 children included, 34.9% had opisthorchiasis. The sensitization to any allergen when estimated by positive SPT was 12.8%, while much higher, 24.0%, when measured by sIgE. Atopic symptoms in the past year (flexural eczema and/or rhinoconjunctivitis) were reported in 12.4% of the children. SPT was positively related to flexural eczema and rhinoconjunctivitis, but not to wheezing. Opisthorchiasis showed association with lower SPT response, as well as borderline association with low IgE reactivity to any allergen. However, the effect of opisthorchiasis on SPT response was not mediated by IgE, suggesting that opisthorchiasis influences SPT response through another mechanism. Opisthorchiasis also showed borderline association with lower atopic symptoms. CONCLUSIONS: There is a negative association between a chronic helminth infection and skin prick test reactivity even in a developed country.
Bowden J, Del Greco M F, Minelli C, et al., 2017, A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization, Statistics in Medicine, Vol: 36, Pages: 1783-1802, ISSN: 1097-0258
Mendelian randomization (MR) uses genetic data to probe questions of causality in epidemiological research, by invoking the Instrumental Variable (IV) assumptions. In recent years, it has become commonplace to attempt MR analyses by synthesising summary data estimates of genetic association gleaned from large and independent study populations. This is referred to as two-sample summary data MR. Unfortunately, due to the sheer number of variants that can be easily included into summary data MR analyses, it is increasingly likely that some do not meet the IV assumptions due to pleiotropy. There is a pressing need to develop methods that can both detect and correct for pleiotropy, in order to preserve the validity of the MR approach in this context. In this paper, we aim to clarify how established methods of meta-regression and random effects modelling from mainstream meta-analysis are being adapted to perform this task. Specifically, we focus on two contrastin g approaches: the Inverse Variance Weighted (IVW) method which assumes in its simplest form that all genetic variants are valid IVs, and the method of MR-Egger regression that allows all variants to violate the IV assumptions, albeit in a specific way. We investigate the ability of two popular random effects models to provide robustness to pleiotropy under the IVW approach, and propose statistics to quantify the relative goodness-of-fit of the IVW approach over MR-Egger regression.
Bowden J, Del Greco M F, Minelli C, et al., 2016, Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2I2 statistic, International Journal of Epidemiology, Vol: 45, Pages: 1961-1974, ISSN: 1464-3685
BACKGROUND: MR-Egger regression has recently been proposed as a method for Mendelian randomization (MR) analyses incorporating summary data estimates of causal effect from multiple individual variants, which is robust to invalid instruments. It can be used to test for directional pleiotropy and provides an estimate of the causal effect adjusted for its presence. MR-Egger regression provides a useful additional sensitivity analysis to the standard inverse variance weighted (IVW) approach that assumes all variants are valid instruments. Both methods use weights that consider the single nucleotide polymorphism (SNP)-exposure associations to be known, rather than estimated. We call this the `NO Measurement Error' (NOME) assumption. Causal effect estimates from the IVW approach exhibit weak instrument bias whenever the genetic variants utilized violate the NOME assumption, which can be reliably measured using the F-statistic. The effect of NOME violation on MR-Egger regression has yet to be studied. METHODS: An adaptation of the [Formula: see text] statistic from the field of meta-analysis is proposed to quantify the strength of NOME violation for MR-Egger. It lies between 0 and 1, and indicates the expected relative bias (or dilution) of the MR-Egger causal estimate in the two-sample MR context. We call it [Formula: see text] The method of simulation extrapolation is also explored to counteract the dilution. Their joint utility is evaluated using simulated data and applied to a real MR example. RESULTS: In simulated two-sample MR analyses we show that, when a causal effect exists, the MR-Egger estimate of causal effect is biased towards the null when NOME is violated, and the stronger the violation (as indicated by lower values of [Formula: see text]), the stronger the dilution. When additionally all genetic variants are valid instruments, the type I error rate of the MR-Egger test for pleiotropy is inflated and the causal effect underestimated. Simulation extrapolation
Nieuwenhuis MA, Vonk JM, Himes BE, et al., 2016, PTTG1IP and MAML3, novel GWAS genes for severity of hyperresponsiveness in adult asthma., Allergy, Vol: 72, Pages: 792-801, ISSN: 0105-4538
BACKGROUND: The severity of bronchial hyperresponsiveness (BHR) is a fundamental feature of asthma. The severity of BHR varies between asthmatics and is associated with lack of asthma control. The mechanisms underlying this trait are still unclear. This study aims to identify genes associated with BHR severity, using a genome wide association study (GWAS) on the slope of BHR in adult asthmatics. METHODS: We performed a GWAS on BHR severity in adult asthmatics from the Dutch Asthma GWAS cohort (n=650), adjusting for smoking and inhaled corticosteroid use, and verified results in 3 other cohorts. Furthermore, we performed eQTL and co-expression analyses in lung tissue. RESULTS: In the discovery cohort, one genome wide significant hit located in phosphodiesterase 4D, cAMP-specif (PDE4D) and 26 SNPs with p-values <1*10(-5) were found. None of our findings replicated in adult and childhood replication cohorts jointly. In adult cohorts separately, rs1344110 in pituitary tumor-transforming 1 interacting protein (PTTG1IP) and rs345983 in Mastermind-like 3 (MAML3) replicated nominally; minor alleles of rs345983 and rs1344110 were associated with less severe BHR and higher lung tissue gene expression. PTTG1IP showed significant co-expression with pituitary tumor-transforming 1, the binding factor of PTTG1lP, and with Vimentin and E-Cadherin1. MAML3 co-expressed significantly with Mastermind-like 2 (MAML2), both involved in Notch signalling. CONCLUSIONS: PTTG1IP and MAML3 are associated with BHR severity in adult asthma. The relevance of these genes is supported by the eQTL analyses and co-expression of PTTG1lP with Vimentin and E-Cadherin1, and MAML3 with MAML2. This article is protected by copyright. All rights reserved.
Pereira M, Thompson JR, Weichenberger CX, et al., 2016, Differential shrinkage as a way of integrating prior knowledge in a Bayesian model to improve the analysis of genetic association studies, Annual Meeting of the International-Genetic-Epidemiology-Society, Publisher: Wiley, Pages: 656-656, ISSN: 1098-2272
We propose a method of integrating external biological information about SNPs in a Bayesian hierarchical shrinkage model that jointly estimates SNP effects with the aim of increasing the power to detect variants in genetic association studies. Our method induces shrinkage on the SNP effects that is inversely proportional to prior information: SNPs with more information are subject to little shrinkage and more likely to be detected, while SNPs without prior information are strongly shrunk towards zero (no effect).The performance of the method was tested in a simulation study with 1000 datasets, each with 500 subjects and ∼1200 SNPs, divided in 10 Linkage Disequilibrium (LD) blocks. One LD block was simulated to be truly associated with the outcome. The method was further tested on an empirical example using BMI as the outcome and data from the European Community Respiratory Health Survey: 1,829 subjects and 2,614 SNPs from 30 blocks, 6 of which known to be truly associated with BMI. Prior knowledge was retrieved using the bioinformatic tool Dintor and incorporated in the model.The Bayesian model with inclusion of prior information outperformed the classical analysis. In the simulation study, the mean ranking of the true LD block was 2.8 for the Bayesian model vs. 3.6 for the classical analysis. Similarly, the mean ranking of the six true blocks in the empirical example was 8.3 vs. 11.7 in the classical analysis. These results suggest that our method represents a more powerful approach to detect new variants in genetic association studies.
Amaral AF, Garcia Larsen V, De Matteis S, et al., 2016, Understanding the Influence of genes, diet, and occupation on respiratory health, American Journal of Respiratory and Critical Care Medicine, Vol: 194, Pages: 236-238, ISSN: 1535-4970
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