Showing papers by "George Davey Smith published in 2011"

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

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.

Hydrogen production from formic acid decomposition at room temperature using a Ag-Pd core-shell nanocatalyst

Abstract: Formic acid (HCOOH) has great potential as an in situ source of hydrogen for fuel cells, because it offers high energy density, is non-toxic and can be safely handled in aqueous solution. So far, there has been a lack of solid catalysts that are sufficiently active and/or selective for hydrogen production from formic acid at room temperature. Here, we report that Ag nanoparticles coated with a thin layer of Pd atoms can significantly enhance the production of H₂ from formic acid at ambient temperature. Atom probe tomography confirmed that the nanoparticles have a core-shell configuration, with the shell containing between 1 and 10 layers of Pd atoms. The Pd shell contains terrace sites and is electronically promoted by the Ag core, leading to significantly enhanced catalytic properties. Our nanocatalysts could be used in the development of micro polymer electrolyte membrane fuel cells for portable devices and could also be applied in the promotion of other catalytic reactions under mild conditions.

Multiple risk factor interventions for primary prevention of coronary heart disease

Abstract: Multiple risk factor interventions using counselling and educational methods assumed to be efficacious and cost-effective in reducing coronary heart disease (CHD) mortality and morbidity and that they should be expanded. Trials examining risk factor changes have cast doubt on the effectiveness of these interventions. The objective of this review is to assess the effects of multiple risk factor interventions for reducing total mortality, fatal and non-fatal events from CHD and cardiovascular risk factors among adults assumed to be without prior clinical evidence of CHD..

Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function

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.

What are the causal effects of breastfeeding on IQ, obesity and blood pressure? Evidence from comparing high-income with middle-income cohorts

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.

Epidemiology, epigenetics and the ‘Gloomy Prospect’: embracing randomness in population health research and practice

Abstract: Epidemiologists aim to identify modifiable causes of disease, this often being a prerequisite for the application of epidemiological findings in public health programmes, health service planning and clinical medicine. Despite successes in identifying causes, it is often claimed that there are missing additional causes for even reasonably well-understood conditions such as lung cancer and coronary heart disease. Several lines of evidence suggest that largely chance events, from the biographical down to the sub-cellular, contribute an important stochastic element to disease risk that is not epidemiologically tractable at the individual level. Epigenetic influences provide a fashionable contemporary explanation for such seemingly random processes. Chance events—such as a particular lifelong smoker living unharmed to 100 years—are averaged out at the group level. As a consequence population-level differences (for example, secular trends or differences between administrative areas) can be entirely explicable by causal factors that appear to account for only a small proportion of individual-level risk. In public health terms, a modifiable cause of the large majority of cases of a disease may have been identified, with a wild goose chase continuing in an attempt to discipline the random nature of the world with respect to which particular individuals will succumb. The quest for personalized medicine is a contemporary manifestation of this dream. An evolutionary explanation of why randomness exists in the development of organisms has long been articulated, in terms of offering a survival advantage in changing environments. Further, the basic notion that what is near-random at one level may be almost entirely predictable at a higher level is an emergent property of many systems, from particle physics to the social sciences. These considerations suggest that epidemiological approaches will remain fruitful as we enter the decade of the epigenome.

Instrumental Variable Estimation of Causal Risk Ratios and Causal Odds Ratios in Mendelian Randomization Analyses

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.

Association between Common Variation at the FTO Locus and Changes in Body Mass Index from Infancy to Late Childhood: The Complex Nature of Genetic Association through Growth and Development

Abstract: An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10-20) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10-23). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (-0.40% (95% CI: -0.74, -0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (-4.72% (-5.81, -3.63), p = 10-17), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.

Unnecessary contraindications for mobile-bearing unicompartmental knee replacement

Abstract: The contraindications for unicompartmental knee replacement (UKR) remain controversial. The views of many surgeons are based on Kozinn and Scott's 1989 publication which stated that patients who weighed more than 82 kg, were younger than 60 years, undertook heavy labour, had exposed bone in the patellofemoral joint or chondrocalcinosis, were not ideal candidates for UKR. Our aim was to determine whether these potential contraindications should apply to patients with a mobile-bearing UKR. In order to do this the outcome of patients with these potential contraindications was compared with that of patients without the contraindications in a prospective series of 1000 UKRs. The outcome was assessed using the Oxford knee score, the American Knee Society score, the Tegner activity score, revision rate and survival. The clinical outcome of patients with each of the potential contraindications was similar to or better than those without each contraindication. Overall, 678 UKRs (68%) were performed in patients who had at least one potential contraindication and only 322 (32%) in patients deemed to be ideal. The survival at ten years was 97.0% (95% confidence interval 93.4 to 100.0) for those with potential contraindications and 93.6% (95% confidence interval 87.2 to 100.0) in the ideal patients. We conclude that the thresholds proposed by Kozinn and Scott using weight, age, activity, the state of the patellofemoral joint and chondrocalcinosis should not be considered to be contraindications for the use of the Oxford UKR.

Blood Pressure Loci Identified with a Gene-Centric Array

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.

Social Determinants and the Decline of Cardiovascular Diseases: Understanding the Links

Abstract: This article reviews the historical declines in cardiovascular mortality and provides an overview of the contribution of social and economic factors to disease change. We document the magnitude of declines in cardiovascular diseases and the major role of changes in conventional risk factors, and we review the contributions of social determinants to changes in disease rates. We conclude by arguing that understanding patterns and trends of social inequalities in cardiovascular disease and its risk factors requires consideration of the specific intersections of health and social exposures acting across the life course in different settings, in both time and place.

Genome-wide population-based association study of extremely overweight young adults--the GOYA study.

Abstract: Background: Thirty-two common variants associated with body mass index (BMI) have been identified in genome-wide association studies, explaining ,1.45% of BMI variation in general population cohorts. We performed a genome-wide association study in a sample of young adults enriched for extremely overweight individuals. We aimed to identify new loci associated with BMI and to ascertain whether using an extreme sampling design would identify the variants known to be associated with BMI in general populations. Methodology/Principal Findings: From two large Danish cohorts we selected all extremely overweight young men and women (n=2,633), and equal numbers of population-based controls (n=2,740, drawn randomly from the same populations as the extremes, representing ,212,000 individuals). We followed up novel (at the time of the study) association signals (p,0.001) from the discovery cohort in a genome-wide study of 5,846 Europeans, before attempting to replicate the most strongly associated 28 SNPs in an independent sample of Danish individuals (n=20,917) and a population-based cohort of 15-year-old British adolescents (n=2,418). Our discovery analysis identified SNPs at three loci known to be associated with BMI with genome-wide confidence (P,5610 28 ; FTO, MC4R and FAIM2). We also found strong evidence of association at the known TMEM18, GNPDA2, SEC16B, TFAP2B, SH2B1 and KCTD15 loci (p,0.001), and nominal association (p,0.05) at a further 8 loci known to be associated with BMI. However, meta-analyses of our discovery and replication cohorts identified no novel associations. Significance: Our results indicate that the detectable genetic variation associated with extreme overweight is very similar to that previously found for general BMI. This suggests that population-based study designs with enriched sampling of individuals with the extreme phenotype may be an efficient method for identifying common variants that influence quantitative traits and a valid alternative to genotyping all individuals in large population-based studies, which may require tens of thousands of subjects to achieve similar power.

Use of genetic markers and gene-diet interactions for interrogating population-level causal influences of diet on health

Abstract: Differences in diet appear to contribute substantially to the burden of disease in populations, and therefore changes in diet could lead to major improvements in public health. This is predicated on the reliable identification of causal effects of nutrition on health, and unfortunately nutritional epidemiology has deficiencies in terms of identifying these. This is reflected in the many cases where observational studies have suggested that a nutritional factor is protective against disease, and randomized controlled trials have failed to verify this. The use of genetic variants as proxy measures of nutritional exposure—an application of the Mendelian randomization principle—can contribute to strengthening causal inference in this field. Genetic variants are not subject to bias due to reverse causation (disease processes influencing exposure, rather than vice versa) or recall bias, and if obvious precautions are applied are not influenced by confounding or attenuation by errors. This is illustrated in the case of epidemiological studies of alcohol intake and various health outcomes, through the use of genetic variants related to alcohol metabolism (in ALDH2 and ADH1B). Examples from other areas of nutritional epidemiology and of the informative nature of gene–environment interactions interpreted within the Mendelian randomization framework are presented, and the potential limitations of the approach addressed.

Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function.

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.

Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

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.

Intrauterine Effects of Maternal Prepregnancy Overweight on Child Cognition and Behavior in 2 Cohorts

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.

Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index

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.

Socioeconomic disparities in trajectories of adiposity across childhood

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...

ACTN3 genotype, athletic status, and life course physical capability: meta-analysis of the published literature and findings from nine studies

Abstract: The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, although not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For life course physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research program, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (P = 0.09, n = 7,672 in males; P = 0.90, n = 7,839 in females), standing balance, timed get up and go, or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population.

Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children.

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

Links Between Co-occurring Social-Communication and Hyperactive-Inattentive Trait Trajectories

Abstract: Objective There is overlap between an autistic and hyperactive-inattentive symptomatology when studied cross-sectionally. This study is the first to examine the longitudinal pattern of association between social-communication deficits and hyperactive-inattentive symptoms in the general population, from childhood through adolescence. We explored the interrelationship between trajectories of co-occurring symptoms, and sought evidence for shared prenatal/perinatal risk factors. Method Study participants were 5,383 singletons of white ethnicity from the Avon Longitudinal Study of Parents and Children (ALSPAC). Multiple measurements of hyperactive-inattentive traits (Strengths and Difficulties Questionnaire) and autistic social-communication impairment (Social Communication Disorder Checklist) were obtained between 4 and 17 years. Both traits and their trajectories were modeled in parallel using latent class growth analysis (LCGA). Trajectory membership was subsequently investigated with respect to prenatal/perinatal risk factors. Results LCGA analysis revealed two distinct social-communication trajectories (persistently impaired versus low-risk) and four hyperactive-inattentive trait trajectories (persistently impaired, intermediate, childhood-limited and low-risk). Autistic symptoms were more stable than those of attention-deficit/hyperactivity disorder (ADHD) behaviors, which showed greater variability. Trajectories for both traits were strongly but not reciprocally interlinked, such that the majority of children with a persistent hyperactive-inattentive symptomatology also showed persistent social-communication deficits but not vice versa. Shared predictors, especially for trajectories of persistent impairment, were maternal smoking during the first trimester, which included familial effects, and a teenage pregnancy. Conclusions Our longitudinal study reveals that a complex relationship exists between social-communication and hyperactive-inattentive traits. Patterns of association change over time, with corresponding implications for removing exclusivity criteria for ASD and ADHD, as proposed for DSM-5 .

Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance.

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.

Genetic polymorphisms in 15q25 and 19q13 loci, cotinine levels and risk of lung cancer in EPIC

Abstract: BACKGROUNDS: Multiple polymorphisms affecting smoking behavior have been identified through genome-wide association studies. Circulating levels of the nicotine metabolite cotinine is a marker of recent smoking exposure. Hence, genetic variants influencing smoking behavior are expected to be associated with cotinine levels. METHODS: We conducted an analysis in a lung cancer case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We investigated the effects of single-nucleotide polymorphisms (SNP) previously associated with smoking behavior on (i) circulating cotinine and (ii) lung cancer risk. A total of 894 cases and 1,805 controls were analyzed for cotinine and genotyped for 10 polymorphisms on 7p14, 8p11, 10q23, 15q25, and 19q13. RESULTS: Two variants in the nicotinic acetylcholine receptor subunit genes CHRNA5 and CHRNA3 on 15q25, rs16969968 and rs578776, were associated with cotinine (P = 0.001 and 0.03, respectively) in current smokers and with lung cancer risk (P < 0.001 and P = 0.001, respectively). Two 19q13 variants, rs7937 and rs4105144, were associated with increased cotinine (P = 0.003 and P < 0.001, respectively) but decreased lung cancer risk (P = 0.01 for both, after adjusting for cotinine). Variants in 7p14, 8p11, and 10q23 were not associated with cotinine or lung cancer risk. CONCLUSIONS: 15q25 and 19q13 SNPs were associated with circulating cotinine. The directions of association for 15q25 variants with cotinine were in accordance with that expected of lung cancer risk, whereas SNPs on 19q13 displayed contrasting associations of cotinine and lung cancer that require further investigation. IMPACT: This study is the largest to date investigating the effects of polymorphisms affecting smoking behavior on lung cancer risk using circulating cotinine measures as proxies for recent smoking behavior.

Modifiable risk factors for prostate cancer mortality in London: forty years of follow-up in the Whitehall study

Abstract: The determinants of prostate cancer––aside from established but non-modifiable risk factors of increased age, black ethnicity, and a positive family history––are poorly understood. We examined the association of a series of baseline socioeconomic, behavioral, and metabolic characteristics with the risk of prostate cancer mortality in a 40-year follow-up of study members from the original Whitehall cohort study. During this period there were 578 prostate cancer deaths in 17,934 men. After adjustment for a series of baseline covariates, results from proportional hazards regression analyses indicated that marital status (hazard ratio; 95% confidence interval: widowed/divorced vs. married: 1.44; 0.95, 2.18), raised blood cholesterol (tertile 3 vs. 1: 1.35; 1.11, 1.65), and increased physical stature (tertile 3 vs. 1: 1.37; 1.09, 1.74) were associated with death from prostate cancer, although statistical significance at conventional levels was not apparent in all analyses. There was no evidence that physical activity, smoking habit, socio-economic status, component of either blood pressure or diabetes predicted the risk of death from this malignancy herein. In the present study, there was a suggestion that marital status, blood cholesterol, and height were risk indices for death from prostate cancer.

Socio-demographic patterning of physical activity across migrant groups in India: results from the Indian Migration Study.

Abstract: Objective To investigate the relationship between rural to urban migration and physical activity (PA) in India. Methods 6,447 (42% women) participants comprising 2077 rural, 2,094 migrants and 2,276 urban were recruited. Total activity (MET hr/day), activity intensity (min/day), PA Level (PAL) television viewing and sleeping (min/day) were estimated and associations with migrant status examined, adjusting for the sib-pair design, age, site, occupation, education, and socio-economic position (SEP). Results Total activity was highest in rural men whereas migrant and urban men had broadly similar activity levels (p<0.001). Women showed similar patterns, but slightly lower levels of total activity. Sedentary behaviour and television viewing were lower in rural residents and similar in migrant and urban groups. Sleep duration was highest in the rural group and lowest in urban non-migrants. Migrant men had considerably lower odds of being in the highest quartile of total activity than rural men, a finding that persisted after adjustment for age, SEP and education (OR 0.53, 95% CI 0.37, 0.74). For women, odds ratios attenuated and associations were removed after adjusting for age, SEP and education. Conclusion Our findings suggest that migrants have already acquired PA levels that closely resemble long-term urban residents. Effective public health interventions to increase PA are needed.

Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53,221 adults

Abstract: OBJECTIVE: We used genetic variants that are robustly associated with adiposity to examine the causal association of adiposity with psychological distress. METHODS: We examined the association of adiposity with psychological distress in a large (N = 53,221) general population cohort of 20- to 99-year-old adults from Copenhagen, Denmark. Psychological distress was assessed using four questions that asked about: feeling stressed; not accomplishing very much; wanting to give up; and regular use of antidepressants/sedatives. We used the genetic loci FTO rs9939609 and MC4R rs17782313 as instrumental variables for adiposity quantified by body mass index (BMI) and waist to hip ratio (WHR). RESULTS: In conventional multivariable analyses, BMI and WHR were positively associated with distress. For example, the odds ratio of reporting not accomplishing for each additional standard deviation increase for BMI was 1.11 (95% CI: 1.09, 1.13) and for WHR was 1.10 (95% CI: 1.08, 1.13) in the fully adjusted analyses. In contrast, instrumental variable analyses showed an inverse association of adiposity on distress; corresponding odds ratio in instrumental variable analyses was 0.64 (95% CI: 0.46, 0.89) for BMI and 0.49 (95% CI: 0.25, 0.94) for WHR (P-values for difference between the two approaches both = 0.001). CONCLUSION: The inverse associations of adiposity and psychological distress when genetic variants are used as instrumental variables could be explained by biological pathways linking adiposity and distress. The positive associations of adiposity with distress in multivariable analyses might be explained by residual confounding or reverse causality.

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Abstract: Blood pressure (BP) is a heritable trait1 influenced by multiple biological pathways and is responsive to environmental stimuli. Over one billion people worldwide have hypertension (BP ≥140 mm Hg systolic [SBP] or ≥90 mm Hg diastolic [DBP])2. Even small increments in BP are associated with increased risk of cardiovascular events3. This genome-wide association study of SBP and DBP, which used a multi-stage design in 200,000 individuals of European descent, identified 16 novel loci: six of these loci contain genes previously known or suspected to regulate BP (GUCY1A3-GUCY1B3; NPR3-C5orf23; ADM; FURIN-FES; GOSR2; GNAS-EDN3); the other 10 provide new clues to BP 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 BP in East Asian, South Asian, and African ancestry individuals. Our findings provide new insights into the genetics and biology of BP, and suggest novel potential therapeutic pathways for cardiovascular disease prevention. Genetic approaches have advanced the understanding of biological pathways underlying inter-individual variation in BP. For example, studies of rare Mendelian BP disorders have identified multiple defects in renal sodium handling pathways4. More recently two genomewide association studies (GWAS), each of >25,000 individuals of European-ancestry, identified 13 loci associated with SBP, DBP, and hypertension5,6. We now report results of a new meta-analysis of GWAS data that includes staged follow-up genotyping to identify additional BP loci. Primary analyses evaluated associations between 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and SBP and DBP in 69,395 individuals of European ancestry from 29 studies (Supplementary Materials Sections 1–3, Supplementary Tables 1– 2). Following GWAS meta-analysis, we conducted a three-stage validation experiment that made efficient use of available genotyping resources, to follow up top signals in up to 133,661 additional individuals of European descent (Supplementary Fig. 1 and Supplementary Materials Section 4). Twenty-nine independent SNPs at 28 loci were significantly associated with SBP, DBP, or both in the meta-analysis combining discovery and follow up data (Fig. 1, Table 1, Supplementary Figs 2–3, Supplementary Tables 3–5). All 29 SNPs attained association P <5×10−9, an order of magnitude beyond the standard genome-wide significance level for a single stage experiment (Table 1). Sixteen of these 29 associations were novel (Table 1). Two associations were near the FURIN and GOSR2 genes; prior targeted analyses of variants in these genes suggested they Note added in proof: Since this manuscript was submitted, Kato et al published a BP GWAS in East Asians that identified a SNP highly correlated to the SNP we report at the NPR3-c5orf23 locus28. Author contributions Full author contributions and roles are listed in the Supplementary Materials Section 19. NIH Public Access Author Manuscript Nature. Author manuscript; available in PMC 2012 May 01. Published in final edited form as: Nature. ; 478(7367): 103–109. doi:10.1038/nature10405. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript may be BP loci7,8. At the CACNB2 locus we validated association for a previously reported6 SNP rs4373814 and detected a novel independent association for rs1813353 (pairwise r2 =0.015 in HapMap CEU). Of our 13 previously reported associations5,6, only the association at PLCD3 was not supported by the current results (Supplementary Table 4). Some of the associations are in or near genes involved in pathways known to influence BP (NPR3, GUCY1A3-GUCY1B3, ADM, GNAS-EDN3, NPPA-NPPB, and CYP17A1; Supplementary Fig. 4). Twenty-two of the 28 loci did not contain genes that were a priori strong biological candidates. As expected from prior BP GWAS results, the effects of the novel variants on SBP and DBP were small (Fig. 1 and Table 1). For all variants, the observed directions of effects were concordant for SBP, DBP, and hypertension (Fig. 1, Table 1, Supplementary Fig. 3). Among the genes at the genome-wide significant loci, only CYP17A1, previously implicated in Mendelian congenital adrenal hyperplasia and hypertension, is known to harbour rare variants that have large effects on BP9. We performed several analyses to identify potential causal alleles and mechanisms. First, we looked up the 29 genome-wide significant index SNPs and their close proxies (r2>0.8) among cis-acting expression SNP (eSNP) results from multiple tissues (Supplementary Materials Section 5). For 13/29 index SNPs, we found association between nearby eSNP variants and expression level of at least one gene transcript (10−4 > p > 10−51, Supplementary Table 6). In 5 cases, the index BP SNP and the best eSNP from a genomewide survey were identical, highlighting potential mediators of the SNP-BP associations. Second, because changes in protein sequence are strong a priori candidates to be functional, we sought non-synonymous coding SNPs that were in high LD (r2 >0.8) with the 29 index SNPs. We identified such SNPsat 8 loci (Table 1, Supplementary Materials Section 6, Supplementary Table 7). In addition we performed analyses testing for differences in genetic effect according to body mass index (BMI) or sex, and analyses of copy number variants, pathway enrichment, and metabolomic data, but we did not find any statistically significant results (Supplementary Materials Sections 7–9, Supplementary Tables 8–10). We evaluated whether the BP variants we identified in Europeans were associated with BP in individuals of East Asian (N=29,719), South Asian (N=23,977), and African (N=19,775) ancestries (Table 1, Supplementary Tables 11–13). We found significant associations in individuals of East Asian ancestry for SNPs at 9 loci and in individuals of South Asian ancestry for SNPs at 6 loci; some have been reported previously (Supplementary Tables 12 and 15). The lack of significant association for individual SNPs may reflect small sample sizes, differences in allele frequencies or LD patterns, imprecise imputation for some ancestries using existing reference samples, or a genuinely different underlying genetic architecture. Because of limited power to detect effects of individual variants in the smaller non-European samples, we created genetic risk scores for SBP and DBP incorporating all 29 BP variants weighted according to effect sizes observed in the European samples. In each non-European ancestry group, risk scores were strongly associated with SBP (P=1.1×10−40 in East Asian, P=2.9×10−13 in South Asian, P=9.8×10−4 in African ancestry individuals) and DBP (P=2.9×10−48, P=9.5×10−15, and P=5.3×10−5, respectively; Supplementary Table 13). We also created a genetic risk score to assess association of the variants in aggregate with hypertension and with clinical measures of hypertensive complications including left ventricular mass, left ventricular wall thickness, incident heart failure, incident and prevalent stroke, prevalent coronary artery disease (CAD), kidney disease, and measures of kidney function, using results from other GWAS consortia (Table 2, Supplementary Materials Sections 10–11, Supplementary Table 14). The risk score was weighted using the average of Page 2 Nature. Author manuscript; available in PMC 2012 May 01. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript SBP and DBP effects for the 29 SNPs. In an independent sample of 23,294 women10, an increase of 1 standard deviation in the genetic risk score was associated with a 21% increase in the odds of hypertension (95% CI 19%–28%; Table 2, Supplementary Table 14). Among individuals in the top decile of the risk score, the prevalence of hypertension was 29% compared with 16% in the bottom decile (odds ratio 2.09, 95% CI 1.86–2.36). Similar results were observed in an independent hypertension case-control sample (Table 2). In our study, individuals in the top compared to bottom quintiles of genetic risk score differed by 4.6 mm Hg SBP and 3.0 mm Hg DBP, differences that approach population-averaged BP treatment effects for a single antihypertensive agent11. Epidemiologic data have shown that differences in SBP and DBP of this magnitude, across the population range of BP, are associated with an increase in cardiovascular disease risk3. Consistent with this and in line with findings from randomized trials of BP-lowering medication in hypertensive patients12,13, the genetic risk score was positively associated with left ventricular wall thickness (P=6.0×10−6), occurrence of stroke (P=3.3×10−5) and CAD (P=8.1×10−29). The same genetic risk score was not, however, significantly associated with chronic kidney disease or measures of kidney function, even though these renal outcomes were available in a similar sample size as for the other outcomes (Table 2). The absence of association with kidney phenotypes could be explained by a weaker causal relation of BP with kidney phenotypes than with CAD and stroke. This finding is consistent with the mismatch between observational data that show a positive association of BP with kidney disease, and clinical trial data that show inconsistent evidence of benefit of BP lowering on kidney disease prevention in patients with hypertension14. Thus, several lines of evidence converge to suggest that BP elevation may in part be a consequence rather than a cause of sub-clinical kidney disease. Our discovery meta-analysis (Supplementary Fig. 2) suggests an excess of modestly significant (10−5