Showing papers by "Debbie A Lawlor published in 2013"

Cohort Profile: The ‘Children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children

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.

Cohort Profile: The Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort

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.

Exercise for depression

Abstract: BACKGROUND: Depression is a common and important cause of morbidity and mortality worldwide. Depression is commonly treated with antidepressants and/or psychological therapy, but some people may prefer alternative approaches such as exercise. There are a number of theoretical reasons why exercise may improve depression. This is an update of an earlier review first published in 2009. OBJECTIVES: To determine the effectiveness of exercise in the treatment of depression in adults compared with no treatment or a comparator intervention. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Controlled Trials Register (CCDANCTR) to 13 July 2012. This register includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years); MEDLINE (1950 to date); EMBASE (1974 to date) and PsycINFO (1967 to date). We also searched www.controlled-trials.com, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. No date or language restrictions were applied to the search.We conducted an additional search of the CCDANCTR up to 1st March 2013 and any potentially eligible trials not already included are listed as 'awaiting classification.' SELECTION CRITERIA: Randomised controlled trials in which exercise (defined according to American College of Sports Medicine criteria) was compared to standard treatment, no treatment or a placebo treatment, pharmacological treatment, psychological treatment or other active treatment in adults (aged 18 and over) with depression, as defined by trial authors. We included cluster trials and those that randomised individuals. We excluded trials of postnatal depression. DATA COLLECTION AND ANALYSIS: Two review authors extracted data on primary and secondary outcomes at the end of the trial and end of follow-up (if available). We calculated effect sizes for each trial using Hedges' g method and a standardised mean difference (SMD) for the overall pooled effect, using a random-effects model risk ratio for dichotomous data. Where trials used a number of different tools to assess depression, we included the main outcome measure only in the meta-analysis. Where trials provided several 'doses' of exercise, we used data from the biggest 'dose' of exercise, and performed sensitivity analyses using the lower 'dose'. We performed subgroup analyses to explore the influence of method of diagnosis of depression (diagnostic interview or cut-off point on scale), intensity of exercise and the number of sessions of exercise on effect sizes. Two authors performed the 'Risk of bias' assessments. Our sensitivity analyses explored the influence of study quality on outcome. MAIN RESULTS: Thirty-nine trials (2326 participants) fulfilled our inclusion criteria, of which 37 provided data for meta-analyses. There were multiple sources of bias in many of the trials; randomisation was adequately concealed in 14 studies, 15 used intention-to-treat analyses and 12 used blinded outcome assessors.For the 35 trials (1356 participants) comparing exercise with no treatment or a control intervention, the pooled SMD for the primary outcome of depression at the end of treatment was -0.62 (95% confidence interval (CI) -0.81 to -0.42), indicating a moderate clinical effect. There was moderate heterogeneity (I² = 63%).When we included only the six trials (464 participants) with adequate allocation concealment, intention-to-treat analysis and blinded outcome assessment, the pooled SMD for this outcome was not statistically significant (-0.18, 95% CI -0.47 to 0.11). Pooled data from the eight trials (377 participants) providing long-term follow-up data on mood found a small effect in favour of exercise (SMD -0.33, 95% CI -0.63 to -0.03).Twenty-nine trials reported acceptability of treatment, three trials reported quality of life, none reported cost, and six reported adverse events.For acceptability of treatment (assessed by number of drop-outs during the intervention), the risk ratio was 1.00 (95% CI 0.97 to 1.04).Seven trials compared exercise with psychological therapy (189 participants), and found no significant difference (SMD -0.03, 95% CI -0.32 to 0.26). Four trials (n = 300) compared exercise with pharmacological treatment and found no significant difference (SMD -0.11, -0.34, 0.12). One trial (n = 18) reported that exercise was more effective than bright light therapy (MD -6.40, 95% CI -10.20 to -2.60).For each trial that was included, two authors independently assessed for sources of bias in accordance with the Cochrane Collaboration 'Risk of bias' tool. In exercise trials, there are inherent difficulties in blinding both those receiving the intervention and those delivering the intervention. Many trials used participant self-report rating scales as a method for post-intervention analysis, which also has the potential to bias findings. AUTHORS' CONCLUSIONS: Exercise is moderately more effective than a control intervention for reducing symptoms of depression, but analysis of methodologically robust trials only shows a smaller effect in favour of exercise. When compared to psychological or pharmacological therapies, exercise appears to be no more effective, though this conclusion is based on a few small trials. Language: en

GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment

Abstract: A genome-wide association study of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent SNPs are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (R2 ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈ 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

Cohort Profile: The Born in Bradford multi-ethnic family cohort study

Abstract: Bradford Institute for Health Research, Bradford Teaching Hospitals Foundation Trust, Bradford, UK, School of Health Studies, University of Bradford, Bradford, UK, Edinburgh Ethnicity and Health Research Group, Centre for Population Health Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK, School of Sport, Exercise and Health Sciences, Loughborough University, Leicestershire, UK, Medical Research Council Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK, Paediatric Epidemiology Group, Centre for Epidemiology and Biostatistics, Leeds Institute of Genetics, Health and Therapeutics, Faculty of Medicine and Health, University of Leeds, Leeds, UK and Department of Health Sciences, University of York, York, UK

Genome-wide meta-analysis identifies new susceptibility loci for migraine

Abstract: Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls We identified 12 loci associated with migraine susceptibility (P<5×10(-8)) Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21 Three of these loci were identified in disease subgroup analyses Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B

New loci associated with birth weight identify genetic links between intrauterine growth and adult height 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.

Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts

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.

Loss to follow-up in cohort studies: bias in estimates of socioeconomic inequalities.

Abstract: Background:Although cohort members tend to be healthy and affluent compared with the whole population, some studies indicate this does not bias certain exposure-outcome associations. It is less clear whether this holds when socioeconomic position (SEP) is the exposure of interest.Methods:As an illus

Pregnancy and Birth Cohort Resources in Europe: a Large Opportunity for Aetiological Child Health Research

Abstract: BACKGROUND During the past 25 years, many pregnancy and birth cohorts have been established. Each cohort provides unique opportunities for examining associations of early-life exposures with child development and health. However, to fully exploit the large amount of available resources and to facilitate cross-cohort collaboration, it is necessary to have accessible information on each cohort and its individual characteristics. The aim of this work was to provide an overview of European pregnancy and birth cohorts registered in a freely accessible database located at http://www.birthcohorts.net. METHODS European pregnancy and birth cohorts initiated in 1980 or later with at least 300 mother-child pairs enrolled during pregnancy or at birth, and with postnatal data, were eligible for inclusion. Eligible cohorts were invited to provide information on the data and biological samples collected, as well as the timing of data collection. RESULTS In total, 70 cohorts were identified. Of these, 56 fulfilled the inclusion criteria encompassing a total of more than 500,000 live-born European children. The cohorts represented 19 countries with the majority of cohorts located in Northern and Western Europe. Some cohorts were general with multiple aims, whilst others focused on specific health or exposure-related research questions. CONCLUSION This work demonstrates a great potential for cross-cohort collaboration addressing important aspects of child health. The web site, http://www.birthcohorts.net, proved to be a useful tool for accessing information on European pregnancy and birth cohorts and their characteristics.

Parental depressive and anxiety symptoms during pregnancy and attention problems in children: A cross-cohort consistency study

Abstract: Background: Maternal depression and anxiety during pregnancy have been associated with offspring-attention deficit problems. Aim: We explored possible intrauterine effects by comparing maternal and paternal symptoms during pregnancy, by investigating cross-cohort consistency, and by investigating whether parental symptoms in early childhood may explain any observed intrauterine effect. Methods: This study was conducted in two cohorts (Generation R, n = 2,280 and ALSPAC, n = 3,442). Pregnant women and their partners completed questionnaires to assess symptoms of depression and anxiety. Child attention problems were measured in Generation R at age 3 with the Child Behavior Checklist, and in ALSPAC at age 4 with the Strengths and Difficulties Questionnaire. Results: In both cohorts, antenatal maternal symptoms of depression (Generation R: OR 1.23, 95% CI 1.05-1.43; ALSPAC: OR 1.33, 95% CI 1.19-1.48) and anxiety (Generation R: OR 1.24, 95% CI 1.06-1.46; ALSPAC: OR 1.32, 95% CI 1.19-1.47) were associated with a higher risk of child attention problems. In ALSPAC, paternal depression was also associated with a higher risk of child attention problems (OR 1.11, 95% CI 1.00-1.24). After adjusting for maternal symptoms after giving birth, antenatal maternal depression and anxiety were no longer associated with child attention problems in Generation R. Moreover, there was little statistical evidence that antenatal maternal and paternal depression and anxiety had a substantially different effect on attention problems of the child. Conclusions: The apparent intrauterine effect of maternal depression and anxiety on offspring-behavioural problems may be partly explained by residual confounding. There was little evidence of a difference between the strength of associations of maternal and paternal symptoms during pregnancy with offspring-attention problems. That maternal symptoms after childbirth were also associated with offspring-behavioural problems may indicate a contribution of genetic influences to the association.

Vitamin D and pre-eclampsia: original data, systematic review and meta-analysis

Abstract: Background/Aims: Vitamin D may protect from pre-eclampsia through influences on immune modulation and vascular function. To evaluate the role of vitamin D in the development of pre-eclampsia, we conducted a systematic review and meta-analysis including novel data from 2 large-scale epidemiological studies. Methods: PubMed, EMBASE and the Cochrane Central Register of Controlled Trials were searched for prospective observational studies of association between vitamin D supplementation or status (measured by maternal 25-hydroxyvitamin D, 25(OH)D) with a subsequent risk of pre-eclampsia, or randomised controlled trials using vitamin D supplementation to prevent pre-eclampsia. The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) and the Avon Longitudinal Study of Parents and Children (ALSPAC) were included in meta-analyses with published studies. Results: Mothers receiving vitamin D supplementation earlier in pregnancy had lower odds of pre-eclampsia [pooled odds ratios (OR) 0.81 and 95% confidence interval (CI) 0.75-0.87, p = 2.4 × 10-8, 2 studies] in the meta-analysis of published studies with HCCSCA. The meta-analysis of published studies with ALSPAC suggested an association between higher serum 25(OH)D levels and a reduced risk of pre-eclampsia (pooled OR 0.52 and 95% CI 0.30-0.89, p = 0.02, 6 studies). Randomised trials of supplementation were suggestive of protective association (pooled OR 0.66 and 95% CI 0.52-0.83, p = 0.001, 4 studies). Conclusions: This study suggests that low maternal serum 25(OH)D concentrations increase pre-eclampsia risk and that vitamin D supplementation lowers this risk. The quality of evidence is insufficient to determine a causal association, which highlights the need for adequately powered clinical trials.

Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: systematic review and meta-analysis of 14,015 stroke cases and pooled analysis of primary biomarker data from up to 60,883 individuals

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.

Association of maternal vitamin D status during pregnancy with bone-mineral content in offspring: a prospective cohort study

Abstract: Maternal vitamin D status in pregnancy is a suggested determinant of bone-mineral content (BMC) in offspring, but has been assessed in small studies. The authors investigated this association in a large prospective study.

The Society for Social Medicine John Pemberton Lecture 2011. Developmental overnutrition—an old hypothesis with new importance?

Abstract: This paper is concerned with whether mothers who are more adipose or have higher glucose levels during pregnancy may overfeed their developing infants in utero and in doing so may set them on a pathway to greater adiposity throughout their lives. If this is the case, then the more adipose daughters of these mothers may also subsequently overfeed their infants in utero, thereby perpetuating the risk of greater adiposity across generations. I begin with the historical context of how gestational diabetes was first recognized and early evidence that diabetes in pregnancy results in increased birth size and adiposity. I then consider four questions, which are the main focus of the paper. Each of the four questions involves an exposure during pregnancy and evidence concerned with whether the exposure is causally related to offspring adiposity via intra-uterine mechanisms. The four related exposures are: (i) pregnancy diabetes; (ii) extreme maternal pregnancy obesity (440 kg/m or meeting criteria for bariatric surgery); (iii) incrementally greater pre-/early pregnancy adiposity across the whole distribution seen in pregnant women; and (iv) gestational weight gain. Since randomized controlled trial evidence is not available I focus on methods that can provide the best causal evidence from observational data such as negative control studies, family comparisons and using genetic variants as instrumental variables (i.e. Mendelian randomization studies). Having addressed these four questions I go on to briefly discuss the possible role of epigenetic modification mediating any effects of maternal exposures on offspring outcomes. I conclude with a discussion about the future research and policy implications of evidence to date in this field.

Hypertensive Disorders of Pregnancy and Cardiometabolic Health in Adolescent Offspring

Abstract: An accumulating body of evidence suggests that offspring of mothers with preeclampsia have higher blood pressure during childhood and young adulthood compared with women without preeclampsia. However, the evidence with regard to offspring glucose metabolism and lipids is more scant. We examined whether maternal hypertensive disorders of pregnancy (preeclampsia and gestational hypertension) are associated with a range of cardiometabolic health measures in adolescent offspring. We included data for mother–offspring pairs from a United Kingdom prospective birth cohort (the Avon Longitudinal Study of Parents and Children). Repeat antenatal clinic measures of blood pressure and proteinuria (median 14 and 11, respectively) were used to ascertain maternal preeclampsia (n=53) and gestational hypertension (n=431). Offspring had blood pressure (n=4438), and fasting lipids, insulin, and glucose (n=2888) measured at a mean age of 17 years. There was no strong evidence of differences in fasting insulin, glucose, or lipid concentrations. Systolic and diastolic blood pressures were higher in offspring of mothers with gestational hypertension (mean difference, 2.06 mm Hg; 95% confidence interval, 1.28–2.84 and 1.11 mm Hg; 95% confidence interval, 0.54–1.69, respectively) and preeclampsia (1.12 mm Hg; 95% confidence interval, −0.89–3.12 and 1.71 mm Hg; 95% confidence interval, 0.23–3.17, respectively) compared with offspring of mothers without hypertensive disorders of pregnancy, adjusting for potential confounders (age, sex, maternal age at delivery, household social class, prepregnancy body mass index, parity, and smoking in pregnancy). Results suggest a specific association between maternal hypertensive disorders of pregnancy and offspring blood pressure that may be driven by genetics or familial nongenetic risk factors particular to blood pressure.

Genome-wide association study identifies loci affecting blood copper, selenium and zinc

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).

Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes

Abstract: Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

Mining the human phenome using allelic scores that index biological intermediates

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.

Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women

Abstract: Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n=4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p=1.7x109) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p=1.3x108) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5597 for femoral neck; n=4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3x1011; ESR1/C6orf97 joint p=1.4x1010). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p<1x105). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. (c) 2013 American Society for Bone and Mineral Research.

Exploring causal associations between alcohol and coronary heart disease risk factors: findings from a Mendelian randomization study in the Copenhagen General Population Study

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.

Maternal 25‐hydroxyvitamin D and its association with childhood atopic outcomes and lung function

Abstract: It has been suggested that maternal vitamin D status in pregnancy influences the risk of asthma and atopy in the offspring. The epidemiological evidence to support these claims is conflicting and may reflect chance findings and differences in how vitamin D was assessed.

Association of a Body Mass Index Genetic Risk Score with Growth throughout Childhood and Adolescence

Abstract: Background: While the number of established genetic variants associated with adult body mass index (BMI) is growing, the relationships between these variants and growth during childhood are yet to be fully characterised. We examined the association between validated adult BMI associated single nucleotide polymorphisms (SNPs) and growth trajectories across childhood. We investigated the timing of onset of the genetic effect and whether it was sex specific. Methods: Children from the ALSPAC and Raine birth cohorts were used for analysis (n=9,328). Genotype data from 32 adult BMI associated SNPs were investigated individually and as an allelic score. Linear mixed effects models with smoothing splines were used for longitudinal modelling of the growth parameters and measures of adiposity peak and rebound were derived. Results: The allelic score was associated with BMI growth throughout childhood, explaining 0.58% of the total variance in BMI in females and 0.44% in males. The allelic score was associated with higher BMI at the adiposity peak (females = 0.0163 kg/m 2 per allele, males = 0.0123 kg/m 2 per allele) and earlier age (-0.0362 years per allele in males and females) and higher BMI (0.0332 kg/m 2 per allele in females and 0.0364 kg/m 2 per allele in males) at the adiposity rebound. No gene:sex interactions were detected for BMI growth. Conclusions: This study suggests that known adult genetic determinants of BMI have observable effects on growth from early childhood, and is consistent with the hypothesis that genetic determinants of adult susceptibility to obesity act from early childhood and develop over the life course.

UK-born Pakistani-origin infants are relatively more adipose than white British infants: findings from 8704 mother-offspring pairs in the Born-in-Bradford prospective birth cohort

Abstract: Background Previous studies have shown markedly lower birth weight among infants of South Asian origin compared with those of White European origin. Whether such differences mask greater adiposity in South Asian infants and whether they persist across generations in contemporary UK populations is unclear. Our aim was to compare birth weight, skinfold thickness and cord leptin between Pakistani and White British infants and to investigate the explanatory factors, including parental and grandparental birthplace. Methods We examined the differences in birth weight and skinfold thickness between 4649 Pakistani and 4055 White British infants born at term in the same UK maternity unit and compared cord leptin in a subgroup of 775 Pakistani and 612 White British infants. Results Pakistani infants were lighter (adjusted mean difference −234 g 95% CI −258 to −210) and were smaller in both subscapular and triceps skinfold measurements. The differences for subscapular and triceps skinfold thickness (mean z-score difference −0.27 95% CI −0.34 to −0.20 and −0.23 95% CI −0.30 to −0.16, respectively) were smaller than the difference in birth weight (mean z-score difference −0.52 95% CI −0.58 to −0.47) and attenuated to the null with adjustment for birth weight (0.03 95% CI −0.03 to 0.09 and −0.01 95% CI −0.08 to 0.05, respectively). Cord leptin concentration (indicator of fat mass) was similar in Pakistani and White British infants without adjustment for birth weight, but with adjustment became 30% higher (95% CI 17% to 44%) among Pakistani infants compared with White British infants. The magnitudes of difference did not differ by generation. Conclusions Despite being markedly lighter, Pakistani infants had similar skinfold thicknesses and greater total fat mass, as indicated by cord leptin, for a given birth weight than White British infants. Any efforts to reduce ethnic inequalities in birth weight need to consider differences in adiposity and the possibility that increasing birth weight in South Asian infants might inadvertently worsen health by increasing relative adiposity.

Associations of Maternal Weight Gain in Pregnancy With Offspring Cognition in Childhood and Adolescence: Findings From the Avon Longitudinal Study of Parents and Children

Abstract: An association of gestational weight gain (GWG) with offspring cognition has been postulated. We used data from the Avon Longitudinal Study of Parents and Children, a United Kingdom prospective cohort (1990 through the present) with a median of 10 maternal weight measurements in pregnancy. These were used to allocate participants to 2009 Institute of Medicine weight-gain categories and in random effect linear spline models. Outcomes were School Entry Assessment score (age, 4 years; n = 5,832), standardized intelligence quotient assessed by Wechsler Intelligence Scale for Children (age, 8 years; n = 5,191), and school final-examination results (age, 16 years; n = 7,339). Offspring of women who gained less weight than recommended had a 0.075 standard deviation lower mean School Entry Assessment score (95% confidence interval: -0.127, -0.023) and were less likely to achieve adequate final-examination results (odds ratio = 0.88, 95% confidence interval: 0.78, 0.99) compared with offspring of women who gained as recommended. GWG in early pregnancy (defined as 0-18 weeks on the basis of a knot point at 18 weeks) and midpregnancy (defined as 18-28 weeks on the basis of knot points at 18 and 28 weeks) was positively associated with School Entry Assessment score and intelligence quotient. GWG in late pregnancy (defined as 28 weeks onward on the basis of a knot point at 28 weeks) was positively associated with offspring intelligence quotient and with increased odds of offspring achieving adequate final-examination results in mothers who were overweight prepregnancy. Findings support small positive associations between GWG and offspring cognitive development, which may have lasting effects on educational attainment up to age 16 years.

Prospective association of 25-hydroxyvitamin d3 and d2 with childhood lung function, asthma, wheezing, and flexural dermatitis

Abstract: BACKGROUND: Higher serum total 25-hydroxyvitamin D (25(OH)D) concentrations have been associated with better lung function and lower risk of allergic disease. 25(OH)D3 constitutes the majority of total 25(OH)D and has been suggested to be more potent than 25(OH)D2. We studied the prospective associations of 25(OH)D2 and 25(OH)D3 with asthma, wheezing, flexural dermatitis, and lung function in children who participated in the Avon Longitudinal Study of Parents and Children - a population-based contemporary birth cohort of children born in 1991-1992 from South West England. METHODS: Serum 25(OH)D2 and 25(OH)D3 concentrations, measured at a mean age of 9.8 years, were related to incident cases of wheezing (study sample: n = 3,323, 141 cases; 4%), asthma (n = 3,323, 464 cases; 14%), and flexural dermatitis (n = 3,748, 300 cases; 8%), as well as lung function (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and mid-forced expiratory flow assessed at a mean age of 15.5 years: n = 2,259). RESULTS: 25(OH)D2 was inversely associated with flexural dermatitis (adjusted odds ratio per doubling of exposure = 0.83 [95% confidence interval = 0.72-0.94]) and wheezing (0.83 [0.68-1.00]), and 25(OH)D3 was positively associated with flexural dermatitis (1.09 [1.00-1.18]) and wheezing (1.14 [1.03-1.28]). 25(OH)D2 was weakly positively associated with FEV1, and FVC. 25(OH)D3 was not associated with lung function. CONCLUSIONS: These results suggest that higher 25(OH)D3 concentrations are associated with increased risk of wheezing and flexural dermatitis. Despite being one of the few prospective studies and being able to adjust for confounders, these findings need replication. Our results do not provide strong evidence that lower concentrations of vitamin D are detrimental to respiratory and allergic health in children.

GWAS of 126,559 individuals identifies genetic variants associated with educational attainment

Abstract: Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467, published online 30 May; see the Perspective by Flint and Munafò) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment. Three genetic loci are found to explain variation associated with educational achievement. [Also see Perspective by Flint and Munafò] A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R2 ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.