Showing papers by "George Davey Smith published in 2013"
TL;DR: The Avon Longitudinal Study of Parents and Children (ALSPAC) is a transgenerational prospective observational study investigating influences on health and development across the life course and is currently set up as a supported access resource.
Abstract: The Avon Longitudinal Study of Parents and Children (ALSPAC) is a transgenerational prospective observational study investigating influences on health and development across the life course. It considers multiple genetic, epigenetic, biological, psychological, social and other environmental exposures in relation to a similarly diverse range of health, social and developmental outcomes. Recruitment sought to enroll pregnant women in the Bristol area of the UK during 1990-92; this was extended to include additional children eligible using the original enrollment definition up to the age of 18 years. The children from 14541 pregnancies were recruited in 1990-92, increasing to 15247 pregnancies by the age of 18 years. This cohort profile describes the index children of these pregnancies. Follow-up includes 59 questionnaires (4 weeks-18 years of age) and 9 clinical assessment visits (7-17 years of age). The resource comprises a wide range of phenotypic and environmental measures in addition to biological samples, genetic (DNA on 11343 children, genome-wide data on 8365 children, complete genome sequencing on 2000 children) and epigenetic (methylation sampling on 1000 children) information and linkage to health and administrative records. Data access is described in this article and is currently set up as a supported access resource. To date, over 700 peer-reviewed articles have been published using ALSPAC data.
2,440 citations
TL;DR: The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children.
Abstract: Summary The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children. All pregnant women resident in a defined area in the South West of England, with an expected date of delivery between 1st April 1991 and 31st December 1992, were eligible and 13 761 women (contributing 13 867 pregnancies) were recruited. These women have been followed over the last 19–22 years and have completed up to 20 questionnaires, have had detailed data abstracted from their medical records and have information on any cancer diagnoses and deaths through record linkage. A follow-up assessment was completed 17–18 years postnatal at which anthropometry, blood pressure, fat, lean and bone mass and carotid intima media thickness were assessed, and a fasting blood sample taken. The second follow-up clinic, which additionally measures cognitive function, physical capability, physical activity (with accelerometer) and wrist bone architecture, is underway and two further assessments with similar measurements will take place over the next 5 years. There is a detailed biobank that includes DNA, with genome-wide data available on >10 000, stored serum and plasma taken repeatedly since pregnancy and other samples; a wide range of data on completed biospecimen assays are available. Details of how to access these data are provided in this cohort profile.
1,902 citations
TL;DR: Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins, and evidence available to date showed that primary prevention with statin is likely to be cost-effective and may improve patient quality of life.
Abstract: Cardiovascular disease (CVD), which comprises heart attacks (myocardial infarction), angina and strokes, is ranked as the number one cause of mortality and is a major cause of morbidity world wide. High blood cholesterol is linked to CVD events and is an important risk factor. Reducing high blood cholesterol, is thus an important way to reduce the chances of suffering a CVD event. Statins - cholesterol lowering drugs - (e.g. simvastatin, pravastatin, atorvastatin) are the first-choice treatments. Since the early statin randomised controlled trials were reported in the 1990s, several reviews of the effects of statins have been published highlighting their benefits particularly in people with a past history of CVD. Benefits include a reduction in CVD events. Statins have also been shown to reduce the risk of a first event in otherwise healthy individuals at high risk of CVD (primary prevention) but information on possible hazards has not been reported fully. The aim of this updated systematic review is to assess the effects, both in terms of benefits and harms of statins, for the primary prevention of CVD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE until 2011. We found 18 randomised controlled trials with 19 trial arms (56,934 patients) dating from 1994 to 2008. All were randomised control trials comparing statins with usual care or placebo. The mean age of the participants was 57 years (range 28 - 97 years), 60.3% were men, and of the eight trials that reported on ethnicity, 85.9 % were Caucasian. Duration of treatment was a minimum one year and with follow-up of a minimum of six months. All-cause mortality and fatal and non-fatal CVD events were reduced with the use of statins as was the need for revascularisation (the restoration of an adequate blood supply to the heart) by means of surgery (coronary artery bypass graft ) or by angioplasty (PTCA). Of 1000 people treated with a statin for five years, 18 would avoid a major CVD event which compares well with other treatments used for preventing cardiovascular disease. Taking statins did not increase the risk of serious adverse effects such as cancer. Statins are likely to be cost-effective in primary prevention.
1,456 citations
TL;DR: Use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder in the MoBa cohort, and similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use wasassociated with the same maternal characteristics as folic Acid use.
Abstract: Importance Prenatal folic acid supplements reduce the risk of neural tube defects in children, but it has not been determined whether they protect against other neurodevelopmental disorders. Objective To examine the association between maternal use of prenatal folic acid supplements and subsequent risk of autism spectrum disorders (ASDs) (autistic disorder, Asperger syndrome, pervasive developmental disorder–not otherwise specified [PDD-NOS]) in children. Design, Setting, and Patients The study sample of 85 176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002-2008; by the end of follow-up on March 31, 2012, the age range was 3.3 through 10.2 years (mean, 6.4 years). The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy, defined as the first day of the last menstrual period before conception. Relative risks of ASDs were estimated by odds ratios (ORs) with 95% CIs in a logistic regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity. Main Outcome Measure Specialist-confirmed diagnosis of ASDs. Results At the end of follow-up, 270 children in the study sample had been diagnosed with ASDs: 114 with autistic disorder, 56 with Asperger syndrome, and 100 with PDD-NOS. In children whose mothers took folic acid, 0.10% (64/61 042) had autistic disorder, compared with 0.21% (50/24 134) in those unexposed to folic acid. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, 0.41-0.90). No association was found with Asperger syndrome or PDD-NOS, but power was limited. Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use. Conclusions and Relevance Use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder in the MoBa cohort. Although these findings cannot establish causality, they do support prenatal folic acid supplementation.
460 citations
Marcel den Hoed1, Mark Eijgelsheim2, Tõnu Esko3, Bianca J. J. M. Brundel4 +264 more•Institutions (85)
TL;DR: A 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci, providing fresh insights into the mechanisms regulating heart rate.
Abstract: Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
332 citations
Momoko Horikoshi1, Hanieh Yaghootkar2, Dennis O. Mook-Kanamori3, Dennis O. Mook-Kanamori4 +171 more•Institutions (53)
TL;DR: The number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking, are extended and highlight genetic links between fetal growth and postnatal growth and metabolism.
Abstract: Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
309 citations
TL;DR: Assessment of associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure and the potentially confounding role of body mass index suggests a role for elevated body massIndex or obesity in the development of uric Acid related conditions.
Abstract: Objectives To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index. Design Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index). Setting Two large, prospective cohort studies in Denmark. Participants We measured levels of uric acid and related covariables in 58 072 participants from the Copenhagen General Population Study and 10 602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively. Main outcome Blood pressure and prospectively assessed ischaemic heart disease. Results Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%). Conclusion By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions.
250 citations
TL;DR: In this study, Prokopenko and colleagues provide novel evidence for causal relationship between adiposity and heart failure and increased liver enzymes using a Mendelian randomization study design.
Abstract: Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it ...
197 citations
University of Helsinki1, UCL Institute of Child Health2, Medical Research Council3, University of Western Australia4, QIMR Berghofer Medical Research Institute5, Erasmus University Rotterdam6, Center for Applied Genomics7, VU University Amsterdam8, Copenhagen University Hospital9, King's College London10, Wellcome Trust Centre for Human Genetics11, University of Exeter12, Wellcome Trust Sanger Institute13, University of Oulu14, University of London15, University of Oxford16, University of Bristol17, Broad Institute18, Helsinki University Central Hospital19, University of Southampton20, University of Tampere21, Turku University Hospital22, Mount Sinai Hospital, Toronto23, Ontario Institute for Cancer Research24, Ludwig Maximilian University of Munich25, Children's Hospital of Philadelphia26, University of Pennsylvania27, Boston University28, National Institutes of Health29, University of Copenhagen30, University of Valencia31, University Medical Center Groningen32, Churchill Hospital33
TL;DR: This study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations, and uncovers part of the complex genetic architecture linking Pubertal height growth, the timing of puberty and childhood obesity.
Abstract: The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P 1.67 10(8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.
189 citations
TL;DR: In this article, the authors investigated the effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity and circulating insulin-like growth factor (IGF)-I, which regulates growth.
Abstract: Importance Evidence that longer-term and exclusive breastfeeding reduces child obesity risk is based on observational studies that are prone to confounding. Objective To investigate effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity and circulating insulin-like growth factor (IGF)-I, which regulates growth. Design, Setting, and Participants Cluster-randomized controlled trial in 31 Belarusian maternity hospitals and their affiliated clinics, randomized into 1 of 2 groups: breastfeeding promotion intervention (n = 16) or usual practices (n = 15). Participants were 17 046 breastfeeding mother-infant pairs enrolled in 1996 and 1997, of whom 13 879 (81.4%) were followed up between January 2008 and December 2010 at a median age of 11.5 years. Intervention Breastfeeding promotion intervention modeled on the WHO/UNICEF Baby-Friendly Hospital Initiative (World Health Organization/United Nations Children's Fund). Main Outcome Measures Body mass index (BMI), fat and fat-free mass indices (FMI and FFMI), percent body fat, waist circumference, triceps and subscapular skinfold thicknesses, overweight and obesity, and whole-blood IGF-I. Primary analysis was based on modified intention-to-treat (without imputation), accounting for clustering within hospitals and clinics. Results The experimental intervention substantially increased breastfeeding duration and exclusivity when compared with the control (43% vs 6% exclusively breastfed at 3 months and 7.9% vs 0.6% at 6 months). Cluster-adjusted mean differences in outcomes at 11.5 years of age between experimental vs control groups were: 0.19 (95% CI, −0.09 to 0.46) for BMI; 0.12 (−0.03 to 0.28) for FMI; 0.04 (−0.11 to 0.18) for FFMI; 0.47% (−0.11% to 1.05%) for percent body fat; 0.30 cm (−1.41 to 2.01) for waist circumference; −0.07 mm (−1.71 to 1.57) for triceps and −0.02 mm (−0.79 to 0.75) for subscapular skinfold thicknesses; and −0.02 standard deviations (−0.12 to 0.08) for IGF-I. The cluster-adjusted odds ratio for overweight/obesity (BMI ≥85th vs Conclusions and Relevance Among healthy term infants in Belarus, an intervention that succeeded in improving the duration and exclusivity of breastfeeding did not prevent overweight or obesity, nor did it affect IGF-I levels at age 11.5 years. Breastfeeding has many advantages but population strategies to increase the duration and exclusivity of breastfeeding are unlikely to curb the obesity epidemic. Trial Registration isrctn.org: ISRCTN37687716; and clinicaltrials.gov: NCT01561612
156 citations
University of London1, University College London2, Peking Union Medical College3, University of Edinburgh4, Uppsala University5, University of Bristol6, Utrecht University7, University of Cambridge8, University of Copenhagen9, Duke University10, Leiden University11, Osaka University12, National Institutes of Health13, University of Virginia14, Mayo Clinic15
TL;DR: A cross-domain concordance supports a causal role of LDL-C on ischaemic stroke and in people of European ancestry, APOE genotype showed a positive dose-response association with LDL- C, C-IMT and ischaemia stroke.
Abstract: Background At the APOE gene, encoding apolipoprotein E, genotypes of the epsilon 2/epsilon 3/epsilon 4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk. Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT). Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84-1.43) for epsilon 2/epsilon 2; 0.85 (95% CrI: 0.78-0.92) for epsilon 2/epsilon 3; 1.05 (95% CrI: 0.89-1.24) for epsilon 2/epsilon 4; 1.05 (95% CrI: 0.99-1.12) for epsilon 3/epsilon 4; and 1.12 (95% CrI: 0.94-1.33) for epsilon 4/epsilon 4 using the epsilon 3/epsilon 3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 x 10(-152)), apolipoprotein B (P-trend: 8.7 x 10(-06)) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 x 10(-26)) and HDL-C (P-trend: 1.6 x 10(-12)). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear. Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE epsilon 2/epsilon 2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.
TL;DR: In this paper, a mechanistic understanding of the importance of controlling the oxygen content in the powder during MA, and the resulting impact on the formation of the oxide-dispersion-strengthened microstructure was provided.
TL;DR: It is proposed that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.
Abstract: Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68×10-9), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR≤5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR≤5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development. © 2013 Brandler et al.
TL;DR: Short sleep and reductions in sleep are associated with average levels of inflammation over a 5-year period, and adjustment for longstanding illness and major cardiometabolic risk factors indicated that disease processes may partially underlie these associations.
Abstract: Cross-sectional evidence suggests associations between sleep duration and levels of the inflammatory markers, C-reactive protein and interleukin-6. This longitudinal study uses data from the London-based Whitehall II study to examine whether changes in sleep duration are associated with average levels of inflammation from 2 measures 5 years apart. Sleep duration (≤5, 6, 7, 8, ≥9 hours on an average week night) was assessed in 5,003 middle-aged women and men in 1991/1994 and 1997/1999. Fasting levels of C-reactive protein and interleukin-6 were measured in 1997/1999 and 2002/2004. Cross-sectional analyses indicated that shorter sleep is associated with higher levels of inflammatory markers. Longitudinal analyses showed that each hour per night decrease in sleep duration between 1991/1994 and 1997/1999 was associated with higher levels of C-reactive protein (8.1%) and interleukin-6 (4.5%) averaged across measures in 1997/1999 and 2002/2004. Adjustment for longstanding illness and major cardiometabolic risk factors indicated that disease processes may partially underlie these associations. An increase in sleep duration was not associated with average levels of inflammatory markers. These results suggest that both short sleep and reductions in sleep are associated with average levels of inflammation over a 5-year period.
01 Jan 2013
TL;DR: In a more recent study as discussed by the authors, the extent of inequality in premature mortality as measured between geographical areas in Britain was investigated and the relative index of inequality (RII) and ratios of inequalities in age-sex standardised mortality ratios were reported.
Abstract: Objective To report on the extent of inequality in premature mortality as measured between geographical areas in Britain. Design Observational study of routinely collected mortality data and public records. Population subdivided by age, sex, and geographical area (parliamentary constituencies from 1991 to2007, pre-1974 local authorities over a longer time span). Setting Great Britain. Participants Entire population aged under 75 from 1990 to 2007, and entire population aged under 65 in the periods 1921-39, 1950-3, 1959-63, 1969-73, and 1981-2007. Main outcome measure Relative index of inequality (RII) and ratios of inequality in age-sex standardised mortality ratios under ages 75 and 65. The relative index of inequality is the relative rate of mortality for the hypothetically worst-off compared with the hypothetically best-off person in the population, assuming a linear association between socioeconomic position and risk of mortality. The ratio of inequality is the ratio of the standardised mortality ratio of the most deprived 10% to the least deprived 10%. Results When measured by the relative index of inequality, geographical inequalities in age-sex standardised rates of mortality below age 75 have increased every two years from 1990-1 to 2006-7 without exception. Over this period the relative index of inequality increased from 1.61 (95% confidence interval 1.52 to 1.69) in 1990-1 to 2.14 (2.02 to 2.27) in 2006-7. Simple ratios indicated a brief period around 2001 when a small reduction in inequality was recorded, but this was quickly reversed and inequalities up to the age of 75 have now reached the highest levels reported since at least 1990. Similarly, inequalities in mortality ratios under the age of 65 improved slightly in the early years of this century but the latest figures surpass the most extreme previously reported. Comparison of crudely age-sex standardised rates for those below age 65 from historical records showed that geographical inequalities in mortality are higher in the most recent decade than in any similar time period for which records are available since at least 1921. Conclusions Inequalities in premature mortality between areas of Britain continued to rise steadily during the first decade of the 21st century. The last time in the long economic record that inequalities were almost as high was in the lead up to the economic crash of 1929 and the economic depression of the 1930s. The economic crash of 2008 might precede even greater inequalities in mortality between areas in Britain.
TL;DR: A checklist of information and specification tests that studies using instrumental variables should report is proposed, and it is proposed that the instrument is associated with the exposure but not with measured confounding factors.
Abstract: Instrumental variables can be used to estimate the causal effects of exposures on outcomes in the presence of residual or uncontrolled confounding. To assess the validity of analyses using instrumental variables, specific information about whether underlying assumptions are met must be presented, in particular to demonstrate that the instrument is associated with the exposure but not with measured confounding factors. We systematically reviewed the epidemiological literature in Embase and Medline for articles containing the term "instrumental variable$" to investigate whether reporting of test statistics in studies using instrumental variables was sufficient to assess the validity of the results. We extracted the information each study reported about their instrumental variables, including specification tests used to check assumptions. The search found 756 studies of which 90 were relevant and were included. Only 25 (28%) studies reported appropriate tests of the strength of the associations between instruments and exposure. Forty-four (49%) studies reported associations between the instrumental variables and observed covariates. Studies using instrumental variables had wide confidence intervals and so effect estimates were imprecise. We propose a checklist of information and specification tests that studies using instrumental variables should report.
TL;DR: Testing for allelic effects of single-nucleotide polymorphisms on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK foundome-wide significant associations for each element.
Abstract: Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) usinginductivelycoupledplasmamassspectrometry.GenotypingwasperformedwithIlluminachipsand >2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P 5 5.03 3 10 210 , and rs2769264, P 5 2.63 3 10 220 ); for Se, a locus on chromosome 5 was significant in both cohorts (combined P 5 9.40 3 10 228 at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P 5 6.40 3 10 212 ; rs2120019, P 5 1.55 3 10 218 ; and rs4826508, P 5 1.40 3 10 212 , respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).
TL;DR: In this article, the authors used the Breit-Wigner model to determine the invariant mass distributions or "line shapes" of the {Sigma}{sup +} {pi}{sup -}, {Sigm {pi}{pi} + {p}i] final states, from threshold at 1328 MeV/c^2 through the mass range of the Lambda}(1405) and the {Lambda} (1520).
Abstract: The reaction {gamma} + p -> K{sup +} + {Sigma} + {p}i was used to determine the invariant mass distributions or "line shapes" of the {Sigma}{sup +} {pi}{sup -}, {Sigma}{sup -} {pi}{sup +} and {Sigma}{sup 0} {pi}{sup 0} final states, from threshold at 1328 MeV/c^2 through the mass range of the {Lambda}(1405) and the {Lambda}(1520). The measurements were made with the CLAS system at Jefferson Lab using tagged real photons, for center-of-mass energies 1.95 < W < 2.85 GeV. The three mass distributions differ strongly in the vicinity of the I=0 {Lambda}(1405), indicating the presence of substantial I=1 strength in the reaction. Background contributions to the data from the {Sigma}{sup 0}(1385) and from K* {Sigma} production were studied and shown to have negligible influence. To separate the isospin amplitudes, Breit-Wigner model fits were made that included channel-coupling distortions due to the Nkbar threshold. A best fit to all the data was obtained after including a phenomenological I=1, J{sup P} = 1/2{sup -} amplitude with a centroid at 1394\pm20 MeV/c^2 and a second I=1 amplitude at 1413\pm10 MeV/c^2. The centroid of the I=0 {Lambda}(1405) strength was found at the {Sigma} {pi} threshold, with the observed shape determined largely by channel-coupling, leadingmore » to an apparent overall peak near 1405 MeV/c^2.« less
TL;DR: Using data from the Indian Migration Study, Christopher Millett and colleagues examine the associations between active travel to work and overweight, hypertension, and diabetes.
Abstract: BACKGROUND: Increasing active travel (walking, bicycling, and public transport) is promoted as a key strategy to increase physical activity and reduce the growing burden of noncommunicable diseases (NCDs) globally. Little is known about patterns of active travel or associated cardiovascular health benefits in low- and middle-income countries. This study examines mode and duration of travel to work in rural and urban India and associations between active travel and overweight, hypertension, and diabetes. METHODS AND FINDINGS: Cross-sectional study of 3,902 participants (1,366 rural, 2,536 urban) in the Indian Migration Study. Associations between mode and duration of active travel and cardiovascular risk factors were assessed using random-effect logistic regression models adjusting for age, sex, caste, standard of living, occupation, factory location, leisure time physical activity, daily fat intake, smoking status, and alcohol use. Rural dwellers were significantly more likely to bicycle (68.3% versus 15.9%; p Language: en
TL;DR: Allelic scores derived from known variants and allelic scoresderived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease.
Abstract: It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.
TL;DR: The results show adverse effects of long-term alcohol consumption on body mass index (BMI), blood pressure, lipids, fibrinogen, and glucose and novel evidence for a potentially beneficial effect on triglyceride levels, which needs further replication.
Abstract: Aims To explore the causal effect of long-term alcohol consumption on coronary heart disease risk factors.
Methods and results We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on body mass index (BMI), blood pressure (BP), lipids, fibrinogen, and glucose. Analyses were undertaken in 54 604 Danes (mean age 56 years). Both confounder-adjusted multivariable and IV analyses suggested that a greater alcohol consumption among those who drank any alcohol resulted in a higher BP [mean difference in SBP per doubling of alcohol consumption among drinkers: 0.76 mmHg (95% CI: 0.63, 0.90) from multivariable analyses and 0.94 mmHg (−3.03, 4.69) from IV analyses; P -value for difference in these results = 0.95]. The positive association of alcohol with HDLc in the multivariable analyses [4.9% (4.7, 5.1)] appeared stronger than in the IV analyses [1.5% (−4.5, 7.4)], and the weak inverse association with fibrinogen in the multivariable analysis [−2.0% (−2.1, −1.8)] was not present in the IV analyses [0.6% (−3.8, 5.0)], but statistically the results for both of these could not be reliably distinguished from each other ( P -values 0.21 and 0.32, respectively). The weak inverse association of alcohol with BMI [−0.13 kg/m2 (−0.16, −0.10)] and with triglycerides [−0.4% (−0.7, 0.4)] in multivariable analyses were in contrast to the strong positive association of alcohol with BMI [1.37 kg/m2 (0.59, 2.15)] and the strong inverse association with triglycerides [−14.9% (−25.6, −4.3)] in IV analyses; P = 0.006 and 0.01, respectively, for difference between the two. Alcohol was not associated with non-HDLc or glucose.
Conclusion Our results show adverse effects of long-term alcohol consumption on BP and BMI. We also found novel evidence for a potentially beneficial effect on triglyceride levels, which needs further replication.
TL;DR: In this paper, the authors examined potential self-selection bias in a large pregnancy cohort by comparing exposure-outcome associations from the cohort to similar associations obtained from nationwide registry data.
Abstract: Background
This study examined potential self-selection bias in a large pregnancy cohort by comparing exposure-outcome associations from the cohort to similar associations obtained from nationwide registry data. The outcome under study was specialist-confirmed diagnosis of autism spectrum disorders.
TL;DR: The unconfounded Mendelian randomization estimates suggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes.
Abstract: Background There is substantial debate as to whether moderate alcohol useduring pregnancy could have subtle but important effects on offspring, by impairing later cognitive function and thus schoolperformance. The authors aimed to investigate the unconfoundedeffect of moderately increased prenatal alcohol exposure oncognitive/educational performance. Methods We used mother-offspring pairs participating in the AvonLongitudinal Study of Parents and Children (ALSPAC) and performedboth conventional observational analyses and Mendeliarandomization using an ADH1B variant (rs1229984) associatedwith reduced alcohol consumption. Women of White European origin with genotype and self-reported prenatal alcohol consumption, whose offspring's IQ score had been assessed in clinic (N1/44061 pairs) or Key Stage 2 (KS2) academic achievement score was available through linkage to the National Pupil Database (N1/46268), contributed to the analyses. Results Women reporting moderate drinking before and during early pregnancy were relatively affluent compared with women reporting lighter drinking, and their children had higher KS2 and IQscores. In contrast, children whose mothers' genotype predisposesto lower consumption or abstinence during early pregnancy hadhigher KS2 scores (mean difference 1.7, 95% confidence interval0.4, 3.0) than children of mothers whose genotype predisposed to heavier drinking, after adjustment for population stratification. Conclusions Better offspring cognitive/educational outcomes observed in association with prenatal alcohol exposure presumably reflected residual confounding by factors associated with social position and maternaleducation. The unconfounded Mendelian randomization estimatessuggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes.
University of Bristol1, Imperial College London2, University of Oxford3, Wellcome Trust Centre for Human Genetics4, Cardiff University5, National Institutes of Health6, University of Eastern Finland7, Oulu University Hospital8, University College London9, Statens Serum Institut10, Aarhus University11
TL;DR: The results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.
Abstract: Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption we performed a population based genome-wide association study of ‘age at first tooth’ and ‘number of teeth’ using 5998 and 6609 individuals respectively from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2,446,724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of fifteen independent loci, with ten loci reaching genome-wide significance (p<5x10−8) for ‘age at first tooth’ and eleven loci for ‘number of teeth’. Together these associations explain 6.06% of the variation in ‘age of first tooth’ and 4.76% of the variation in ‘number of teeth’. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including a SNP in the protein-coding region of BMP4 (rs17563, P= 9.080x10−17). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.
TL;DR: In this article, the authors report the exclusive photoproduction cross sections for the Sigma(1385), Lambda(1405), and Lambda (1520) in the reactions gamma + p -> K+ + Y* using the CLAS detector for energies from near the respective production thresholds up to a center-of-mass energy W of 2.85 GeV.
Abstract: We report the exclusive photoproduction cross sections for the Sigma(1385), Lambda(1405), and Lambda(1520) in the reactions gamma + p -> K+ + Y* using the CLAS detector for energies from near the respective production thresholds up to a center-of-mass energy W of 2.85 GeV. The differential cross sections are integrated to give the total exclusive cross sections for each hyperon. Comparisons are made to current theoretical models based on the effective Lagrangian approach and fitted to previous data. The accuracy of these models is seen to vary widely. The cross sections for the Lambda(1405) region are strikingly different for the Sigma+pi-, Sigma0 pi0, and Sigma- pi+ decay channels, indicating the effect of isospin interference, especially at W values close to the threshold.
TL;DR: By applying this method of cluster parameter selection combined with a 'matrix correction' to account for trajectory aberrations, differences in the oxide nanoclusters can then be reliably quantified.
TL;DR: Mendelian randomization is increasingly used to infer causality in observational epidemiology through the random assignment of genetic predisposition, and remnant cholesterol (remnant-C) is a case in point.
TL;DR: Heterogeneities in several relevant genes suggest possible genetic predisposition to MeHg neurotoxicity in a substantial proportion of the population, and future studies need to address this possibility.
Abstract: BACKGROUND Cognitive consequences at school age associated with prenatal methylmercury (MeHg) exposure may need to take into account nutritional and sociodemographic cofactors as well as relevant genetic polymorphisms. METHODS A subsample (n = 1,311) of the Avon Longitudinal Study of Parents and Children (Bristol, UK) was selected, and mercury (Hg) concentrations were measured in freeze-dried umbilical cord tissue as a measure of MeHg exposure. A total of 1135 children had available data on 247 single-nucleotide polymorphisms (SNPs) within relevant genes, as well as the Wechsler Intelligence Scale for Children Intelligence Quotient (IQ) scores at age 8 years. Multivariate regression models were used to assess the associations between MeHg exposure and IQ and to determine possible gene-environment interactions. RESULTS Hg concentrations indicated low background exposures (mean = 26 ng/g, standard deviation = 13). Log10-transformed Hg was positively associated with IQ, which attenuated after adjustment for nutritional and sociodemographic cofactors. In stratified analyses, a reverse association was found in higher social class families (for performance IQ, P value for interaction = 0.0013) among whom there was a wider range of MeHg exposure. Among 40 SNPs showing nominally significant main effects, MeHg interactions were detected for rs662 (paraoxonase 1) and rs1042838 (progesterone receptor) (P < 0.05) and for rs3811647 (transferrin) and rs2049046 (brain-derived neurotrophic factor) (P < 0.10). CONCLUSIONS In this population with a low level of MeHg exposure, there were only equivocal associations between MeHg exposure and adverse neuropsychological outcomes. Heterogeneities in several relevant genes suggest possible genetic predisposition to MeHg neurotoxicity in a substantial proportion of the population. Future studies need to address this possibility.