RESUMEN
Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment.
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Peso Corporal , Herencia Multifactorial/genética , Obesidad/patología , Adolescente , Índice de Masa Corporal , Niño , Bases de Datos Factuales , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Recién Nacido , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Obesidad/genética , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Multimorbidity is a rising public health challenge with important implications for health management and policy. The most common multimorbidity pattern is the combination of cardiometabolic and osteoarticular diseases. Here, we study the genetic underpinning of the comorbidity between type 2 diabetes and osteoarthritis. We find genome-wide genetic correlation between the two diseases and robust evidence for association-signal colocalization at 18 genomic regions. We integrate multi-omics and functional information to resolve the colocalizing signals and identify high-confidence effector genes, including FTO and IRX3, which provide proof-of-concept insights into the epidemiologic link between obesity and both diseases. We find enrichment for lipid metabolism and skeletal formation pathways for signals underpinning the knee and hip osteoarthritis comorbidities with type 2 diabetes, respectively. Causal inference analysis identifies complex effects of tissue-specific gene expression on comorbidity outcomes. Our findings provide insights into the biological basis for the type 2 diabetes-osteoarthritis disease co-occurrence.
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Diabetes Mellitus Tipo 2 , Osteoartritis , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Comorbilidad , Osteoartritis/epidemiología , Osteoartritis/genética , Obesidad/complicaciones , Obesidad/epidemiología , Obesidad/genética , Causalidad , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genéticaRESUMEN
ERAP2 is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to Yersinia pestis, have marked changes in allele frequency of the single-nucleotide polymorphism (SNP) rs2549794, with the T allele suggested to be deleterious during this period, while ERAP2 is also implicated in autoimmune diseases. This study explored the association between variation at ERAP2 and (1) infection, (2) autoimmune disease, and (3) parental longevity. Genome-wide association studies (GWASs) of these outcomes were identified in contemporary cohorts (UK Biobank, FinnGen, and GenOMICC). Effect estimates were extracted for rs2549794 and rs2248374, a haplotype tagging SNP. Additionally, cis expression and protein quantitative trait loci (QTLs) for ERAP2 were used in Mendelian randomization (MR) analyses. Consistent with decreased survival in the Black Death, the T allele of rs2549794 showed evidence of association with respiratory infection (odds ratio; OR for pneumonia 1.03; 95% CI 1.01-1.05). Effect estimates were larger for more severe phenotypes (OR for critical care admission with pneumonia 1.08; 95% CI 1.02-1.14). In contrast, opposing effects were identified for Crohn disease (OR 0.86; 95% CI 0.82-0.90). This allele was shown to associate with decreased ERAP2 expression and protein levels, independent of haplotype. MR analyses suggest that ERAP2 expression may be mediating disease associations. Decreased ERAP2 expression is associated with severe respiratory infection with an opposing association with autoimmune diseases. These data support the hypothesis of balancing selection at this locus driven by autoimmune and infectious disease.
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Enfermedades Autoinmunes , Peste , Humanos , Estudio de Asociación del Genoma Completo , Genotipo , Haplotipos/genética , Enfermedades Autoinmunes/genética , Polimorfismo de Nucleótido Simple/genética , Predisposición Genética a la Enfermedad , Aminopeptidasas/genética , Aminopeptidasas/metabolismoRESUMEN
Genetic studies of disease progression can be used to identify factors that may influence survival or prognosis, which may differ from factors that influence on disease susceptibility. Studies of disease progression feed directly into therapeutics for disease, whereas studies of incidence inform prevention strategies. However, studies of disease progression are known to be affected by collider (also known as "index event") bias since the disease progression phenotype can only be observed for individuals who have the disease. This applies equally to observational and genetic studies, including genome-wide association studies and Mendelian randomisation (MR) analyses. In this paper, our aim is to review several statistical methods that can be used to detect and adjust for index event bias in studies of disease progression, and how they apply to genetic and MR studies using both individual- and summary-level data. Methods to detect the presence of index event bias include the use of negative controls, a comparison of associations between risk factors for incidence in individuals with and without the disease, and an inspection of Miami plots. Methods to adjust for the bias include inverse probability weighting (with individual-level data), or Slope-Hunter and Dudbridge et al.'s index event bias adjustment (when only summary-level data are available). We also outline two approaches for sensitivity analysis. We then illustrate how three methods to minimise bias can be used in practice with two applied examples. Our first example investigates the effects of blood lipid traits on mortality from coronary heart disease, while our second example investigates genetic associations with breast cancer mortality.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Sesgo , Factores de Riesgo , Fenotipo , Análisis de la Aleatorización Mendeliana/métodos , Progresión de la EnfermedadRESUMEN
BACKGROUND: Obesity is among the leading public health threats globally. Over the last few years, visceral adiposity index (VAI), and body adiposity index (BAI), derived from anthropometric, and biochemical measures, have gained importance as a measure of obesity. However, unlike other common indices like body mass index, and waist circumference, the genetic predisposition of VAI, and BAI under-examined. METHODS: 2265 sib-pairs from Indian Migration Study were used for examining the association of genetic variants from the Cardio-Metabochip array with VAI, and BAI. Mixed linear regression models were run, and all inferences were based on the within-sib component of the Fulker's association models. Gene-environment/lifestyle interaction analyses were also undertaken. RESULTS: rs6659428 at LOC400796 | SEC16B (ß = 0.26, SE = 0.05), and rs7611535 at DRD3 | LOC645180 (ß = 0.18, SE = 0.04) were associated with VAI at suggestive significance value of <8.21 × 10-6. For BAI, rs73300702 at JAZF1-AS1 (ß = 0.27, SE = 0.06), was the top hit at p value < 8.21 × 10-6. Further, rs6659428 showed marginal effect modification with rural/urban location (ß = 0.26, SE = 0.13, p value = 0.047), and rs73300702 with physical activity (ß = -0.29,SE = 0.14, p value = 0.034). CONCLUSION: We report three novel genetic loci for VAI, and BAI in Indians that are important indicators of adiposity. These findings need to be replicated and validated with larger samples from different ethnicities. Further, functional studies for understanding the biological mechanisms of these adiposity indices need to be undertaken to understand the underlying pathophysiology.
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Spousal comparisons have been proposed as a design that can both reduce confounding and estimate effects of the shared adulthood environment. However, assortative mating, the process by which individuals select phenotypically (dis)similar mates, could distort associations when comparing spouses. We evaluated the use of spousal comparisons, as in the within-spouse pair (WSP) model, for aetiological research such as genetic association studies. We demonstrated that the WSP model can reduce confounding but may be susceptible to collider bias arising from conditioning on assorted spouse pairs. Analyses using UK Biobank spouse pairs found that WSP genetic association estimates were smaller than estimates from random pairs for height, educational attainment, and BMI variants. Within-sibling pair estimates, robust to demographic and parental effects, were also smaller than random pair estimates for height and educational attainment, but not for BMI. WSP models, like other within-family models, may reduce confounding from demographic factors in genetic association estimates, and so could be useful for triangulating evidence across study designs to assess the robustness of findings. However, WSP estimates should be interpreted with caution due to potential collider bias.
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Conducta Sexual , Adulto , Índice de Masa Corporal , Estudios de Cohortes , Femenino , Humanos , Masculino , Esposos , Reino UnidoRESUMEN
Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer's Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer's disease, 6 genes with Parkinson's disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.
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Enfermedad de Alzheimer/genética , Descubrimiento de Drogas , Predisposición Genética a la Enfermedad , Transcriptoma/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Trastorno Bipolar/patología , Encéfalo/metabolismo , Encéfalo/patología , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Terapia Molecular Dirigida , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo/genética , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Esquizofrenia/patologíaRESUMEN
AIMS: It is unclear whether higher triglyceride metabolism per se contributes to mortality separate from elevated triglyceride-rich lipoproteins and body mass index. This study tested the hypotheses that higher triglyceride metabolism, measured as higher plasma glycerol and ß-hydroxybutyrate, is associated with increased all-cause, cardiovascular, cancer, and other mortality. METHODS AND RESULTS: This study included 30 000 individuals nested within 109 751 individuals from the Copenhagen General Population Study. During a median follow-up of 10.7 years, 9897 individuals died (2204 from cardiovascular, 3366 from cancer, and 2745 from other causes), while none were lost to follow-up. In individuals with glycerol >80 µmol/L (highest fourth) vs. individuals with glycerol <52 µmol/L (lowest fourth), the multivariable adjusted hazard ratio for all-cause mortality was 1.31 (95% confidence interval 1.22-1.40). In individuals with ß-hydroxybutyrate >154 µmol/L (highest fourth) vs. individuals with ß-hydroxybutyrate <91 µmol/L (lowest fourth), the multivariable adjusted hazard ratio for all-cause mortality was 1.18 (1.11-1.26). Corresponding values for higher plasma glycerol and ß-hydroxybutyrate were 1.37 (1.18-1.59) and 1.18 (1.03-1.35) for cardiovascular mortality, 1.24 (1.11-1.39) and 1.16 (1.05-1.29) for cancer mortality, and 1.45 (1.28-1.66) and 1.23 (1.09-1.39) for other mortality, respectively. Results were robust to exclusion of first years of follow-up, to stratification for covariates including plasma triglycerides and body mass index, and to further adjustments. CONCLUSION: This study observed an increased risk of all-cause, cardiovascular, cancer, and other mortality with higher triglyceride metabolism. This was not explained by higher plasma triglycerides and body mass index. The hypothesis studied in the present paper should be further validated by isotope flux studies.
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Glicerol , Neoplasias , Humanos , Ácido 3-Hidroxibutírico , Triglicéridos , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: Effervescent formulations of paracetamol containing sodium bicarbonate have been reported to associate with increased blood pressure and a higher risk of cardiovascular diseases and all-cause mortality. Given the major implications of these findings, the reported associations were re-examined. METHODS: Using linked electronic health records data, a cohort of 475 442 UK individuals with at least one prescription of paracetamol, aged between 60 and 90 years, was identified. Outcomes in patients taking sodium-based paracetamol were compared with those taking non-sodium-based formulations of the same. Using a deep learning approach, associations with systolic blood pressure (SBP), major cardiovascular events (myocardial infarction, heart failure, and stroke), and all-cause mortality within 1 year after baseline were investigated. RESULTS: A total of 460 980 and 14 462 patients were identified for the non-sodium-based and sodium-based paracetamol exposure groups, respectively (mean age: 74 years; 64% women). Analysis revealed no difference in SBP [mean difference -0.04 mmHg (95% confidence interval -0.51, 0.43)] and no association with major cardiovascular events [relative risk (RR) 1.03 (0.91, 1.16)]. Sodium-based paracetamol showed a positive association with all-cause mortality [RR 1.46 (1.40, 1.52)]. However, after further accounting of other sources of residual confounding, the observed association attenuated towards the null [RR 1.08 (1.01, 1.16)]. Exploratory analyses revealed dysphagia and related conditions as major sources of uncontrolled confounding by indication for this association. CONCLUSIONS: This study does not support previous suggestions of increased SBP and an elevated risk of cardiovascular events from short-term use of sodium bicarbonate paracetamol in routine clinical practice.
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Enfermedades Cardiovasculares , Hipertensión , Infarto del Miocardio , Humanos , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Masculino , Presión Sanguínea , Hipertensión/complicaciones , Acetaminofén/efectos adversos , Antihipertensivos/uso terapéutico , Sodio , Bicarbonato de Sodio/farmacología , Infarto del Miocardio/complicacionesRESUMEN
AIMS/HYPOTHESIS: Determining how high BMI at different time points influences the risk of developing type 2 diabetes and affects insulin secretion and insulin sensitivity is critical. METHODS: By estimating childhood BMI in 441,761 individuals in the UK Biobank, we identified which genetic variants had larger effects on adulthood BMI than on childhood BMI, and vice versa. All genome-wide significant genetic variants were then used to separate the independent genetic effects of high childhood BMI from those of high adulthood BMI on the risk of type 2 diabetes and insulin-related phenotypes using Mendelian randomisation. We performed two-sample MR using external studies of type 2 diabetes, and oral and intravenous measures of insulin secretion and sensitivity. RESULTS: We found that a childhood BMI that was one standard deviation (1.97 kg/m2) higher than the mean, corrected for the independent genetic liability to adulthood BMI, was associated with a protective effect for seven measures of insulin sensitivity and secretion, including increased insulin sensitivity index (ß=0.15; 95% CI 0.067, 0.225; p=2.79×10-4) and reduced fasting glucose levels (ß=-0.053; 95% CI -0.089, -0.017; p=4.31×10-3). However, there was little to no evidence of a direct protective effect on type 2 diabetes (OR 0.94; 95% CI 0.85, 1.04; p=0.228) independently of genetic liability to adulthood BMI. CONCLUSIONS/INTERPRETATION: Our results provide evidence of the protective effect of higher childhood BMI on insulin secretion and sensitivity, which are crucial intermediate diabetes traits. However, we stress that our results should not currently lead to any change in public health or clinical practice, given the uncertainty regarding the biological pathway of these effects and the limitations of this type of study.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina/genética , Índice de Masa Corporal , Fenotipo , Insulina/genética , Análisis de la Aleatorización Mendeliana , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited. METHODS: We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake. RESULTS: We identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke). CONCLUSION: This study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.
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Consumo de Bebidas Alcohólicas , Pueblos del Este de Asia , Rubor , Humanos , Masculino , Alcohol Deshidrogenasa/genética , Consumo de Bebidas Alcohólicas/genética , Aldehído Deshidrogenasa Mitocondrial/genética , Pueblos del Este de Asia/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Rubor/inducido químicamenteRESUMEN
From a life-course perspective, genetic and environmental factors driving childhood obesity may have a lasting influence on health later in life. However, how obesity trajectories vary throughout the life-course remains unknown. Recently, Richardson et al. created powerful early life and adult gene scores for body mass index (BMI) in a comprehensive attempt to separate childhood and adult obesity. The childhood score was derived using questionnaire-based data administered to adults aged 40-69 regarding their relative body size at age 10, making it prone to recall and misclassification bias. We therefore attempted to validate the childhood and adult scores using measured BMI data in adolescence and adulthood among 66 963 individuals from the HUNT Study in Norway from 1963 to 2019. The predictive performance of the childhood score was better in adolescence and early adulthood, whereas the predictive performance of the adult score was better in adulthood. In the age group 12-15.9 years, the variance explained by the childhood polygenic risk score (PRS) was 6.7% versus 2.4% for the adult PRS. In the age group 24-29.9 years, the variance explained by the adult PRS was 3.9% versus 3.6% for the childhood PRS. Our findings support that genetic factors driving BMI differ at young age and in adulthood. Within the framework of multivariable Mendelian randomization, the validated childhood gene score can now be used to determine the consequence of childhood obesity on later disease.
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Adiposidad , Índice de Masa Corporal , Predisposición Genética a la Enfermedad , Obesidad/epidemiología , Obesidad/genética , Adolescente , Adulto , Anciano , Niño , Estudios Cruzados , Humanos , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Obesidad/patología , Factores de Riesgo , Adulto JovenRESUMEN
Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes are unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study, and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization, we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.
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Biomarcadores , Genética de Población , Estudio de Asociación del Genoma Completo , Troponina I/genética , Alelos , Mapeo Cromosómico , Expresión Génica , Variación Genética , Análisis de la Aleatorización Mendeliana , Especificidad de Órganos , Sitios de Carácter Cuantitativo , Troponina T/genéticaRESUMEN
BACKGROUND: Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. METHODS: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. RESULTS: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98-1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00-1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04-1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77-1.22) and colon cancer (OR: 0.97, 95% CI: 0.76-1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90-1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). CONCLUSIONS: Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.
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Neoplasias del Colon , Obesidad Infantil , Adulto , Humanos , Niño , Persona de Mediana Edad , Adiposidad/genética , Factores de Riesgo , Análisis de la Aleatorización Mendeliana , Estudio de Asociación del Genoma Completo , Índice de Masa Corporal , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Timing of developmental milestones, such as age at first walking, is associated with later diagnoses of neurodevelopmental disorders. However, its relationship to genetic risk for neurodevelopmental disorders in the general population is unknown. Here, we investigate associations between attainment of early-life language and motor development milestones and genetic liability to autism, attention deficit hyperactivity disorder (ADHD), and schizophrenia. METHODS: We use data from a genotyped sub-set (N = 25699) of children in the Norwegian Mother, Father and Child Cohort Study (MoBa). We calculate polygenic scores (PGS) for autism, ADHD, and schizophrenia and predict maternal reports of children's age at first walking, first words, and first sentences, motor delays (18 months), and language delays and a generalised measure of concerns about development (3 years). We use linear and probit regression models in a multi-group framework to test for sex differences. RESULTS: We found that ADHD PGS were associated with earlier walking age (ß = -0.033, padj < 0.001) in both males and females. Additionally, autism PGS were associated with later walking (ß = 0.039, padj = 0.006) in females only. No robust associations were observed for schizophrenia PGS or between any neurodevelopmental PGS and measures of language developmental milestone attainment. CONCLUSIONS: Genetic liabilities for neurodevelopmental disorders show some specific associations with the age at which children first walk unsupported. Associations are small but robust and, in the case of autism PGS, differentiated by sex. These findings suggest that early-life motor developmental milestone attainment is associated with genetic liability to ADHD and autism in the general population.
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Trastorno Autístico , Trastornos del Neurodesarrollo , Niño , Humanos , Preescolar , Femenino , Masculino , Estudios de Cohortes , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/genética , Genotipo , MadresRESUMEN
[This corrects the article DOI: 10.1371/journal.pbio.3000572.].
RESUMEN
BACKGROUND: Low levels of high-density lipoprotein (HDL) cholesterol have been associated with higher rates and severity of infection. Alterations in inflammatory mediators and infection are associated with alterations in HDL cholesterol. It is unknown whether the association between HDL and infection is present for all particle sizes, and whether the observed associations are confounded by IL-6 signalling. METHODS: In the UK Biobank, ~ 270,000 individuals have data on HDL subclasses derived from nuclear magnetic resonance analysis. We estimated the association of particle count of total HDL and HDL subclasses (small, medium, large, and extra-large HDL) with sepsis, sepsis-related death, and critical care admission in a Cox regression model. We subsequently utilised genetic data from UK Biobank and FinnGen to perform Mendelian randomisation (MR) of each HDL subclass and sepsis to test for a causal relationship. Finally, we explored the role of IL-6 signalling as a potential causal driver of changes in HDL subclasses. RESULTS: In observational analyses, higher particle count of small HDL was associated with protection from sepsis (Hazard ratio, HR 0.80; 95% CI 0.74-0.86, p = 4 × 10-9 comparing Quartile 4, highest quartile of HDL to Quartile 1, lowest quartile of HDL), sepsis-related death (HR 0.80; 95% CI 0.74-0.86, p = 2 × 10-4), and critical care admission with sepsis (HR 0.72 95% CI 0.60-0.85, p = 2 × 10-4). Parallel associations with other HDL subclasses were likely driven by changes in the small HDL compartment. MR analyses did not strongly support causality of small HDL particle count on sepsis incidence (Odds ratio, OR 0.98; 95% CI 0.89-1.07, p = 0.6) or death (OR 0.94, 95% CI 0.75-1.17, p = 0.56), although the estimate on critical care admission with sepsis supported protection (OR 0.73, 95% CI 0.57-0.95, p = 0.02). Bidirectional MR analyses suggested that increased IL-6 signalling was associated with reductions in both small (beta on small HDL particle count - 0.16, 95% CI - 0.10 to - 0.21 per natural log change in SD-scaled CRP, p = 9 × 10-8).and total HDL particle count (beta - 0.13, 95% CI - 0.09 to - 0.17, p = 7 × 10-10), but that the reverse effect of HDL on IL-6 signalling was largely null. CONCLUSIONS: Low number of small HDL particles are associated with increased hazard of sepsis, sepsis-related death, and sepsis-related critical care admission. However, genetic analyses did not strongly support this as causal. Instead, we demonstrate that increased IL-6 signalling, which is known to alter infection risk, could confound associations with reduced HDL particle count, and suggest this may explain part of the observed association between (small) HDL particle count and sepsis.
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Interleucina-6 , Sepsis , Humanos , HDL-Colesterol , Espectroscopía de Resonancia Magnética , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: There are many ways in which selection bias might impact COVID-19 research. Here we focus on selection for receiving a polymerase-chain-reaction (PCR) SARS-CoV-2 test and how known changes to selection pressures over time may bias research into COVID-19 infection. METHODS: Using UK Biobank (N = 420,231; 55% female; mean age = 66.8 [SD = 8·11]) we estimate the association between socio-economic position (SEP) and (i) being tested for SARS-CoV-2 infection versus not being tested (ii) testing positive for SARS-CoV-2 infection versus testing negative and (iii) testing negative for SARS-CoV-2 infection versus not being tested. We construct four distinct time-periods between March 2020 and March 2021, representing distinct periods of testing pressures and lockdown restrictions and specify both time-stratified and combined models for each outcome. We explore potential selection bias by examining associations with positive and negative control exposures. RESULTS: The association between more disadvantaged SEP and receiving a SARS-CoV-2 test attenuated over time. Compared to individuals with a degree, individuals whose highest educational qualification was a GCSE or equivalent had an OR of 1·27 (95% CI: 1·18 to 1·37) in March-May 2020 and 1·13 (95% CI: 1.·10 to 1·16) in January-March 2021. The magnitude of the association between educational attainment and testing positive for SARS-CoV-2 infection increased over the same period. For the equivalent comparison, the OR for testing positive increased from 1·25 (95% CI: 1·04 to 1·47), to 1·69 (95% CI: 1·55 to 1·83). We found little evidence of an association between control exposures, and any considered outcome. CONCLUSIONS: The association between SEP and SARS-CoV-2 testing changed over time, highlighting the potential of time-specific selection pressures to bias analyses of COVID-19. Positive and negative control analyses suggest that changes in the association between SEP and SARS-CoV-2 infection over time likely reflect true increases in socioeconomic inequalities.
Asunto(s)
COVID-19 , Femenino , Humanos , Anciano , Masculino , Sesgo de Selección , COVID-19/diagnóstico , COVID-19/epidemiología , Pandemias , Prueba de COVID-19 , SARS-CoV-2 , Control de Enfermedades Transmisibles , EscolaridadRESUMEN
BACKGROUND: Sex differences in cardiometabolic disease risk are commonly observed across the life course but are poorly understood and may be due to different associations of adiposity with cardiometabolic risk in females and males. We examined whether adiposity is differently associated with cardiometabolic trait levels in females and males at 3 different life stages. METHODS AND FINDINGS: Data were from 2 generations (offspring, Generation 1 [G1] born in 1991/1992 and their parents, Generation 0 [G0]) of a United Kingdom population-based birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). Follow-up continues on the cohort; data up to 25 y after recruitment to the study are included in this analysis. Body mass index (BMI) and total fat mass from dual-energy X-ray absorptiometry (DXA) were measured at mean age 9 y, 15 y, and 18 y in G1. Waist circumference was measured at 9 y and 15 y in G1. Concentrations of 148 cardiometabolic traits quantified using nuclear magnetic resonance spectroscopy were measured at 15 y, 18 y, and 25 y in G1. In G0, all 3 adiposity measures and the same 148 traits were available at 50 y. Using linear regression models, sex-specific associations of adiposity measures at each time point (9 y, 15 y, and 18 y) with cardiometabolic traits 3 to 6 y later were examined in G1. In G0, sex-specific associations of adiposity measures and cardiometabolic traits were examined cross-sectionally at 50 y. A total of 3,081 G1 and 4,887 G0 participants contributed to analyses. BMI was more strongly associated with key atherogenic traits in males compared with females at younger ages (15 y to 25 y), and associations were more similar between the sexes or stronger in females at 50 y, particularly for apolipoprotein B-containing lipoprotein particles and lipid concentrations. For example, a 1 standard deviation (SD) (3.8 kg/m2) higher BMI at 18 y was associated with 0.36 SD (95% confidence interval [CI] = 0.20, 0.52) higher concentrations of extremely large very-low-density lipoprotein (VLDL) particles at 25 y in males compared with 0.15 SD (95% CI = 0.09, 0.21) in females, P value for sex difference = 0.02. By contrast, at 50 y, a 1 SD (4.8 kg/m2) higher BMI was associated with 0.33 SD (95% CI = 0.25, 0.42) and 0.30 SD (95% CI = 0.26, 0.33) higher concentrations of extremely large VLDL particles in males and females, respectively, P value for sex difference = 0.42. Sex-specific associations of DXA-measured fat mass and waist circumference with cardiometabolic traits were similar to findings for BMI and cardiometabolic traits at each age. The main limitation of this work is its observational nature, and replication in independent cohorts using methods that can infer causality is required. CONCLUSIONS: The results of this study suggest that associations of adiposity with adverse cardiometabolic risk begin earlier in the life course among males compared with females and are stronger until midlife, particularly for key atherogenic lipids. Adolescent and young adult males may therefore be high priority targets for obesity prevention efforts.