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Structural equation models (SEMs) involving feedback loops may offer advantages over standard instrumental variables estimators in terms of modelling causal effects in the presence of bidirectional relationships. In the following note, we show that in the case of a single "exposure" and "outcome" variable, modelling relationships using a SEM with a simple bidirectional linear feedback loop offers no advantage over traditional instrumental variables estimators in terms of consistency (i.e. both approaches yield consistent estimates of the causal effect, provided that causal estimates are obtained in both directions). In the case of finite samples, traditional IV estimators and SEM exhibited similar power across many of the conditions we examined, although which method performed best depended on the residual correlation between variables and the strength of the instruments. In particular, the power of SEM was insensitive to the residual correlation between variables, whereas the power of the Wald estimator/2SLS improved (deteriorated) relative to SEM as the magnitude of the residual correlation increased (decreased) assuming a positive causal effect of the exposure on the outcome. The power of SEM improved relative to the Wald estimator/2SLS as the instruments explained more residual variance in the "outcome" variable.
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Análise da Randomização Mendeliana , Humanos , Análise da Randomização Mendeliana/métodos , Modelos Genéticos , Modelos Estatísticos , Causalidade , RetroalimentaçãoRESUMO
The phenotypic impact of genetic variation of repetitive features in the human genome is currently understudied. One such feature is the multi-copy 47S ribosomal DNA (rDNA) that codes for rRNA components of the ribosome. Here, we present an analysis of rDNA copy number (CN) variation in the UK Biobank (UKB). From the first release of UKB whole-genome sequencing (WGS) data, a discovery analysis in White British individuals reveals that rDNA CN associates with altered counts of specific blood cell subtypes, such as neutrophils, and with the estimated glomerular filtration rate, a marker of kidney function. Similar trends are observed in other ancestries. A range of analyses argue against reverse causality or common confounder effects, and all core results replicate in the second UKB WGS release. Our work demonstrates that rDNA CN is a genetic influence on trait variance in humans.
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Bancos de Espécimes Biológicos , Variações do Número de Cópias de DNA , Humanos , Variações do Número de Cópias de DNA/genética , Reino Unido , Taxa de Filtração Glomerular/genética , DNA Ribossômico/genética , Rim/metabolismo , Masculino , Feminino , Sequenciamento Completo do Genoma , Genoma Humano , Biobanco do Reino UnidoRESUMO
Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study of 57 essential and non-essential trace elements. We perform genome-wide association meta-analyses of 14 trace elements in up to 6564 Scandinavian whole blood samples, and genome-wide association studies of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identify 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide association meta-analyses. In HUNT, several genome-wide significant loci are also indicated for other trace elements. Using two-sample Mendelian randomization, we find several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our current understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health.
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Selênio , Oligoelementos , Masculino , Humanos , Oligoelementos/metabolismo , Estudo de Associação Genômica Ampla , Zinco , Selênio/análise , ManganêsRESUMO
We propose TetraHer, a method for estimating the liability heritability of binary phenotypes. TetraHer has five key features. First, it can be applied to data from complex pedigrees that contain multiple types of relationships. Second, it can correct for ascertainment of cases or controls. Third, it can accommodate covariates. Fourth, it can model the contribution of common environment. Fifth, it produces a likelihood that can be used for significance testing. We first demonstrate the validity of TetraHer on simulated data. We then use TetraHer to estimate liability heritability for 229 codes from the tenth International Classification of Diseases (ICD-10). We identify 107 codes with significant heritability (p < 0.05/229), which can be used in future analyses for investigating the genetic architecture of human diseases.
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Estudo de Associação Genômica Ampla , Modelos Genéticos , Humanos , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Upregulation of TGFß and Cox2 in the tumor microenvironment results in blockade of T-cell penetration into the tumor. Without access to tumor antigens, the T-cell response will not benefit from administration of the immune checkpoint antibodies. We created an intravenous polypeptide nanoparticle that can deliver two siRNAs (silencing TGFß and Cox2). Systemic administration in mice, bearing a syngeneic orthotopic hepatocellular carcinoma (HCC), delivers the siRNAs to various cells in the liver, and significantly reduces the tumor. At 2 mg/kg (BIW) the nanoparticle demonstrated a single agent action and induced tumor growth inhibition to undetectable levels after five doses. Reducing the siRNAs to 1mg/kg BIW demonstrated greater inhibition in the presence of PD-L1 mAbs. After only three doses BIW, we could still recover a smaller tumor and, in tumor sections, showed an increase in penetration of CD4+ and CD8+ T-cells deeper into the remaining tumor that was not evident in animals treated with non-silencing siRNA. The combination of TGFß and Cox2 siRNA co-administered in a polypeptide nanoparticle can act as a novel therapeutic alone against HCC and may augment the activity of the immune checkpoint antibodies. Silencing TGFß and Cox2 converts an immune excluded (cold) tumor into a T-cell inflamed (hot) tumor.
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OBJECTIVES: We sought to assess whether genetic associations with metabolite concentrations in septic shock patients could be used to identify pathways of potential importance for understanding sepsis pathophysiology. DESIGN: Retrospective multicenter cohort studies of septic shock patients. SETTING: All participants who were admitted to 27 participating hospital sites in three countries (Australia, New Zealand, and the United Kingdom) were eligible for inclusion. PATIENTS: Adult, critically ill, mechanically ventilated patients with septic shock (n = 230) who were a subset of the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock trial (ClinicalTrials.gov number: NCT01448109). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A genome-wide association study was conducted for a range of serum metabolite levels for participants. Genome-wide significant associations (p ≤ 5 × 10-8) were found for the two major ketone bodies (3-hydroxybutyrate [rs2456680] and acetoacetate [rs2213037] and creatinine (rs6851961). One of these single-nucleotide polymorphisms (SNPs) (rs2213037) was located in the alcohol dehydrogenase cluster of genes, which code for enzymes related to the metabolism of acetoacetate and, therefore, presents a plausible association for this metabolite. None of the three SNPs showed strong associations with risk of sepsis, 28- or 90-day mortality, or Acute Physiology and Chronic Health Evaluation score (a measure of sepsis severity). CONCLUSIONS: We suggest that the genetic associations with metabolites may reflect a starvation response rather than processes involved in sepsis pathophysiology. However, our results require further investigation and replication in both healthy and diseased cohorts including those of different ancestry.
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Importance: Conventional epidemiological analyses have suggested that lower birth weight is associated with later neurodevelopmental difficulties; however, it is unclear whether this association is causal. Objective: To investigate the relationship between intrauterine growth and offspring neurodevelopmental difficulties. Design, Setting, and Participants: MoBa is a population-based pregnancy cohort that recruited pregnant women from June 1999 to December 2008 included approximately 114â¯500 children, 95â¯200 mothers, and 75â¯200 fathers. Observational associations between birth weight and neurodevelopmental difficulties were assessed with a conventional epidemiological approach. Mendelian randomization analyses were performed to investigate the potential causal association between maternal allele scores for birth weight and offspring neurodevelopmental difficulties conditional on offspring allele scores. Exposures: Birth weight and maternal allele scores for birth weight (derived from genetic variants robustly associated with birth weight) were the exposures in the observational and mendelian randomization analyses, respectively. Main Outcomes and Measures: Clinically relevant maternal ratings of offspring neurodevelopmental difficulties at 6 months, 18 months, 3 years, 5 years, and 8 years of age assessing language and motor difficulties, inattention and hyperactivity-impulsivity, social communication difficulties, and repetitive behaviors. Results: The conventional epidemiological sample included up to 46â¯970 offspring, whereas the mendelian randomization sample included up to 44â¯134 offspring (median offspring birth year, 2005 [range, 1999-2009]; mean [SD] maternal age at birth, 30.1 [4.5] years; mean [SD] paternal age at birth, 32.5 [5.1] years). The conventional epidemiological analyses found evidence that birth weight was negatively associated with several domains at multiple offspring ages (outcome of autism-related trait scores: Social Communication Questionnaire [SCQ]-full at 3 years, ß = -0.046 [95% CI, -0.057 to -0.034]; SCQ-Restricted and Repetitive Behaviors subscale at 3 years, ß = -0.049 [95% CI, -0.060 to -0.038]; attention-deficit/hyperactivity disorder [ADHD] trait scores: Child Behavior Checklist [CBCL]-ADHD subscale at 18 months, ß = -0.035 [95% CI, -0.045 to -0.024]; CBCL-ADHD at 3 years, ß = -0.032 [95% CI, -0.043 to -0.021]; CBCL-ADHD at 5 years, ß = -0.050 [95% CI, -0.064 to -0.037]; Rating Scale for Disruptive Behavior Disorders [RS-DBD]-ADHD at 8 years, ß = -0.036 [95% CI, -0.049 to -0.023]; RS-DBD-Inattention at 8 years, ß = -0.037 [95% CI, -0.050 to -0.024]; RS-DBD-Hyperactive-Impulsive Behavior at 8 years, ß = -0.027 [95% CI, -0.040 to -0.014]; Conners Parent Rating Scale-Revised [Short Form] at 5 years, ß = -0.041 [95% CI, -0.054 to -0.028]; motor scores: Ages and Stages Questionnaire-Motor Difficulty [ASQ-MOTOR] at 18 months, ß = -0.025 [95% CI, -0.035 to -0.015]; ASQ-MOTOR at 3 years, ß = -0.029 [95% CI, -0.040 to -0.018]; and Child Development Inventory-Gross and Fine Motor Skills at 5 years, ß = -0.028 [95% CI, -0.042 to -0.015]). Mendelian randomization analyses did not find any evidence for an association between maternal allele scores for birth weight and offspring neurodevelopmental difficulties. Conclusions and Relevance: This study found that the maternal intrauterine environment, as proxied by maternal birth weight genetic variants, is unlikely to be a major determinant of offspring neurodevelopmental outcomes.
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Transtorno do Deficit de Atenção com Hiperatividade , Efeitos Tardios da Exposição Pré-Natal , Criança , Recém-Nascido , Humanos , Feminino , Gravidez , Pré-Escolar , Masculino , Mães , Estudos de Coortes , Análise da Randomização Mendeliana , Peso ao Nascer , Idioma , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , PaiRESUMO
BACKGROUND: Single nucleotide polymorphisms in the human leukocyte antigen (HLA) region in both maternal and fetal genomes have been robustly associated with birthweight (BW) in previous genetic association studies. However, no study to date has partitioned the association between BW and classical HLA alleles into maternal and fetal components. METHODS: We used structural equation modelling (SEM) to estimate the maternal and fetal effects of classical HLA alleles on BW. Our SEM leverages the data structure of the UK Biobank (UKB), which includes â¼270â000 participants' own BW and/or the BW of their firstborn child. RESULTS: We show via simulation that our model yields asymptotically unbiased estimates of the maternal and fetal allelic effects on BW and appropriate type I error rates, in contrast to simple regression models. Asymptotic power calculations show that we have sufficient power to detect moderate-sized maternal or fetal allelic effects of common HLA alleles on BW in the UKB. Applying our SEM to imputed classical HLA alleles and own and offspring BW from the UKB replicated the previously reported association at the HLA-C locus and revealed strong evidence for maternal (HLA-A*03:01, B*35:01, B*39:06, P <0.001) and fetal allelic effects (HLA-B*39:06, P <0.001) of non-HLA-C alleles on BW. CONCLUSIONS: Our model yields asymptotically unbiased estimates, appropriate type I error rates and appreciable power to estimate maternal and fetal effects on BW. These novel allelic associations between BW and classical HLA alleles provide insight into the immunogenetics of fetal growth in utero.
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Família , Antígenos HLA , Criança , Humanos , Peso ao Nascer/genética , Análise de Classes Latentes , Antígenos HLA/genética , Polimorfismo de Nucleotídeo Único , AlelosRESUMO
Fetal growth is an indicator of fetal survival, regulated by maternal and fetal factors, but little is known about the underlying molecular mechanisms. We used Mendelian randomization to explore the effects of maternal and fetal genetically-instrumented plasma proteins on birth weight using genome-wide association summary data (n=406,063 with maternal and/or fetal genotype), with independent replication (n=74,932 mothers and n=62,108 offspring), and colocalisation. Higher genetically-predicted maternal levels of PCSK1 increased birthweight (mean-difference: 9g (95% CI: 5g, 13g) per 1 standard deviation protein level). Higher maternal levels of LGALS4 decreased birthweight (-54g (-29g, -80g)), as did VCAM1, RAD51D and GP1BA. In the offspring, higher genetically-predicted fetal levels of LGALS4 (46g (23g, 70g)) increased birthweight, alongside FCGR2B. Higher offspring levels of PCSK1 decreased birth weight (-9g (-16g, 4g), alongside LEPR. Results support maternal and fetal protein effects on birth weight, implicating roles for glucose metabolism, energy homeostasis, endothelial function and adipocyte differentiation.
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Perinatal traits are influenced by genetic variants from both fetal and maternal genomes. Genome-wide association studies (GWAS) of these phenotypes have typically involved separate fetal and maternal scans, however, this approach may be inefficient as it does not utilize the information shared across the individual GWAS. In this manuscript we investigate the performance of three strategies to detect loci in maternal and fetal GWAS of the same trait: (i) the traditional strategy of analysing maternal and fetal GWAS separately; (ii) a novel two degree of freedom test which combines information from maternal and fetal GWAS; and (iii) a novel one degree of freedom test where signals from maternal and fetal GWAS are meta-analysed together conditional on the estimated sample overlap. We demonstrate through a combination of analytical formulae and data simulation that the optimal strategy depends on the extent of sample overlap/relatedness between the maternal and fetal GWAS, the correlation between own and offspring phenotypes, whether loci jointly exhibit fetal and maternal effects, and if so, whether these effects are directionally concordant. We apply our methods to summary results statistics from a recent GWAS meta-analysis of birth weight from deCODE, the UK Biobank and the Early Growth Genetics (EGG) consortium. Both the two degree of freedom (213 loci) and meta-analytic approach (226 loci) dramatically increase the number of robustly associated genetic loci for birth weight relative to separately analysing the scans (183 loci). Our best strategy identifies an additional 62 novel loci compared to the most recent published meta-analysis of birth weight and implicates both known and new biological pathways in the aetiology of the trait. We implement our methods in the online DINGO (Direct and INdirect effects analysis of Genetic lOci) software package, which allows users to perform one and/or two degree of freedom tests easily and computationally efficiently across the genome. We conclude that whilst the novel two degree of freedom test may be particularly useful for the analysis of certain perinatal phenotypes where many loci exhibit discordant maternal and fetal genetic effects, for most phenotypes, a simple meta-analytic strategy is likely to perform best, particularly in situations where maternal and fetal GWAS only partially overlap.
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BACKGROUND: Hip minimum joint space width (mJSW) provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest. METHODS: GWAS meta-analysis of hip mJSW derived from plain X-rays and DXA was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA. FINDINGS: 50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (ORIVW 0.98 [95% CI 0.82-1.18]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life. INTERPRETATIONS: One group of mJSW loci reduce HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to HOA risk via a growth-related mechanism. FUNDING: Primarily funded by the Medical Research Council and Wellcome Trust.
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Estudo de Associação Genômica Ampla , Osteoartrite do Quadril , Humanos , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/genética , Articulações , Análise por Conglomerados , Análise da Randomização MendelianaRESUMO
BACKGROUND: Previous Mendelian randomization (MR) studies using population samples (population MR) have provided evidence for beneficial effects of educational attainment on health outcomes in adulthood. However, estimates from these studies may have been susceptible to bias from population stratification, assortative mating and indirect genetic effects due to unadjusted parental genotypes. MR using genetic association estimates derived from within-sibship models (within-sibship MR) can avoid these potential biases because genetic differences between siblings are due to random segregation at meiosis. METHODS: Applying both population and within-sibship MR, we estimated the effects of genetic liability to educational attainment on body mass index (BMI), cigarette smoking, systolic blood pressure (SBP) and all-cause mortality. MR analyses used individual-level data on 72â932 siblings from UK Biobank and the Norwegian HUNT study, and summary-level data from a within-sibship Genome-wide Association Study including >140â000 individuals. RESULTS: Both population and within-sibship MR estimates provided evidence that educational attainment decreased BMI, cigarette smoking and SBP. Genetic variant-outcome associations attenuated in the within-sibship model, but genetic variant-educational attainment associations also attenuated to a similar extent. Thus, within-sibship and population MR estimates were largely consistent. The within-sibship MR estimate of education on mortality was imprecise but consistent with a putative effect. CONCLUSIONS: These results provide evidence of beneficial individual-level effects of education (or liability to education) on adulthood health, independently of potential demographic and family-level confounders.
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Sucesso Acadêmico , Análise da Randomização Mendeliana , Humanos , Análise da Randomização Mendeliana/métodos , Estudo de Associação Genômica Ampla , Escolaridade , Polimorfismo de Nucleotídeo Único , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Parental genes may indirectly influence offspring psychiatric outcomes through the environment that parents create for their children. These indirect genetic effects, also known as genetic nurture, could explain individual differences in common internalising and externalising psychiatric symptoms during childhood. Advanced statistical genetic methods leverage data from families to estimate the overall contribution of parental genetic nurture effects. This study included up to 10,499 children, 5990 mother-child pairs, and 6,222 father-child pairs from the Norwegian Mother Father and Child Study. Genome-based restricted maximum likelihood (GREML) models were applied using software packages GCTA and M-GCTA to estimate variance in maternally reported depressive, disruptive, and attention-deficit hyperactivity disorder (ADHD) symptoms in 8-year-olds that was explained by direct offspring genetic effects and maternal or paternal genetic nurture. There was no strong evidence of genetic nurture in this sample, although a suggestive paternal genetic nurture effect on offspring depressive symptoms (variance explained (V) = 0.098, standard error (SE) = 0.057) and a suggestive maternal genetic nurture effect on ADHD symptoms (V = 0.084, SE = 0.058) was observed. The results indicate that parental genetic nurture effects could be of some relevance in explaining individual differences in childhood psychiatric symptoms. However, robustly estimating their contribution is a challenge for researchers given the current paucity of large-scale samples of genotyped families with information on childhood psychiatric outcomes.
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Transtorno do Deficit de Atenção com Hiperatividade , Pais , Feminino , Humanos , Pais/psicologia , Mães/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Genótipo , Variação GenéticaRESUMO
BACKGROUND: Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression; however, the contribution of specific maternal amino acids to fetal growth is unclear. METHODS: We explored the effect of maternal circulating amino acids on fetal growth, proxied by birthweight, using two-sample Mendelian randomisation (MR) and summary data from a genome-wide association study (GWAS) of serum amino acids levels (sample 1, n = 86,507) and a maternal GWAS of offspring birthweight in UK Biobank and Early Growth Genetics Consortium, adjusting for fetal genotype effects (sample 2, n = 406,063 with maternal and/or fetal genotype effect estimates). A total of 106 independent single nucleotide polymorphisms robustly associated with 19 amino acids (p < 4.9 × 10-10) were used as genetic instrumental variables (IV). Wald ratio and inverse variance weighted methods were used in MR main analysis. A series of sensitivity analyses were performed to explore IV assumption violations. FINDINGS: Our results provide evidence that maternal circulating glutamine (59 g offspring birthweight increase per standard deviation increase in maternal amino acid level, 95% CI: 7, 110) and serine (27 g, 95% CI: 9, 46) raise, while leucine (-59 g, 95% CI: -106, -11) and phenylalanine (-25 g, 95% CI: -47, -4) lower offspring birthweight. These findings are supported by sensitivity analyses. INTERPRETATION: Our findings strengthen evidence for key roles of maternal circulating amino acids during pregnancy in healthy fetal growth. FUNDING: A full list of funding bodies that contributed to this study can be found under Acknowledgments.
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Aminoácidos , Estudo de Associação Genômica Ampla , Humanos , Gravidez , Feminino , Peso ao Nascer/genética , Genótipo , Desenvolvimento Fetal , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
CONTEXT: Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown. OBJECTIVE: This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity. METHODS: We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n = 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-sample Mendelian randomization. RESULTS: In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (ß [95% CI] -0.19 [-0.21 to -0.17]), body fat (-0.12 [-0.14 to -0.10), and fasting C-peptide (-2.04 [-2.46 to -1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose clamp in 2 independent clinical studies (-0.5 [-0.7 to -0.4] and -0.5 [-0.6 to -0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-sample Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, -1.72 [-2.86 to -0.58], and -0.20 [-0.36 to -0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-sample Mendelian randomization suggested no causal effect of fasting glucose on sOb-R. CONCLUSION: BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sOb-R. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Leptina , Insulina , Receptores para Leptina , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/epidemiologia , Estudos Transversais , Resistência à Insulina/fisiologia , GlucoseRESUMO
BACKGROUND: Higher urate levels are associated with higher systolic blood pressure (SBP) in adults, and in pregnancy with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birthweight. We therefore tested for a causal effect of maternal urate on offspring birthweight. METHODS: We tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH; n = 872) and UK Biobank (UKB; n = 133â187). We conducted two-sample MR to test for a causal effect of maternal urate [114 single-nucleotide polymorphisms (SNPs); n = 288â649 European ancestry] on offspring birthweight (n = 406â063 European ancestry; maternal SNP effect estimates adjusted for fetal effects). We assessed a causal relationship between urate and SBP using one-sample MR in UKB women (n = 199â768). RESULTS: Higher maternal urate was associated with lower offspring birthweight with similar confounder-adjusted magnitudes in EFSOCH [22 g lower birthweight per 1-SD higher urate (95% CI: -50, 6); P = 0.13] and UKB [-28 g (95% CI: -31, -25); P = 1.8 × 10-75]. The MR causal effect estimate was directionally consistent, but smaller [-11 g (95% CI: -25, 3); PIVW = 0.11]. In women, higher urate was causally associated with higher SBP [1.7 mmHg higher SBP per 1-SD higher urate (95% CI: 1.4, 2.1); P = 7.8 × 10-22], consistent with that previously published in women and men. CONCLUSION: The marked attenuation of the MR result of maternal urate on offspring birthweight compared with the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible small effect on birthweight. Maternal urate levels are unlikely to be an important contributor to offspring birthweight.
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Análise da Randomização Mendeliana , Ácido Úrico , Masculino , Adulto , Gravidez , Humanos , Feminino , Peso ao Nascer/genética , Causalidade , Cuidado Pré-Natal , Polimorfismo de Nucleotídeo Único , Estudo de Associação Genômica AmplaRESUMO
One of the longstanding debates in life-course epidemiology is whether an adverse intrauterine environment, often proxied by birth weight, causally increases the future risk of cardiometabolic disease. The use of a discordant twin study design, which controls for the influence of shared genetic and environmental confounding factors, may be useful to investigate whether this relationship is causal. We conducted a discordant twin study of 120 monozygotic (MZ) and 148 dizygotic (DZ) twin pairs from the UK Biobank to explore the potential causal relationships between birth weight and a broad spectrum of later-life cardiometabolic risk factors. We used a linear mixed model to investigate the association between birth weight and later-life cardiometabolic risk factors for twins, allowing for both within-pair differences and between-pair differences in birth weight. Of primary interest is the within-pair association between differences in birth weight and cardiometabolic risk factors, which could reflect an intrauterine effect on later-life risk factors. We found no strong evidence of association in MZ twins between the within-pair differences in birth weight and most cardiometabolic risk factors in later life, except for nominal associations with C-reactive protein and insulin-like growth factor 1. However, these associations were not replicated in DZ twin pairs. Our study provided no strong evidence for intrauterine effects on later-life cardiometabolic risk factors, which is consistent with previous large-scale studies of singletons testing the potential causal relationship. It does not support the hypothesis that adverse intrauterine environments increase the risk of cardiometabolic disease in later life.
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Bancos de Espécimes Biológicos , Doenças Cardiovasculares , Humanos , Peso ao Nascer , Gêmeos Monozigóticos/genética , Reino Unido/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologiaRESUMO
The Barker Hypothesis posits that adverse intrauterine environments result in fetal growth restriction and increased risk of cardiometabolic disease through developmental compensations. Here we introduce a new statistical model using the genomic SEM software that is capable of simultaneously partitioning the genetic covariation between birthweight and cardiometabolic traits into maternally mediated and offspring mediated contributions. We model the covariance between birthweight and later life outcomes, such as blood pressure, non-fasting glucose, blood lipids and body mass index in the Norwegian HUNT study, consisting of 15,261 mother-eldest offspring pairs with genetic and phenotypic data. Application of this model showed some evidence for maternally mediated effects of systolic blood pressure on offspring birthweight, and pleiotropy between birthweight and non-fasting glucose mediated through the offspring genome. This underscores the importance of genetic links between birthweight and cardiometabolic phenotypes and offer alternative explanations to environmentally based hypotheses for the phenotypic correlation between these variables.
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Fatores de Risco Cardiometabólico , Doenças Cardiovasculares , Humanos , Peso ao Nascer/genética , Análise de Classes Latentes , Genômica , Doenças Cardiovasculares/genética , Fatores de RiscoRESUMO
BACKGROUND: Coffee consumption has been associated with several adverse pregnancy outcomes, although data from randomized-controlled trials are lacking. We investigate whether there is a causal relationship between coffee consumption and miscarriage, stillbirth, birthweight, gestational age and pre-term birth using Mendelian randomization (MR). METHODS: A two-sample MR study was performed using summary results data from a genome-wide association meta-analysis of coffee consumption (N = 91â462) from the Coffee and Caffeine Genetics Consortium. Outcomes included self-reported miscarriage (N = 49â996 cases and 174â109 controls from a large meta-analysis); the number of stillbirths [N = 60â453 from UK Biobank (UKBB)]; gestational age and pre-term birth (N = 43â568 from the 23andMe, Inc cohort) and birthweight (N = 297â356 reporting own birthweight and N = 210â248 reporting offspring's birthweight from UKBB and the Early Growth Genetics Consortium). Additionally, a one-sample genetic risk score (GRS) analysis of coffee consumption in UKBB women (N up to 194â196) and the Avon Longitudinal Study of Parents and Children (N up to 6845 mothers and 4510 children) and its relationship with offspring outcomes was performed. RESULTS: Both the two-sample MR and one-sample GRS analyses showed no change in risk of sporadic miscarriages, stillbirths, pre-term birth or effect on gestational age connected to coffee consumption. Although both analyses showed an association between increased coffee consumption and higher birthweight, the magnitude of the effect was inconsistent. CONCLUSION: Our results suggest that coffee consumption during pregnancy might not itself contribute to adverse outcomes such as stillbirth, sporadic miscarriages and pre-term birth or lower gestational age or birthweight of the offspring.