Showing papers by "Debbie A Lawlor published in 2011"
TL;DR: A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function, and these findings suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
1,829 citations
TL;DR: BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.
914 citations
University of Cambridge1, University College London2, McGill University3, University of Leicester4, University of Bristol5, University of Copenhagen6, University of London7, Copenhagen University Hospital8, University of Queensland9, University of Washington10, University of Vermont11, Sir Charles Gairdner Hospital12, University of Western Australia13, Ontario Institute for Cancer Research14, University of Würzburg15, ETH Zurich16, University of Edinburgh17, University of Warwick18, Utrecht University19, National Heart Foundation of Australia20, Boston University21, University of Kiel22, University of Lübeck23, University Hospital Regensburg24, King's College London25, Mario Negri Institute for Pharmacological Research26, Wake Forest University27, Karolinska Institutet28, University of Leeds29, Harvard University30, Group Health Cooperative31, McMaster University32, University of Oxford33, University of Glasgow34, Imperial College London35, Medical University of Graz36, University of Ulm37, Goethe University Frankfurt38, Lund University39, Helmholtz Zentrum München40, Robert Koch Institute41, Ludwig Maximilian University of Munich42, Umeå University43, University of Pennsylvania44, Johns Hopkins University45, Clinical Trial Service Unit46, Aga Khan University Hospital47, Robertson Centre for Biostatistics48, Tufts University49, University of Bonn50, Erasmus University Rotterdam51, Karolinska University Hospital52, University of Groningen53, Northwestern University54, University of California, Los Angeles55, Glasgow Royal Infirmary56, Glasgow Clinical Research Facility57
TL;DR: Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.
Abstract: Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of ind ...
583 citations
Medical Research Council1, Harvard University2, Lund University3, University of Minnesota4, Duke University5, University of Oulu6, Novo Nordisk7, Technische Universität München8, University College London9, University of Lausanne10, University of Eastern Finland11, National University of Singapore12, King's College London13, University of Bristol14, George Washington University15, National Institutes of Health16, University of Bergen17, University of Michigan18, University of North Carolina at Chapel Hill19, University of Groningen20, Utrecht University21, University of Copenhagen22, Erasmus University Rotterdam23, University of Tübingen24, Harokopio University25, Washington University in St. Louis26, University of Maryland, Baltimore27, University of Granada28, Complutense University of Madrid29, University of Turku30, University of Southern Denmark31, Umeå University32, University of Gothenburg33, Laval University34, University of London35, Pennington Biomedical Research Center36, Lille University of Science and Technology37, Newcastle University38, University of Iceland39, Danube University Krems40, Broad Institute41, University of California, Los Angeles42, Hammersmith Hospital43, University of Cambridge44, National Institute for Health and Welfare45
TL;DR: In this paper, a meta-analysis of data from 45 studies of adults and nine studies of children and adolescents was conducted to confirm or refute unambiguously whether physical activity attenuates the association of FTO with obesity risk.
Abstract: Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n=218,166) and nine studies of children and adolescents (n=19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTOxPA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
447 citations
TL;DR: Most studies found that weaker grip strength and slower walking speed were associated with increased risk of future fractures and cognitive decline, but residual confounding may explain results in some studies.
Abstract: Background: measures of physical capability may be predictive of subsequent health, but existing published studies have not been systematically reviewed. We hypothesised that weaker grip strength, slower walking speed and chair rising and shorter standing balance time, in community-dwelling populations, would be associated with higher subsequent risk of fracture, cognitive outcomes, cardiovascular disease, hospitalisation and institutionalisation.
Methods: studies were identified through systematic searches of the electronic databases MEDLINE and EMBASE (to May 2009). Reference lists of eligible papers were also manually searched.
Results: twenty-four papers had examined the associations between at least one physical capability measure and one of the outcomes. As the physical capability measures and outcomes had been assessed and categorised in different ways in different studies, and there were differences in the potential confounding factors taken into account, this made it impossible to pool results. There were more studies examining fractures than other outcomes, and grip strength and walking speed were the most commonly examined capability measures. Most studies found that weaker grip strength and slower walking speed were associated with increased risk of future fractures and cognitive decline, but residual confounding may explain results in some studies. Associations between physical capability levels and the other specified outcomes have not been tested widely.
Conclusions: there is some evidence to suggest that objective measures of physical capability may be predictors of subsequent health in older community-dwelling populations. Most hypothesised associations have not been studied sufficiently to draw definitive conclusions suggesting the need for further research.
415 citations
TL;DR: This article identified new regions showing association with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2.
Abstract: Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
394 citations
TL;DR: A short-term effect of exercise on depression is suggested: on average, depression scores 0.4 of a standard deviation lower in clinically depressed patients randomly assigned to an exercise intervention at the end of that intervention compared to those randomly assignedto a none exercise group.
Abstract: Objective To assess the effectiveness of exercise in adults with clinical depression. Data sources The databases CINAHL, Embase, Cochrane Database of Systematic reviews, Cochrane Controlled Trials Register, MEDLINE, and PsycINFO were searched (1806-2008) using medical subject headings (MeSH) and text word terms depression, depressive disorder and exercise, aerobic, non-aerobic, physical activity, physical fitness, walk*, jog*, run*, bicycling, swim*, strength, and resistance. Study selection Randomized trials including adults with clinical depression according to any diagnostic system were included. Data extraction Two investigators evaluated trials using a prepiloted structured form. Data synthesis Thirteen trials were identified that fulfilled the inclusion criteria. Eight had adequate allocation concealment, 6 had a blinded outcome, and 5 used intention-to-treat analyses. The pooled standardized mean difference (SMD) calculated using a random-effects model was -0.40 (95% CI, -0.66 to -0.14), with evidence of heterogeneity between trials (I(2) = 57.2%, P = .005). There was an inverse association between duration of intervention and the magnitude of the association of exercise with depression (P = .002). No other characteristics were related to between-study heterogeneity. Pooled analysis of 5 trials with long-term follow-up (ie, that examined outcomes beyond the end of the intervention) suggested no long-term benefit (SMD, -0.01; 95% CI, -0.28 to 0.26), with no strong evidence of heterogeneity in this pooled analysis (I(2) = 23.4%, P = .27). There was no strong statistical evidence for small study bias (P > .27). Only 3 studies were assessed as high quality (adequately concealed random allocation, blinded outcome assessment, and intention-to-treat analysis). When we pooled results from these, the estimated beneficial effect of exercise was more modest (SMD, -0.19; 95% CI, -0.70 to 0.31) than the pooled result for all 13 studies, with no strong evidence of benefit. Conclusions Our results suggest a short-term effect of exercise on depression: on average, depression scores 0.4 of a standard deviation lower in clinically depressed patients randomly assigned to an exercise intervention at the end of that intervention compared to those randomly assigned to a none exercise group. There is little evidence of a long-term beneficial effect of exercise in patients with clinical depression.
323 citations
TL;DR: While reported associations of breastfeeding with child BP and BMI are likely to reflect residual confounding, breastfeeding may have causal effects on IQ.
Abstract: BACKGROUND: A novel approach is explored for improving causal inference in observational studies by comparing cohorts from high-income with low- or middle-income countries (LMIC) where confounding structures differ. This is applied to assessing causal effects of breastfeeding on child blood pressure (BP) body mass index (BMI) and intelligence quotient (IQ). METHODS: Standardized approaches for assessing the confounding structure of breastfeeding by socio-economic position were applied to the British Avon Longitudinal Study of Parents and Children (ALSPAC) (N approximately 5000) and Brazilian Pelotas 1993 cohorts (N approximately 1000). This was used to improve causal inference regarding associations of breastfeeding with child BP BMI and IQ. Analyses were extended to include results from a meta-analysis of five LMICs (N approximately 10 000) and compared with a randomized trial of breastfeeding promotion. Findings Although higher socio-economic position was strongly associated with breastfeeding in ALSPAC there was little such patterning in Pelotas. In ALSPAC breastfeeding was associated with lower BP lower BMI and higher IQ adjusted for confounders but in the directions expected if due to socioeconomic patterning. In contrast in Pelotas breastfeeding was not strongly associated with BP or BMI but was associated with higher IQ. Differences in associations observed between ALSPAC and the LMIC meta-analysis were in line with those observed between ALSPAC and Pelotas but with robust evidence of heterogeneity detected between ALSPAC and the LMIC meta-analysis associations. Trial data supported the conclusions inferred by the cross-cohort comparisons which provided evidence for causal effects on IQ but not for BP or BMI. CONCLUSION: While reported associations of breastfeeding with child BP and BMI are likely to reflect residual confounding breastfeeding may have causal effects on IQ. Comparing associations between populations with differing confounding structures can be used to improve causal inference in observational studies.
285 citations
University College London1, University of London2, GlaxoSmithKline3, University of Cambridge4, Erasmus University Rotterdam5, University of Wisconsin-Madison6, Imperial College London7, University of Edinburgh8, Utrecht University9, Leiden University10, University of Zurich11, University of Copenhagen12, National Institutes of Health13, University of Virginia14, University of Western Australia15, University of Bristol16, Mayo Clinic17, Wellcome Trust Sanger Institute18
TL;DR: In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke.
283 citations
TL;DR: Using the HFEA database of all 144,018 live births in all IVF cycles in the UK between 2003 and 2007, Scott Nelson and Debbie Lawlor show that couple- and treatment-specific factors can be used to help predict successful outcome following IVF.
Abstract: Using the HFEA database of all 144,018 live births in all IVF cycles in the UK between 2003 and 2007, Scott Nelson and Debbie Lawlor show that couple- and treatment-specific factors can be used to help predict successful outcome following IVF.
256 citations
TL;DR: The authors conclude that point estimates from various IV methods can differ in practical applications, and suggest that structural mean models make weaker assumptions than other IV estimators and can therefore be expected to be consistent in a wider range of situations.
Abstract: In this paper, the authors describe different instrumental variable (IV) estimators of causal risk ratios and odds ratios with particular attention to methods that can handle continuously measured exposures. The authors present this discussion in the context of a Mendelian randomization analysis of the effect of body mass index (BMI; weight (kg)/height (m)(2)) on the risk of asthma at age 7 years (Avon Longitudinal Study of Parents and Children, 1991-1992). The authors show that the multiplicative structural mean model (MSMM) and the multiplicative generalized method of moments (MGMM) estimator produce identical estimates of the causal risk ratio. In the example, MSMM and MGMM estimates suggested an inverse relation between BMI and asthma but other IV estimates suggested a positive relation, although all estimates had wide confidence intervals. An interaction between the associations of BMI and fat mass and obesity-associated (FTO) genotype with asthma explained the different directions of the different estimates, and a simulation study supported the observation that MSMM/MGMM estimators are negatively correlated with the other estimators when such an interaction is present. The authors conclude that point estimates from various IV methods can differ in practical applications. Based on the theoretical properties of the estimators, structural mean models make weaker assumptions than other IV estimators and can therefore be expected to be consistent in a wider range of situations.
TL;DR: Maternal diabetes mellitus has long-term consequences for greater BMI in offspring; this association is likely to be via intrauterine mechanisms, and is independent of maternal BMI in early pregnancy.
Abstract: Background—Maternal diabetes mellitus in pregnancy results in greater offspring adiposity at birth. It is unclear whether it is associated with greater adiposity into adulthood, and if so, whether ...
TL;DR: Analysis of eight population-based and occupational cohorts from the UK reveals the patterns of change of blood pressure in the population through the life course.
Abstract: Background: Much of our understanding of the age-related progression of systolic blood pressure (SBP) comes from crosssectional data, which do not directly capture within-individual change. We estimated life course trajectories of SBP using longitudinal data from seven population-based cohorts and one predominantly white collar occupational cohort, each from the United Kingdom and with data covering different but overlapping age periods. Methods and Findings: Data are from 30,372 individuals and comprise 102,580 SBP observations spanning from age 7 to 80+y. Multilevel models were fitted to each cohort. Four life course phases were evident in both sexes: a rapid increase in SBP coinciding with peak adolescent growth, a more gentle increase in early adulthood, a midlife acceleration beginning in the fourth decade, and a period of deceleration in late adulthood where increases in SBP slowed and SBP eventually declined. These phases were still present, although at lower levels, after adjusting for increases in body mass index though adulthood. The deceleration and decline in old age was less evident after excluding individuals who had taken antihypertensive medication. Compared to the population-based cohorts, the occupational cohort had a lower mean SBP, a shallower annual increase in midlife, and a later midlife acceleration. The maximum sex difference was found at age 26 (+8.2 mm Hg higher in men, 95% CI: 6.7, 9.8); women then experienced steeper rises and caught up by the seventh decade. Conclusions: Our investigation shows a general pattern of SBP progression from childhood in the UK, and suggests possible differences in this pattern during adulthood between a general population and an occupational population. Please see later in the article for the Editors’ Summary.
TL;DR: GWG in all stages of pregnancy was positively associated with later BMI, WC, increased odds of overweight or obesity, and central adiposity and this support initiatives aimed at optimizing prepregnancy weight.
TL;DR: Pre-pregnancy obesity or excessive GWG are associated with greater risk of pregnancy complications, caesarean delivery and greater birth and placenta weight and it is vital that clinical practice considers excess GWG as another indicator of adverse pregnancy outcomes.
Abstract: It is relatively less known whether pre-pregnancy obesity and excess gestational weight gain (GWG) are associated with caesarean delivery, pregnancy complications, preterm birth, birth and placenta weights and increased length of postnatal hospital stay. We used a population-based cohort of 6632 women who gave birth in Brisbane, Australia, between 1981 and 1983. The independent associations of pre-pregnancy obesity, GWG and institute of medicine (IOM) categories of combined pre-pregnancy BMI and GWG with outcomes were examined using multivariable regression (for continuous outcomes) and multivariable multinomial regression (for categorical outcomes) models. We found women who were obese prior to pregnancy and women who gained excess weight during pregnancy were at greater risk for a pregnancy complications (OR: 2.10; 1.74, 2.54; age adjusted model), caesarean section (OR 1.29; 1.09, 1.54), higher birth weight difference (206.45 gm; 178.82, 234.08) and greater placental weight difference (41.16 gm; 33.83, 48.49) and longer length of hospital stay. We also found that mothers who gained inadequate weight or were underweight before pregnancy were at greater risk of preterm birth (2.27; 1.71, 3.00), lower risk of pregnancy complications (0.58; 0.44, 0.77) and had lower birth (-190.63;-221.05,-160.20) and placental (-37.16; -45.23,-29.09) weights. Results indicate that all associations remain consistent after adjustment for a range of potential confounding factors with the exception of the association between pre-pregnancy obesity and hospital stay. Pre-pregnancy obesity or excessive GWG are associated with greater risk of pregnancy complications, caesarean delivery and greater birth and placenta weight. Excess GWG is associated with a longer stay in hospital after delivery, independent of pre-pregnancy BMI, pregnancy complications and caesarean delivery. In addition to pre-pregnancy obesity, it is vital that clinical practice considers excess GWG as another indicator of adverse pregnancy outcomes.
Queen Mary University of London1, Medical Research Council2, King's College London3, University of Glasgow4, Glenfield Hospital5, University of Leicester6, University College London7, Imperial College London8, University of Ioannina9, University College Dublin10, St George's, University of London11, University of Cambridge12, University of Dundee13, Centre for Mental Health14, University of Edinburgh15, University of Michigan16, Health Protection Agency17, University Medical Center Groningen18, University of Sassari19, Mount Carmel Health20, University of Milan21, Katholieke Universiteit Leuven22, French Institute of Health and Medical Research23, Paris Descartes University24, University of Tartu25, Tallinn University of Technology26, University of Gothenburg27, University of Oslo28, Lund University29, University of Ottawa30, Clinical Trial Service Unit31, John Radcliffe Hospital32, Wellcome Trust Centre for Human Genetics33, Karolinska University Hospital34, University of Münster35, Wellcome Trust Sanger Institute36, University of London37, GlaxoSmithKline38, AstraZeneca39, Harvard University40, Royal College of Surgeons in Ireland41
TL;DR: An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci and highlighted the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
Abstract: Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
University of Leicester1, University of Oxford2, Nottingham University Hospitals NHS Trust3, University of Bristol4, Queen Mary University of London5, University of Glasgow6, Ontario Institute for Cancer Research7, Mount Sinai Hospital, Toronto8, University College London9, St George's, University of London10, Wellcome Trust Sanger Institute11, University of Cambridge12, University of Southampton13, University of Gothenburg14, University of Edinburgh15, University of Nottingham16, National Institute for Health and Welfare17, University of Helsinki18, AstraZeneca19, Southampton General Hospital20, Sir Charles Gairdner Hospital21, University of St Andrews22
TL;DR: Variants in TNS1, GSTCD, and HTR4 are associated with COPD and the association of the risk score to lung function and COPD was significant for three loci and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4.
Abstract: Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.
Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP.
Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD.
Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10–12 risk alleles was associated with a reduction in FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 10−5).
Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.
TL;DR: It is shown that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
Abstract: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 x 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 x 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 x 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
TL;DR: In normal-weight mothers, most of the association between MWG and later offspring BMI is explained by shared familial and early environmental characteristics, whereas evidence indicates a contribution of intrauterine mechanisms in overweight and obese women.
01 Jan 2011
TL;DR: In this article, the authors examined the association of greater maternal weight gain (MWG; postnatal weight minus weight at the first antenatal clinic assessment) with greater offspring body mass index (BMI), but whether this association is caused by intrauterine mechanisms or by shared genetic and environmental risk factors for adiposity is unclear.
Abstract: Background: A small number of relatively small studies have found greater gestational weight gain to be associated with greater offspring body mass index (BMI; in kg/m 2 ), but whether this association is caused by intrauterine mechanisms or by shared genetic and environmental risk factors for adiposity is unclear. Objective: The objective was to examine the association of greater maternal weight gain (MWG; postnatal weight minus weight at the first antenatal clinic assessment) with greater offspring BMI and to explore whether any observed association is explained by intrauterine mechanisms. Design: This was a prospective cohort study that used record linkage data (n = 146,894 individuals from 136,050 families). To compare the within-sibling and between-nonsibling associations, we used fixed- and between-cluster linear regression models. Results: Associations of MWG with later offspring BMI differed by the mother’s early-pregnancy overweight or obesity status (P for interaction ,0.0001). MWG was positively associated with BMI at a mean age of 18 y in the offspring of normal-weight women but only between unrelated men (0.07; 95% CI: 0.06, 0.07) per 1-kg greater MWG; no within-sibling association (0.00; 95% CI: 20.02, 0.02) per 1-kg greater MWG was found. In contrast, in overweight and obese women we found a within-sibling association (0.06; 95% CI: 0.01, 0.12) and an association between unrelated men (0.02; 95% CI: 0.01, 0.03) per 1-kg greater MWG. Conclusion: In normal-weight mothers, most of the association between MWG and later offspring BMI is explained by shared familial (genetic and early environmental) characteristics, whereas evidence indicates a contribution of intrauterine mechanisms in overweight and obese women. Am J Clin Nutr doi: 10. 3945/ajcn.110.009324.
TL;DR: There is little consistent evidence of intrauterine effects of maternal prepregnancy overweight on child cognition and behavior, and associations initially observed were not consistently replicated across cohorts or robust to adjustment for confounding factors.
Abstract: OBJECTIVE: Greater maternal prepregnancy adiposity has been associated with behavioral problems, such as attention-deficit/hyperactivity disorder, and lower intellectual function in offspring. However, few studies of humans have explored this, and it is unclear if intrauterine mechanisms or confounding factors drive these associations. PATIENTS AND METHODS: Parental adiposity and offspring verbal skills, nonverbal skills, and behavioral problems were assessed in the British Avon Longitudinal Study of Parents and Children ( N = ∼5000) and Dutch Generation R ( N = ∼2500) cohorts. We aimed to determine the plausibility of intrauterine effects by (1) adjusting for multiple confounders, (2) comparing associations between maternal and paternal overweight with offspring cognition/behaviors, and (3) searching for cross-cohort consistency. RESULTS: Maternal prepregnancy overweight was associated with reduced child verbal skills (unadjusted). However, after adjusting for confounders, this result was not consistently observed in both cohorts. Maternal overweight was also associated with child total behavior problems and externalizing problems even after adjusting for confounders. However, this was observed in Generation R only and was not replicated in the British Avon Longitudinal Study of Parents and Children. No associations of maternal overweight with child attention problems, emotional/internalizing problems, or nonverbal skills were observed in either cohort. Paternal overweight was not associated with any of the child outcomes but was also less strongly related to potential confounding factors than was maternal overweight. CONCLUSIONS: Overall, we found little consistent evidence of intrauterine effects of maternal prepregnancy overweight on child cognition and behavior. Some associations initially observed were not consistently replicated across cohorts or robust to adjustment for confounding factors and, thus, are likely to reflect confounding by socioeconomic or postnatal factors.
TL;DR: Smoking status modifies the association between the 15q25 SNP, rs1051730, and BMI, which strengthens evidence that smoking exposure is causally associated with reduced BMI.
Abstract: Background Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers.
Methods We stratified nine European study samples by smoking status and, in each stratum, analysed the association between genotype of the 15q25 SNP, rs1051730, and BMI. We meta-analysed the results (n = 24 198) and then tested for a genotype × smoking status interaction.
Results There was no evidence of association between BMI and genotype in the never smokers {difference per T-allele: 0.05 kg/m2 [95% confidence interval (95% CI): −0.05 to 0.18]; P = 0.25}. However, in ever smokers, each additional smoking-related T-allele was associated with a 0.23 kg/m2 (95% CI: 0.13–0.31) lower BMI (P = 8 × 10−6). The effect size was larger in current [0.33 kg/m2 lower BMI per T-allele (95% CI: 0.18–0.48); P = 6 × 10−5], than in former smokers [0.16 kg/m2 (95% CI: 0.03–0.29); P = 0.01]. There was strong evidence of genotype × smoking interaction (P = 0.0001).
Conclusions Smoking status modifies the association between the 15q25 variant and BMI, which strengthens evidence that smoking exposure is causally associated with reduced BMI. Smoking cessation initiatives might be more successful if they include support to maintain a healthy BMI.
TL;DR: The results imply that interventions to prevent inequalities in childhood obesity should begin in pre-school years, with daughters of more educated women being less adipose.
Abstract: Background. Socioeconomic inequalities in obesity are consistently observed in high-income countries. The development of such inequalities across childhood; however, has not been studied using long...
Medical Research Council1, University of Bristol2, university of lille3, Pasteur Institute4, University of Western Australia5, Wellcome Trust Sanger Institute6, Harokopio University7, University of Southern Denmark8, University of Oxford9, University of Toronto10, Wellcome Trust Centre for Human Genetics11, Nancy-Université12, University of Glasgow13, Imperial College London14, Örebro University15
TL;DR: Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults, suggesting age-independent effects of these fasting glucose Loci contribute to long-term interindividual differences in glucose levels from childhood onwards.
Abstract: OBJECTIVE-To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents. RESEARCH DESIGN AND METHODS-A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS-Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced p-cell function, as indicated by homeostasis model assessment of beta-cell function. Analysis using a weighted risk score showed an increase [beta (95% CI)] in fasting glucose level of 0.026 mrnol/L (0.021-0.031) for each unit increase in the score. CONCLUSIONS-Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards. Diabetes 60:1805-1812, 2011
TL;DR: It was found that at 18 weeks of gestation, the prevalence of engaging in physical activity that was sufficient to cause sweating for ≥3 h/week (referred to as strenuous physical activity) was 48.8%, and this percentage was similar at 32 the authors weeks of gestation.
Abstract: We sought to examine the levels, types, and changes of physical activity and their correlates among pregnant women. Data came from 9,889 pregnant women with due dates between April 1, 1991 and December 31, 1992 who were participants of the Avon Longitudinal Study of Parents and Children (ALSPAC) in Bristol, Avon, Southwest England. Self-reported physical activity during pregnancy was collected via questionnaires administered at 18 and 32 weeks of gestation. We found, at 18 weeks of gestation, the prevalence of engaging in physical activity that was sufficient to cause sweating for ≥3 h/week (referred to as strenuous physical activity) was 48.8%. This percentage was similar at 32 weeks of gestation. The most common physical activity during pregnancy reported by these women was brisk walking, followed by swimming and ante-natal exercise. In models that mutually adjusted for all characteristics examined, younger women, women in lower social classes, those not employed during pregnancy, married and parous women (compared to those not in each of these groups) were more likely to report engaging in strenuous physical activity. After becoming pregnant, about two out of three of these women reported reducing physical activity levels at 18 weeks of gestation. In mutually adjusted models, women who were younger, fit and well, parous, and women from lower social classes (compared to those not in each of these groups) were less likely to report reducing their physical activity. Our findings provide insights that are relevant to the design of future observational and intervention studies concerned with the effects of physical activity during pregnancy on health outcomes for mothers and offspring.
TL;DR: Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals, and one explanation for the results is that raised circulating lipid levels are predominantly secondary to the diabetes disease process rather than causal.
Abstract: OBJECTIVE The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance. RESEARCH DESIGN AND METHODS We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies. RESULTS Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002). CONCLUSIONS Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal.
TL;DR: The findings suggest that different mechanisms underlie the association of younger and older maternal age with adverse perinatal outcomes, with different mechanisms explained by Socio-economic position and other characteristics shared by sisters.
Abstract: BACKGROUND: The mechanisms underlying the association between maternal age (both young and older maternal age) and adverse perinatal outcomes are unclear.
METHODS: We examined the association of maternal age at first birth with preterm birth (<37 weeks gestation) and small for gestational age (SGA) in a cohort of 264 695 Danish women, each of which had at least one sister in the cohort (n = 121 859 sibling groups). We compared cohort analyses with sister-controlled analyses. The sister-controlled analyses control for all observed and unobserved characteristics that are identical or very similar between sisters, such as childhood socio-economic characteristics-a confounder we hypothesized would exaggerate the young maternal age-adverse outcomes association but mask the older maternal age-adverse outcome association.
RESULTS: There was a U-shaped association of maternal age with risk of preterm birth (lowest risk age 24-30 years) and SGA (lowest risk age 26-30 years) in cohort analyses. In analyses with sister control, there was a J-shaped association of maternal age with preterm birth, with a monotonic increase in risk across the maternal age range from 24 years of maternal age. For SGA, risk increased across the age range in sister-controlled analyses, being lowest at age 15 years and highest at age 45 years (thought with wide confidence intervals at the extremes of the age distribution).
CONCLUSIONS: Our findings suggest that different mechanisms underlie the association of younger and older maternal age with adverse perinatal outcomes. Socio-economic position and other characteristics shared by sisters appear to explain most of the association of young maternal age with adverse perinatal outcomes, but the association of older maternal age with preterm birth, and SGA is not explained by this confounding and may even be masked by it.
TL;DR: Overweight and obesity at all ages had a strong tendency to persist to age 15 years as indicated by risk ratios and mid–late childhood (around age 7–11 years) may merit greater attention in future obesity prevention interventions.
TL;DR: Higher calcium levels might be a more important predictor of increased cardiovascular risk in adolescents than lower 25(OH)D levels or PTH levels, but the findings require replication in additional studies and examination in prospective studies.
Abstract: Objective To examine independent associations of serum 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH) and calcium with a range of cardiovascular risk factors in adolescents. Design Cross-sectional population-based study. Setting A nationally representative sample of the US adolescent population. Participants Healthy adolescents (aged 12–19) participating in the National Health and Nutrition Examination Survey (NHANES) between 2001 and 2006. Numbers varied between 740 and 5609 for given exposure and outcome associations. Main outcome measures Systolic blood pressure (SBP), diastolic blood pressure (DBP), lipids (triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)), fasting insulin and glucose, postload glucose and glycohaemoglobin (HbA1c). Results 25(OH)D was inversely associated with SBP (−0.068 standard deviations (SD), 95% CI −0.118 to −0.018), and positively associated with HDL-C (0.101; 0.040 to 0.162) and HbA1c (0.073; 0.021 to 0.125) after adjustment for gender, age, ethnicity, socioeconomic status and waist circumference. In adjusted models, PTH was inversely associated with triglycerides (−0.115; −0.188 to −0.042) and LDL-C (−0.133; −0.207 to −0.060). In adjusted models, calcium was positively associated with fasting insulin (0.110; 0.060 to 0.160), postload glucose (0.116; 0.000 to 0.232), HbA1c (0.079; 0.035 to 0.123), triglycerides (0.182; 0.122 to 0.242), HDL-C (0.049; 0.010 to 0.088) and LDL-C (0.137; 0.080 to 0.195). The associations of each exposure with risk factors remained after mutual adjustment for each other. Conclusion Higher calcium levels might be a more important predictor of increased cardiovascular risk in adolescents than lower 25(OH)D levels or PTH levels, but the findings require replication in additional studies and examination in prospective studies.
TL;DR: Established preeclampsia risk factors are associated with higher BP in early pregnancy and faster BP increases later in gestation in normal pregnancy, suggesting a continuum of risk.
Abstract: ObjectiveHypertension during pregnancy is one of the diagnostic criteria for preeclampsia. We investigated the pattern of blood pressure (BP) change across pregnancy and associations of risk factors for preeclampsia with BP changes in normal pregnancy.MethodsWe examined repeat antenatal BP measureme