G Davey Smith

University of Bristol, Bristol, England, United Kingdom

Are you G Davey Smith?

Claim your profile

Publications (274)1730.72 Total impact

  • Neurology 05/2015; DOI:10.1212/WNL.0000000000001606 · 8.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes. © 2015 World Obesity.
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies have demonstrated associations between some early-life exposures and later obesity, but most have used body mass index in childhood or adulthood as the outcome. The objective of this study was to investigate whether early-life exposures were associated with directly measured fat and lean mass in adolescence. This study used data on 4750 mother-offspring pairs, collected as a part of the Avon Longitudinal Study of Parents and Children, Bristol, UK between 1991 and 1992; associations between behavioural exposures occurring from conception up to 5 years of age (maternal and paternal smoking during pregnancy, breastfeeding, age at introduction to solids, dietary patterns and physical inactivity during early childhood) and offspring body composition measured by dual-energy X-ray absorptiometry at ~15 years were assessed. After full adjustment for potential confounders, maternal smoking during pregnancy, having a junk food diet and spending more time watching television in early childhood were all associated with higher fat mass at age 15, whereas maternal smoking, having a healthy diet and playing computer games more frequently in early childhood were all associated with a higher lean mass at age 15. Associations with paternal smoking were generally weaker for both fat and lean mass, but as there was no strong statistical evidence for maternal vs paternal differences, confounding by social factors rather than a direct effect of maternal smoking cannot be ruled out. Early feeding was not associated with fat or lean mass at age 15. This study does not provide compelling evidence for associations between most early-life factors and body composition in adolescence. However, possible associations with dietary patterns and physical inactivity in early childhood require further investigation in other cohorts that have direct measurements of adolescent body composition.
    Nutrition & Diabetes 02/2015; 5(2):e150. DOI:10.1038/nutd.2014.47 · 1.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Evidence of an association between serum vitamin D and cardiovascular disease risk is inconsistent and comes predominantly from studies in high-income settings. We assessed the association between serum levels of 25-hydroxyvitamin D3 (25(OH)D) and cardiovascular disease risk factors in a population of young Indian adults. METHODS: Cross-sectional analyses of data from APCAPS (Andhra Pradesh Children and Parents Study); a prospective birth cohort study in rural south India. Participants were 1038 (40.3% females) adults aged 18-24 years. Main outcome measures were blood pressures, fasting serum lipids (cholesterols and triglycerides), fasting glucose, insulin, measures of arterial stiffness (aortic augmentation index and aortic pulse wave velocity (aPWV)), carotid intima-media thickness, body mass index (BMI) and body fat (dual X-ray absorptiometry). RESULTS: Vitamin D deficiency (</=20ng/ml) was observed in 41.1% of this lean (mean BMI: 19.5) and active (mean minutes of moderate or vigorous physical activity per day: 186) population. Vitamin D deficiency was associated with higher median body fat in both males (15.9% body fat in vitamin D deficient males vs. 14.6% in non-deficient males, p<0.05) and females (29.1% body fat in vitamin D deficient females vs. 27.8% in non-deficient females, p<0.05) but no associations were observed between vitamin D deficiency and mean BMI or median fat mass index (FMI). Except a weak inverse association with fasting insulin in males, there was no clear association between serum vitamin D levels and cardiovascular disease risk factors in fully adjusted models. CONCLUSIONS: We did not find clear evidence for an association between serum vitamin D levels and cardiovascular disease risk factors. Our results, consistent with the limited evidence from randomised trials of vitamin D supplementation and Mendelian randomisation experiments, suggest that the postulated link between serum vitamin D and cardiovascular disease may be non-causal. Instead, it may be attributable to confounding by lifestyle factors such as obesity and physical inactivity which may provide more fruitful targets for cardiovascular disease prevention.
    PLoS ONE 01/2015; 10(6):e0129468. DOI:10.1371/journal.pone.0129468 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Social capital is considered to be an important determinant of life expectancy and cardiovascular health. Evidence on the association between social capital and all-cause mortality, cardiovascular disease (CVD) and cancer was systematically reviewed. Methods: Prospective studies examining the association of social capital with these outcomes were systematically sought in Medline, Embase and PsycInfo, all from inception to 8 October 2012. We categorized the findings from studies according toseven dimensions of social capital, including social participation, social network, civic participation, social support, trust, norm of reciprocity and sense of community, and pooled the estimates across studies to obtain summary relative risks of the health outcomes for each social capital dimension. We excluded studies focusing on children, refugees or immigrants and studies conducted in the former Soviet Union. Results: Fourteen prospective studies were identified. The pooled estimates showed no association between most social capital dimensions and all-cause mortality, CVD or cancer. Limited evidence was found for association of increased mortality with social participation and civic participation when comparing the most extreme risk comparisons. Conclusions: Evidence to support an association between social capital and health outcomes is limited. Lack of consensus on measurements for social capital hinders the comparability of studies and weakens the evidence base.
    International Journal of Epidemiology 11/2014; 43(6). DOI:10.1093/ije/dyu212 · 9.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We previously reported an association between high bone mass (HBM) and a bone-forming phenotype of radiographic hip osteoarthritis (OA). As knee and hip OA have distinct risk factors, in this study we aimed to determine (i) whether HBM is also associated with knee OA, and (ii) whether the HBM knee OA phenotype demonstrates a similar pattern of radiographic features to that observed at the hip.HBM cases (defined by DXA BMD Z-scores) from the UK-based HBM study were compared with unaffected family controls and general population controls from the Chingford and Hertfordshire cohort studies. A single blinded observer graded AP weight-bearing knee radiographs for features of OA (Kellgren–Lawrence score, osteophytes, joint space narrowing (JSN), sclerosis) using an atlas. Analyses used logistic regression, adjusting a priori for age and gender, and additionally for BMI as a potential mediator of the HBM–OA association, using Stata v12.609 HBM knees in 311 cases (mean age 60.8 years, 74% female) and 1937 control knees in 991 controls (63.4 years, 81% female) were analysed. The prevalence of radiographic knee OA, defined as Kellgren–Lawrence grade ≥ 2, was increased in cases (31.5% vs. 20.9%), with age and gender adjusted OR [95% CI] 2.38 [1.81, 3.14], p < 0.001. The association between HBM and osteophytosis was stronger than that for JSN, both before and after adjustment for BMI which attenuated the ORs for knee OA and osteophytes in cases vs. controls by approximately 50%.Our findings support a positive association between HBM and knee OA. This association was strongest for osteophytes, suggesting HBM confers a general predisposition to a subtype of OA characterised by increased bone formation.
    Bone 10/2014; 71. DOI:10.1016/j.bone.2014.10.015 · 4.46 Impact Factor
  • Growth Hormone & IGF Research 10/2014; 24:S13. DOI:10.1016/S1096-6374(14)50032-9 · 1.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
    Nature 07/2014; 514(7520):92-7. DOI:10.1038/nature13545 · 42.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Epidemiological studies have shown an association between increased bone mineral density (BMD) and osteoarthritis (OA), but whether this represents cause or effect remains unclear. In this study, we used a novel approach to investigate this question, determining whether individuals with High Bone Mass (HBM) have a higher prevalence of radiographic hip OA compared with controls. Design HBM cases came from the UK-based HBM study: HBM was defined by BMD Z-score. Unaffected relatives of index cases were recruited as family controls. Age-stratified random sampling was used to select further population controls from the Chingford and Hertfordshire cohort studies. Pelvic radiographs were pooled and assessed by a single observer blinded to case-control status. Analyses used logistic regression, adjusted for age, gender and body mass index (BMI). Results 530 HBM hips in 272 cases (mean age 62.9 years, 74% female) and 1702 control hips in 863 controls (mean age 64.8 years, 84% female) were analysed. The prevalence of radiographic OA, defined as Croft score ≥3, was higher in cases compared with controls (20.0% vs 13.6%), with adjusted odds ratio (OR) [95% CI] 1.52 [1.09, 2.11], P = 0.013. Osteophytes (OR 2.12 [1.61, 2.79], P < 0.001) and subchondral sclerosis (OR 2.78 [1.49, 5.18], P = 0.001) were more prevalent in cases. However, no difference in the prevalence of joint space narrowing (JSN) was seen (OR 0.97 [0.72, 1.33], P = 0.869). Conclusions An increased prevalence of radiographic hip OA and osteophytosis was observed in HBM cases compared with controls, in keeping with a positive association between HBM and OA and suggesting that OA in HBM has a hypertrophic phenotype.
    Osteoarthritis and Cartilage 06/2014; 22(8). DOI:10.1016/j.joca.2014.06.007 · 4.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Maternal smoking during pregnancy has been discussed as a potential risk factor for the increase of autistic symptoms in children, though findings have been inconsistent. It is possible however that maternal smoking might only elevate the expression of autistic symptoms in genetically susceptible individuals, and thus GxE may conceal the true underlying relationship between risk factor and behavioural outcome. Objectives: We aimed to identify genetic moderators of the risk effect of maternal smoking on the expression of autism-related social communication difficulties during childhood and adolescence using a genome-wide GxE analysis. Methods: We performed a 2-stage genome-wide GxE analysis with respect to social communication problems as captured by the Social and Communication Disorders Checklist (SCDC). Measurements were assessed in a large UK population-based birth cohort at 8, 11, 14 and 17 years of age (Avon Longitudinal Study of Parents and Children, N ≤ 5539). During the first stage, we performed a genome-wide screen for differences in phenotypic variance per genotype (Levene’s test) using 2.5 million imputed or genotyped SNPs and investigating each time-point individually. This identified a set of variants, which is likely to be involved in interactions. During the second-stage, we investigated all independent signals with respect to maternal smoking during the first trimester (adjusted for child’s age and sex), performing a joint likelihood ratio test for both G+GxE and E+GxE respectively using negative binomial regression. Results: Maternal smoking during the first trimester was identified as a strong predictor of increased autistic traits at 8 years of age (β=0.23(0.05), measured in log-counts of social-communication problems, P=4.4x10-7), but the risk effect declined during the course of development. During stage one of our GxE screen, we identified 132 independent offspring SNPs (Levene-P<10-5, LD based clumping: r2=0.2, ±500kb, in addition to all SNPs in known ASD candidate regions with P<10-4) across all 4 time-points, which are likely to be involved in interaction effects. The strongest E+GxE signal (Levene-P=5.2x10-5,PGxE=0.00016 (PGxE_adj=0.021), PE+GxE=1.7x10-9) was observed for variation in the ASD-candidate gene A2BP1 (alias RBFOX1) and was associated with social-communication problems at 8 years of age. There was no evidence for a genetic main effect (PG=0.96). Stratification by genotype, showed that the risk effect of maternal smoking was only present in homozygote carriers of the major (risk) allele (0 risk allele: β(smoking) = -0.23(0.20), P =0.27, 1 risk allele: β(smoking) = 0.057(0.084), P=0.50, 2 risk alleles: β(smoking)=0.35(0.057), P=5.8x10-10). The interaction was attenuated with progressive age due to the decline in risk effect of smoking. We found no joint G+GxE effect (P<10-5), which provided more evidence for association than G alone. Replication of the interaction signal is currently being sought within independent cohorts. Conclusions: Our variance-based genome-wide screen identified a small set of SNPs that are probably involved in interactions either with environmental or other SNP variation. We identified one GxE interaction effect, which, if replicated, might indicate that offspring of some smoking mothers are at particularly high risk for social-communication problems in childhood and adolescence.
    2014 International Meeting for Autism Research; 05/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Peer interaction plays an important role in the development of social competence, and problematic childhood peer relationships often precede later maladjusted behaviour. Some links between early peer rejection and later maladaptive functioning however might be mediated through an underlying pathology. This includes impairments in social interaction skills, which are characteristic and heritable symptoms of the autistic dimension including Autism Spectrum disorders (ASD). Objectives: Our study i) aimed to investigate genetic influences contributing to impaired peer relationships during childhood and adolescence, and ii) to identify population-based single SNP signals, which also contribute to risk for ASD. Methods: Heritability was estimated using ≤7366 UK twin pairs (Twins Early Development Study, TEDS) with parent-report on peer problems at 4, 7, 9 and 11 years. A genome-wide analysis was conducted within N≤6000 children from a UK birth-cohort (Avon Longitudinal Study of Parents and children, ALSPAC) with parent-report on peer problems at 4, 7, 8, 10, 12, 13 and 17 years. Association signals were followed-up within independent children from TEDS (N≤2837) and were also investigated in the Autism Genetic Research Exchange (AGRE) sample (793 ASD pedigrees) and the Autism Case-Control cohort (ACC, 1204 ASD subjects, 6491 control subjects). Results: Problematic peer relationships are substantially heritable throughout early/middle childhood (h2=0.60-0.71). During this developmental period however, there might be only few measurable common additive genetic effects (DNA-based h2≤0.12). During later adolescence by contrast the proportion of measurable common additive genetic effects is increasing (DNA-based h2=0.14-0.27). Two population-based signals in ALSPAC (rs6451614 at 5p13.1 near GHR, P17years=9.6x10-6, rs7873232 at 9p24.2 near GLIS3 and RFX3, P13years=7.3x10-6) were identified during later adolescence (out of 50 independent signals with P<10-5 across all time-points) and showed evidence for replication in AGRE (rs6451614 P=0.00058, rs7873232 P=0.0030), but not the ACC (rs1858136, proxy for rs6451614, r2=0.88, P=0.69; rs7873232 P=0.99). No comparable effect was observed within TEDS children spanning a younger age-range. Longitudinal modelling confirmed that genetic effects at both rs6451614 and rs7873232 varied across development, and that the underlying associations are complex. Conclusions: Common genetic effects contribute to variation in problematic peer relationships, however the influence of measurable common additive genetic effect is strongest in later adolescence. Overlaps with the autistic continuum might be present, but many more samples might be required to reliably identify single associations.
    2014 International Meeting for Autism Research; 05/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Epidemiological studies have shown an association between increased bone mineral density (BMD) and osteoarthritis (OA), but whether this represents cause or effect remains unclear. In this study, we used a novel approach to investigate this question, determining whether individuals with High Bone Mass (HBM) have a higher prevalence of radiographic hip OA compared with controls. Design HBM cases came from the UK-based HBM study: HBM was defined by BMD Z-score. Unaffected relatives of index cases were recruited as family controls. Age-stratified random sampling was used to select further population controls from the Chingford and Hertfordshire cohort studies. Pelvic radiographs were pooled and assessed by a single observer blinded to case-control status. Analyses used logistic regression, adjusted for age, gender and BMI. Results 530 HBM hips in 272 cases (mean age 62.9 years, 74% female) and 1702 control hips in 863 controls (mean age 64.8 years, 84% female) were analysed. The prevalence of radiographic OA, defined as Croft score ≥3, was higher in cases compared with controls (20.0% vs. 13.6%), with adjusted OR [95% CI] 1.52 [1.09,2.11], p=0.013. Osteophytes (OR 2.12 [1.61,2.79], p<0.001) and subchondral sclerosis (OR 2.78 [1.49,5.18], p=0.001) were more prevalent in cases. However, no difference in the prevalence of joint space narrowing was seen (OR 0.97 [0.72,1.33], p=0.869). Conclusions An increased prevalence of radiographic hip OA and osteophytosis was observed in HBM cases compared with controls, in keeping with a positive association between HBM and OA and suggesting that OA in HBM has a hypertrophic phenotype.
    Osteoarthritis and Cartilage 04/2014; DOI:10.1016/j.joca.2014.02.636 · 4.66 Impact Factor
  • Osteoarthritis and Cartilage 04/2014; 22:S352. DOI:10.1016/j.joca.2014.02.651 · 4.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background:Few studies have prospectively investigated whether early-life exposures are associated with pre-adolescent eating attitudes.Objective:The objective of this study is to prospectively investigate associations of parental smoking, alcohol use, marital status, measures of maternal satisfaction, self-reported parental body mass index (BMI) and clinically measured childhood BMI, assessed between birth and 6.5 years, with problematic eating attitudes at 11.5 years.Methods:Observational cohort analysis nested within the Promotion of Breastfeeding Intervention Trial, a cluster-randomised trial conducted in 31 maternity hospitals and affiliated polyclinics in Belarus. Our primary outcome was a Children's Eating Attitudes Test (ChEAT) score 22.5 (85th percentile), an indicator of problematic eating attitudes. We employed multivariable mixed logistic regression models, which allow inference at the individual level. We also performed instrumental variable (IV) analysis using parents' BMIs as instruments for the child's BMI, to assess whether associations could be explained by residual confounding or reverse causation.Subjects:Of the 17 046 infants enrolled between 1996 and 1997 across Belarus, 13 751 (80.7%) completed the ChEAT test at 11.5 years.Results:In fully adjusted models, overweight children at age 6.5 years had a 2.14-fold (95% confidence interval (CI): 1.82, 2.52) increased odds of having ChEAT scores 85th percentile at age 11.5 years, and those who were obese had a 3.89-fold (95% CI: 2.95, 5.14) increased odds compared with normal-weight children. Children of mothers or fathers who were themselves overweight or obese were more likely to score 85th percentile (P for trend 0.001). IV analysis was consistent with a child's BMI causally affecting future eating attitudes. There was little evidence that parental smoking, alcohol use, or marital status or maternal satisfaction were associated with eating attitudes.Conclusion:In our large, prospective cohort in Belarus, both parental and childhood overweight and obesity at 6.5 years were associated with pre-adolescent problematic eating attitudes 5 years later.
    Nutrition & Diabetes 01/2014; 4(1):e100. DOI:10.1038/nutd.2013.40 · 1.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding alpha1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
  • K M Keyes, G. Davey Smith, E Susser
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The relationship between prenatal tobacco exposure and hyperactivity remains controversial. To mitigate limitations of prior studies, we used a strategy involving comparison of maternal and paternal smoking reports in a historical sample where smoking during pregnancy was common. Method Data were drawn from a longitudinally followed subsample of the Child Health and Development Study (n = 1752), a population-based pregnancy cohort ascertained in 1961-1963 in California. Maternal prenatal smoking was common (33.4%). Maternal and paternal smoking patterns were assessed at three time points by mother report. Hyperactivity was assessed at the mean of age of 10 years based on mother report to a personality inventory. RESULTS: Unadjusted, maternal smoking during pregnancy was associated with offspring hyperactivity [β = 0.22, 95% confidence interval (CI) 0.11-0.33] and, to a similar degree, when the father smoked (β = 0.18, 95% CI 0.07-0.30). After adjustment, maternal smoking remained robustly predictive of offspring hyperactivity (β = 0.25, 95% CI 0.09-0.40) but father smoking was not (β = 0.02, 95% CI -0.20 to 0.24). When examined among the pairs matched on propensity score, mother smoking was robustly related to offspring hyperactivity whether the father smoked (β = 0.26, 95% CI 0.03-0.49) or did not smoke (β = 0.30, 95% CI 0.04-0.57). By number of cigarettes, associations with hyperactivity were present for 10-19 and 20+ cigarettes per day among mothers. CONCLUSIONS: In a pregnancy cohort recruited in a time period in which smoking during pregnancy was common, we document associations between prenatal smoking exposure and offspring hyperactivity. Novel approaches to inferring causality continue to be necessary in describing the potential adverse consequences of prenatal smoking exposure later in life.
    Psychological Medicine 05/2013; 44(4):1-11. DOI:10.1017/S0033291713000986 · 5.43 Impact Factor
  • 2013 International Meeting for Autism Research; 05/2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17 989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.Molecular Psychiatry advance online publication, 29 January 2013; doi:10.1038/mp.2012.184.
    Molecular Psychiatry 01/2013; DOI:10.1038/mp.2012.184 · 15.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Journal of Child Psychology and Psychiatry 12/2012; 54(5). DOI:10.1111/jcpp.12023 · 5.67 Impact Factor

Publication Stats

22k Citations
1,730.72 Total Impact Points

Institutions

  • 1996–2015
    • University of Bristol
      • • School of Social and Community Medicine
      • • MRC Centre for Causal Analyses in Translational Epidemiology
      Bristol, England, United Kingdom
  • 2014
    • Aarhus University
      • Department of Molecular Biology and Genetics
      Aarhus, Central Jutland, Denmark
  • 2010
    • Bristol Hospital
      Bristol, Connecticut, United States
  • 1992–2007
    • University of Glasgow
      • • MRC/CSO Social and Public Health Sciences Unit
      • • West of Scotland Cancer Surveillance Unit
      Glasgow, Scotland, United Kingdom
  • 2006
    • University of Helsinki
      • Department of Psychology
      Helsinki, Southern Finland Province, Finland
  • 2005–2006
    • Massey University
      • Centre for Public Health Research
      Palmerston North City, Manawatu-Wanganui, New Zealand
    • University of London
      • The London School of Medicine and Dentistry
      Londinium, England, United Kingdom
  • 2000–2006
    • Queen's University Belfast
      • Centre for Public Health
      Béal Feirste, N Ireland, United Kingdom
  • 1989–2006
    • London School of Hygiene and Tropical Medicine
      • Faculty of Epidemiology and Population Health
      London, ENG, United Kingdom
  • 2003
    • The University of Edinburgh
      • School of Philosophy, Psychology and Language Sciences
      Edinburgh, SCT, United Kingdom
    • The University of Manchester
      Manchester, England, United Kingdom
  • 1997–2003
    • University of Birmingham
      • School of Sport and Exercise Sciences
      Birmingham, ENG, United Kingdom
    • University of Bath
      Bath, England, United Kingdom
  • 2001
    • Karolinska Institutet
      Solna, Stockholm, Sweden
  • 1993
    • University College London
      • Department of Epidemiology and Public Health
      London, ENG, United Kingdom