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Showing papers by "George Davey Smith published in 2014"


Journal ArticleDOI
TL;DR: Developments of MR, including two-sample MR, bidirectional MR, network MR, two-step MR, factorial MR and multiphenotype MR, are outlined in this review.
Abstract: Observational epidemiological studies are prone to confounding, reverse causation and various biases and have generated findings that have proved to be unreliable indicators of the causal effects of modifiable exposures on disease outcomes. Mendelian randomization (MR) is a method that utilizes genetic variants that are robustly associated with such modifiable exposures to generate more reliable evidence regarding which interventions should produce health benefits. The approach is being widely applied, and various ways to strengthen inference given the known potential limitations of MR are now available. Developments of MR, including two-sample MR, bidirectional MR, network MR, two-step MR, factorial MR and multiphenotype MR, are outlined in this review. The integration of genetic information into population-based epidemiological studies presents translational opportunities, which capitalize on the investment in genomic discovery research.

1,686 citations


01 Jan 2014
TL;DR: Mendelian randomization (MR) is a method that utilizes genetic variants that are robustly associated with such modifiable exposures to generate more reliable evidence regarding which interventions should produce health benefits.
Abstract: Observational epidemiological studies are prone to confounding, reverse causation and various biases and have generated findings that have proved to be unreliable indicators of the causal effects of modifiable exposures on disease outcomes. Mendelian randomization (MR) is a method that utilizes genetic variants that are robustly associated with such modifiable exposures to generate more reliable evidence regarding which interventions should produce health benefits. The approach is being widely applied, and various ways to strengthen inference given the known potential limitations of MR are now available. Developments of MR, including two-sample MR, bidirectional MR, network MR, two-step MR, factorial MR and multiphenotype MR, are outlined in this review. The integration of genetic information into population-based epidemiological studies presents translational opportunities, which capitalize on the investment in genomic discovery research.

1,402 citations


Journal ArticleDOI
Michael V. Holmes1, Michael V. Holmes2, Caroline Dale3, Luisa Zuccolo  +167 moreInstitutions (62)
10 Jul 2014-BMJ
TL;DR: In this article, the causal role of alcohol consumption in cardiovascular disease was investigated using a Mendelian randomisation meta-analysis of 56 epidemiological studies, including 20 259 coronary heart disease cases and 10 164 stroke events.
Abstract: OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

571 citations


Journal ArticleDOI
John R. B. Perry, Felix R. Day1, Cathy E. Elks1, Patrick Sulem2  +217 moreInstitutions (64)
02 Oct 2014-Nature
TL;DR: In this article, the authors used genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies and found robust evidence for 123 signals at 106 genomic loci associated with age at menarche.
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 × 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 γ-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.

498 citations


Journal ArticleDOI
TL;DR: To what extent elevated body mass index within the normal weight range has causal influences on the detailed systemic metabolite profile in early adulthood using Mendelian randomization analysis is investigated.
Abstract: Background Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood. Methods and findings We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24 ± 4 kg/m(2)). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p Conclusions Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood. Please see later in the article for the Editors' Summary.

282 citations


Journal ArticleDOI
TL;DR: This article identified common genetic variants associated with cognitive performance using a two-stage approach, which they call the proxy-phenotype method, and measured the association of these education-associated SNPs with the cognitive performance.
Abstract: We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.

229 citations


Journal ArticleDOI
TL;DR: The smoking score is a valuable tool for identification of true current smoking behaviour and Explanations for ethnic differences in DNA methylation in association with smoking may provide valuable clues to disease pathways.
Abstract: DNA methylation is strongly associated with smoking status at multiple sites across the genome. Studies have largely been restricted to European origin individuals yet the greatest increase in smoking is occurring in low income countries, such as the Indian subcontinent. We determined whether there are differences between South Asians and Europeans in smoking related loci, and if a smoking score, combining all smoking related DNA methylation scores, could differentiate smokers from non-smokers. Illumina HM450k BeadChip arrays were performed on 192 samples from the Southall And Brent REvisited (SABRE) cohort. Differential methylation in smokers was identified in 29 individual CpG sites at 18 unique loci. Interaction between smoking status and ethnic group was identified at the AHRR locus. Ethnic differences in DNA methylation were identified in non-smokers at two further loci, 6p21.33 and GNG12. With the exception of GFI1 and MYO1G these differences were largely unaffected by adjustment for cell composition. A smoking score based on methylation profile was constructed. Current smokers were identified with 100% sensitivity and 97% specificity in Europeans and with 80% sensitivity and 95% specificity in South Asians. Differences in ethnic groups were identified in both single CpG sites and combined smoking score. The smoking score is a valuable tool for identification of true current smoking behaviour. Explanations for ethnic differences in DNA methylation in association with smoking may provide valuable clues to disease pathways.

228 citations


Journal ArticleDOI
TL;DR: The findings suggest that modifications of DNAm associated with prenatal maternal smoking may persist in exposed offspring for many years—at least until adolescence.
Abstract: Background: Prenatal exposure to maternal cigarette smoking (prenatal smoke exposure) had been associated with altered DNA methylation (DNAm) at birth.Objective: We examined whether such alteration...

164 citations


Journal ArticleDOI
TL;DR: The results suggest that increased adiposity causes a reduction in physical activity in children; however, this study does not exclude lower physical activity also leading to increasing adiposity.
Abstract: Background Cross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose-response association with body mass index ...

162 citations



Journal ArticleDOI
Vardan Khachatryan1, Albert M. Sirunyan1, Armen Tumasyan1, Wolfgang Adam  +2186 moreInstitutions (172)
TL;DR: In this article, a search for new resonances decaying to WW, ZZ, or WZ is presented, based on data corresponding to an integrated luminosity of 19.7 fb^(−1) recorded in proton-proton collisions at √s = 8 TeV.
Abstract: A search for new resonances decaying to WW, ZZ, or WZ is presented. Final states are considered in which one of the vector bosons decays leptonically and the other hadronically. Results are based on data corresponding to an integrated luminosity of 19.7 fb^(−1) recorded in proton-proton collisions at √s = 8 TeV with the CMS detector at the CERN LHC. Techniques aiming at identifying jet substructures are used to analyze signal events in which the hadronization products from the decay of highly boosted W or Z bosons are contained within a single reconstructed jet. Upper limits on the production of generic WW, ZZ, or WZ resonances are set as a function of the resonance mass and width. We increase the sensitivity of the analysis by statistically combining the results of this search with a complementary study of the all-hadronic final state. Upper limits at 95% confidence level are set on the bulk graviton production cross section in the range from 700 to 10 fb for resonance masses between 600 and 2500 GeV, respectively. These limits on the bulk graviton model are the most stringent to date in the diboson final state.

Journal ArticleDOI
01 Oct 2014-BMJ Open
TL;DR: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.
Abstract: Objectives: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. Design: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. Participants: Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Primary outcome measures: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. Results: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. Conclusions: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

Journal ArticleDOI
TL;DR: This work model potential biases that may arise in Mendelian randomization analysis and concludes that genetic variants should robustly associate with exposures in independent samples and can suggest causality despite no true associations.
Abstract: Mendelian randomization methods, which use genetic variants as instrumental variables for exposures of interest to overcome problems of confounding and reverse causality, are becoming widespread for assessing causal relationships in epidemiological studies. The main purpose of this paper is to demonstrate how results can be biased if researchers select genetic variants on the basis of their association with the exposure in their own dataset, as often happens in candidate gene analyses. This can lead to estimates that indicate apparent “causal” relationships, despite there being no true effect of the exposure. In addition, we discuss the potential bias in estimates of magnitudes of effect from Mendelian randomization analyses when the measured exposure is a poor proxy for the true underlying exposure. We illustrate these points with specific reference to tobacco research.

Journal ArticleDOI
TL;DR: The estimated genetic and residual correlations between BMD measured at the upper limbs, lower limbs and skull and a novel association between RIN3 and LL-BMD suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences.
Abstract: Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼ 4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (r(e) = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (r(e) = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n ∼ 9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01 × 10(-37)), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31 × 10(-14)). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4 × 10(-10)). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.

Journal ArticleDOI
TL;DR: Atomic probe tomography (APT) is employed for the first time to probe the spatial characteristics of the nanojunction between cadmium chalcogenide and ZnO crystalline phases, which reveals various degrees of ion exchange between the two crystals to relax large lattice mismatches.
Abstract: A series of highly efficient semiconductor nanocrystal (NC) photocatalysts have been synthesized by growing wurtzite-ZnO tetrahedrons around pre-formed CdS, CdSe, and CdTe quantum dots (QDs). The resulting contact between two small but high-quality crystals creates novel CdX/ZnO heterostructured semiconductor nanocrystals (HSNCs) with extensive type-II nanojunctions that exhibit more efficient photocatalytic decomposition of aqueous organic molecules under UV irradiation. Catalytic testing and characterization indicate that catalytic activity increases as a result of a combination of both the intrinsic chemistry of the chalcogenide anions and the heterojunction structure. Atomic probe tomography (APT) is employed for the first time to probe the spatial characteristics of the nanojunction between cadmium chalcogenide and ZnO crystalline phases, which reveals various degrees of ion exchange between the two crystals to relax large lattice mismatches. In the most extreme case, total encapsulation of CdTe by ZnO as a result of interfacial alloying is observed, with the expected advantage of facilitating hole transport for enhanced exciton separation during catalysis.

Journal ArticleDOI
TL;DR: This analysis shows that a large sample size allows the discovery of secondary effects of human variations on gene expression that can be used to construct short directed gene regulatory networks.
Abstract: Gene expression is a heritable cellular phenotype that defines the function of a cell and can lead to diseases in case of misregulation. In order to detect genetic variations affecting gene expression, we performed association analysis of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with gene expression measured in 869 lymphoblastoid cell lines of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in cis and in trans. We discovered that 3,534 genes (false discovery rate (FDR) = 5%) are affected by an expression quantitative trait locus (eQTL) in cis and 48 genes are affected in trans. We observed that CNVs are more likely to be eQTLs than SNPs. In addition, we found that variants associated to complex traits and diseases are enriched for trans-eQTLs and that trans-eQTLs are enriched for cis-eQTLs. As a variant affecting both a gene in cis and in trans suggests that the cis gene is functionally linked to the trans gene expression, we looked specifically for trans effects of cis-eQTLs. We discovered that 26 cis-eQTLs are associated to 92 genes in trans with the cis-eQTLs of the transcriptions factors BATF3 and HMX2 affecting the most genes. We then explored if the variation of the level of expression of the cis genes were causally affecting the level of expression of the trans genes and discovered several causal relationships between variation in the level of expression of the cis gene and variation of the level of expression of the trans gene. This analysis shows that a large sample size allows the discovery of secondary effects of human variations on gene expression that can be used to construct short directed gene regulatory networks.

Journal ArticleDOI
TL;DR: The results highlight the importance of the developmental timing of the paternal exposure as well as gender differences in offspring outcomes and smoking by boys in mid childhood may contribute to obesity in adolescent boys of the next generation.
Abstract: Despite interest in the idea that transgenerational effects of adverse exposures might contribute to population health trends, there are few human data. This non-genetic inheritance is all the more remarkable when transmission is down the male-line as reported in a historical Swedish study, where the paternal grandfather's food supply in mid childhood was associated with the mortality rate in his grandsons. Using the Avon Longitudinal Study of Parents and Children's questionnaire data on smoking and smoking onset from 9886 fathers, we examined the growth of their children from 7–17 years. Adjusting for potential confounders, we assessed associations between body mass index (BMI), waist circumference, total fat mass and lean mass with the age at which the father had started smoking regularly. Of 5376 fathers who reported having ever smoked, 166 reported regular smoking <11 years of age. Before adjustment, those offspring whose fathers started smoking <11 years had the highest mean BMIs at each age tested. The adjusted mean differences in BMI, waist circumference and total fat mass in those sons whose fathers started smoking <11 years, compared with all other sons, increased with age, being significantly greater from 13 years onwards. There were no significant BMI associations in daughters, but they showed a reduction in total lean mass. Our results highlight the importance of the developmental timing of the paternal exposure as well as gender differences in offspring outcomes. Smoking by boys in mid childhood may contribute to obesity in adolescent boys of the next generation.

Journal ArticleDOI
TL;DR: A suite of methods has been developed in recent years to minimise problems afflicting observational epidemiology, to strengthen causal inference and to provide greater insights into modifiable intra-uterine and early life risk factors, to be applied in the context of birth cohorts and extended along with the development of birth cohort consortia and expansion of "omic" technologies.

Journal ArticleDOI
TL;DR: 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, and may contribute to cortisol-associated degenerative diseases.
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 α1-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.

Journal ArticleDOI
TL;DR: It is found that higher BMI increases the risk of asthma in mid-childhood and used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years.
Abstract: Background: Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach. Methods and Findings: We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7K y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values,0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p=0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m 2 , p=0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p=0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.

Stéphanie Martine van den Berg, Marleen H.M. de Moor, Matt McGue, Erik Pettersson, Antonio Terracciano, Karin J. H. Verweij, Najaf Amin, Jaime Derringer, Tõnu Esko, Gerard van Grootheest, Narelle K. Hansell, Jennifer E. Huffman, Bettina Konte, Jari Lahti, Michelle Luciano, Lindsay K. Matteson, Alexander Viktorin, Jasper Wouda, Arpana Agrawal, Jueri Allik, Laura J. Bierut, Ulla Broms, Harry Campbell, George Davey Smith, Johan G. Eriksson, Luigi Ferrucci, Barbera Franke, Jean-Paul Fox, Eco J. C. de Geus, Ina Giegling, Alan J. Gow, Richard A. Grucza, Annette M. Hartmann, Andrew C. Heath, Kauko Heikkilae, William G. Iacono, Joost G. E. Janzing, Markus Jokela, Lambertus A. Kiemeney, Terho Lehtimäki, Pamela A. F. Madden, Patrik K. E. Magnusson, Kate Northstone, Teresa Nutile, Klaasjan G. Ouwens, Aarno Palotie, Alison Pattie, Anu-Katriina Pesonen, Ozren Polasek, Lea Pulkkinen, Laura Pulkki-Råback, Olli T. Raitakari, Anu Realo, Richard J. Rose, Daniela Ruggiero, Ilkka Seppälä, Wendy S. Slutske, David C. Smyth, Rossella Sorice, John M. Starr, Angelina R. Sutin, Toshiko Tanaka, Josine Verhagen, Sita H. Vermeulen, Eero Vuoksimaa, Elisabeth Widen, Gonneke Willemsen, Margaret J. Wright, Lina Zgaga, Dan Rujescu, Andres Metspalu, James F. Wilson, Marina Ciullo, Caroline Hayward, Igor Rudan, Ian J. Deary, Katri Räikkönen, Alejandro Arias Vasquez, Paul T. Costa, Liisa Keltikangas-Järvinen, Cornelia M. van Duijn, Brenda W.J.H. Penninx, Robert F. Krueger, David M. Evans, Jaakko Kaprio, Nancy L. Pedersen, Nicholas G. Martin, Dorret I. Boomsma 
28 Aug 2014
TL;DR: In this paper, the authors apply Item-Response Theory (IRT) to map item data from different inventories to the same underlying constructs, which can be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.
Abstract: Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.

Journal ArticleDOI
Stéphanie Martine van den Berg1, Marleen H. M. de Moor2, Matt McGue3, Matt McGue4, Erik Pettersson5, Antonio Terracciano6, Antonio Terracciano7, Karin J. H. Verweij8, Karin J. H. Verweij2, Najaf Amin9, Jaime Derringer10, Tõnu Esko11, Gerard van Grootheest2, Narelle K. Hansell8, Jennifer E. Huffman12, Bettina Konte13, Jari Lahti14, Michelle Luciano12, Lindsay K. Matteson4, Alexander Viktorin5, Jasper Wouda2, Arpana Agrawal15, Jüri Allik16, Jüri Allik11, Laura J. Bierut15, Ulla Broms14, Ulla Broms6, Harry Campbell12, George Davey Smith17, Johan G. Eriksson, Luigi Ferrucci6, Barbera Franke18, Jean-Paul Fox1, Eco J. C. de Geus2, Ina Giegling13, Alan J. Gow19, Richard A. Grucza15, Annette M. Hartmann13, Andrew C. Heath15, Kauko Heikkilä14, William G. Iacono4, Joost G. E. Janzing18, Markus Jokela14, Markus Jokela20, Lambertus A. Kiemeney18, Terho Lehtimäki20, Pamela A. F. Madden15, Patrik K. E. Magnusson5, Kate Northstone17, Teresa Nutile, Klaasjan G. Ouwens2, Aarno Palotie21, Aarno Palotie14, Alison Pattie12, Anu-Katriina Pesonen14, Ozren Polasek22, Lea Pulkkinen23, Laura Pulkki-Råback14, Olli T. Raitakari24, Anu Realo11, Richard J. Rose25, Daniela Ruggiero, Ilkka Seppälä20, Wendy S. Slutske26, David C. Smyth8, Rossella Sorice, John M. Starr12, Angelina R. Sutin6, Angelina R. Sutin7, Toshiko Tanaka6, Josine Verhagen27, Sita H. Vermeulen18, Eero Vuoksimaa28, Eero Vuoksimaa14, Elisabeth Widen14, Gonneke Willemsen2, Margaret J. Wright8, Lina Zgaga29, Lina Zgaga12, Dan Rujescu13, Andres Metspalu16, Andres Metspalu11, James F. Wilson12, Marina Ciullo, Caroline Hayward12, Igor Rudan12, Ian J. Deary12, Katri Räikkönen6, Katri Räikkönen14, Alejandro Arias Vasquez18, Paul T. Costa30, Liisa Keltikangas-Järvinen14, Cornelia M. van Duijn9, Brenda W.J.H. Penninx2, Robert F. Krueger4, David M. Evans17, Jaakko Kaprio6, Jaakko Kaprio14, Nancy L. Pedersen5, Nicholas G. Martin8, Dorret I. Boomsma2 
TL;DR: Within the Genetics of Personality Consortium, it is demonstrated for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs.
Abstract: Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.

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TL;DR: Paternal obesity is an independent risk factor for ASDs in children, whereas paternal obesity was associated with an increased risk of autistic disorder and Asperger disorder.
Abstract: OBJECTIVES: The objective of the study was to investigate the associations among maternal prepregnancy BMI, paternal BMI, and the risk of autism spectrum disorders (ASDs) in children. METHODS: The study sample of 92 909 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study. The age range was 4.0 through 13.1 (mean 7.4) years. Relative risks of ASDs were estimated by odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models. RESULTS: At the end of follow-up on December 31, 2012, 419 children in the study sample had been diagnosed with ASDs: 162 with autistic disorder, 103 with Asperger disorder, and 154 with pervasive developmental disorder not otherwise specified. Maternal obesity (BMI ≥30) was only weakly associated with ASD risk, whereas paternal obesity was associated with an increased risk of autistic disorder and Asperger disorder. The risk of autistic disorder was 0.27% (25 of 9267) in children of obese fathers and 0.14% (59 of 41 603) in children of fathers with normal weight (BMI CONCLUSIONS: Paternal obesity is an independent risk factor for ASDs in children. The associations should be investigated further in genetic and epigenetic studies.

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Clive J. Hoggart1, Giulia Venturini2, Massimo Mangino3, Felicia Gomez4, Giulia Ascari2, Jing Hua Zhao5, Alexander Teumer6, Thomas W. Winkler7, Natalia Tšernikova8, Jian'an Luan5, Evelin Mihailov8, Georg Ehret9, Weihua Zhang1, David Lamparter10, Tõnu Esko11, Aurélien Macé10, Sina Rüeger10, Pierre-Yves Bochud12, Matteo Barcella13, Yves Dauvilliers14, Beben Benyamin15, David M. Evans15, Caroline Hayward16, Mary F. Lopez11, Lude Franke17, Alessia Russo18, Iris M. Heid7, Erika Salvi13, Sailaja Vendantam11, Dan E. Arking9, Eric Boerwinkle, John C. Chambers1, Giovanni Fiorito18, Harald Grallert, Simonetta Guarrera, Georg Homuth6, Jennifer E. Huffman16, David J. Porteous16, Darius Moradpour, Alex Iranzo19, Johannes Hebebrand20, John P. Kemp21, Gert J. Lammers22, Vincent Aubert12, Markus H. Heim23, Nicholas G. Martin24, Grant W. Montgomery24, Rosa Peraita-Adrados25, Joan Santamaria19, Francesco Negro, Carsten Oliver Schmidt6, Robert A. Scott5, Tim D. Spector3, Konstantin Strauch26, Henry Völzke6, Nicholas J. Wareham5, Wei Yuan3, Jordana T. Bell3, Aravinda Chakravarti9, Jaspal S. Kooner27, Annette Peters, Giuseppe Matullo18, Henri Wallaschofski6, John Whitfield24, Fred Paccaud12, Peter Vollenweider12, Sven Bergmann10, Jacques S. Beckmann10, Mehdi Tafti12, Nicholas D. Hastie16, Daniele Cusi13, Murielle Bochud12, Timothy M. Frayling28, Andres Metspalu8, Marjo-Riitta Järvelin27, André Scherag20, George Davey Smith21, Ingrid B. Borecki4, Valentin Rousson12, Joel N. Hirschhorn11, Carlo Rivolta2, Ruth J. F. Loos29, Zoltán Kutalik12 
TL;DR: A novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals is presented and it is demonstrated that they play an important role in adult obesity.
Abstract: The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.

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TL;DR: This article showed that a genetic variant near the ROBO2 gene is associated with early language acquisition in the general population and highlight a potential genetic link between language-related common genetic variation and a linkage region for dyslexia, speech-sound disorder and reading.
Abstract: The genetic basis of expressive vocabulary in children around 2 years old is poorly understood. Here, the authors show that a genetic variant near the ROBO2 gene is associated with early language acquisition in the general population and highlight a potential genetic link between language-related common genetic variation and a linkage region for dyslexia, speech-sound disorder and reading.

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TL;DR: Genetic results mimic the controversy in epidemiological studies, and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and Pubertal timing in boys may be complex and requires further genetic studies.
Abstract: Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 × 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 × 10(-5)) and short adult stature (p = 7.5 × 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.

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TL;DR: Analysis of simulated data confirmed that model parameters could be recovered by full information maximum likelihood (FIML) and evaluated the biases that arise in conventional GCTA when indirect genetic effects are ignored.
Abstract: Genome wide complex trait analysis (GCTA) is extended to include environmental effects of the maternal genotype on offspring phenotype ("maternal effects", M-GCTA). The model includes parameters for the direct effects of the offspring genotype, maternal effects and the covariance between direct and maternal effects. Analysis of simulated data, conducted in OpenMx, confirmed that model parameters could be recovered by full information maximum likelihood (FIML) and evaluated the biases that arise in conventional GCTA when indirect genetic effects are ignored. Estimates derived from FIML in OpenMx showed very close agreement to those obtained by restricted maximum likelihood using the published algorithm for GCTA. The method was also applied to illustrative perinatal phenotypes from ~4,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children. The relative merits of extended GCTA in contrast to quantitative genetic approaches based on analyzing the phenotypic covariance structure of kinships are considered.

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21 Jul 2014-Obesity
TL;DR: The aim here was to assess the contribution of common genetic variation to a adjusted version of that phenotype which appropriately accounts for covariation in height in children.
Abstract: per allele G (0.19, 0.38), P 56 3 10 29 ). In contrast, they showed marginal evidence of association with conventional BMI [rs11676272 (0.25 kg/m 2 (0.15, 0.35), P 56 3 10 27 )]. Results were replicated in an independent sample, the Generation R study. Conclusions: Analysis of BMI[x] showed differences to that of conventional BMI. The association signal at ADCY3 appeared to be driven by a missense variant and it was strongly correlated with expression of this gene. Our work highlights the importance of well understood phenotype use (and the danger of convention) in characterising genetic contributions to complex traits.

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TL;DR: This study implicates parent‐of‐origin effects in language impairment, and adds an interesting new dimension to the emerging picture of shared genetic etiology across various neurodevelopmental disorders.
Abstract: Specific language impairment (SLI) is a neurodevelopmental disorder that affects linguistic abilities when development is otherwise normal. We report the results of a genome-wide association study of SLI which included parent-of-origin effects and child genotype effects and used 278 families of language-impaired children. The child genotype effects analysis did not identify significant associations. We found genome-wide significant paternal parent-of-origin effects on chromosome 14q12 (P = 3.74 × 10(-8) ) and suggestive maternal parent-of-origin effects on chromosome 5p13 (P = 1.16 × 10(-7) ). A subsequent targeted association of six single-nucleotide-polymorphisms (SNPs) on chromosome 5 in 313 language-impaired individuals and their mothers from the ALSPAC cohort replicated the maternal effects, albeit in the opposite direction (P = 0.001); as fathers' genotypes were not available in the ALSPAC study, the replication analysis did not include paternal parent-of-origin effects. The paternally-associated SNP on chromosome 14 yields a non-synonymous coding change within the NOP9 gene. This gene encodes an RNA-binding protein that has been reported to be significantly dysregulated in individuals with schizophrenia. The region of maternal association on chromosome 5 falls between the PTGER4 and DAB2 genes, in a region previously implicated in autism and ADHD. The top SNP in this association locus is a potential expression QTL of ARHGEF19 (also called WGEF) on chromosome 1. Members of this protein family have been implicated in intellectual disability. In summary, this study implicates parent-of-origin effects in language impairment, and adds an interesting new dimension to the emerging picture of shared genetic etiology across various neurodevelopmental disorders.

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TL;DR: In this paper, the authors investigated the effects of an experimental intervention to promote increased duration of exclusive breastfeeding on cardiometabolic risk factors in childhood, including blood pressure, fasting insulin, adiponectin, glucose, and apolipoprotein A1.
Abstract: Background—The duration and exclusivity of breastfeeding in infancy have been inversely associated with future cardiometabolic risk. We investigated the effects of an experimental intervention to promote increased duration of exclusive breastfeeding on cardiometabolic risk factors in childhood. Methods and Results—We followed-up children in the Promotion of Breastfeeding Intervention Trial, a cluster-randomized trial of a breastfeeding promotion intervention based on the World Health Organization/United Nations Children’s Fund Baby-Friendly Hospital Initiative. In 1996 to 1997, 17 046 breastfeeding mother-infant pairs were enrolled from 31 Belarusian maternity hospitals and affiliated polyclinics (16 intervention versus 15 control sites); 13 879 (81.4%) children were followed up at 11.5 years, with 13 616 (79.9%) who had fasted and did not have diabetes mellitus. The outcomes were blood pressure; fasting insulin, adiponectin, glucose, and apolipoprotein A1; and the presence of metabolic syndrome. Analysis...