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1.
BMJ ; 366: l4410, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371314

RESUMO

OBJECTIVE: To determine if genetically increased serum calcium levels are associated with improved bone mineral density and a reduction in osteoporotic fractures. DESIGN: Mendelian randomisation study. SETTING: Cohorts used included: the UK Biobank cohort, providing genotypic and estimated bone mineral density data; 25 cohorts from UK, USA, Europe, and China, providing genotypic and fracture data; and 17 cohorts from Europe, providing genotypic and serum calcium data (summary level statistics). PARTICIPANTS: A genome-wide association meta-analysis of serum calcium levels in up to 61 079 individuals was used to identify genetic determinants of serum calcium levels. The UK Biobank study was used to assess the association of genetic predisposition to increased serum calcium with estimated bone mineral density derived from heel ultrasound in 426 824 individuals who had, on average, calcium levels in the normal range. A fracture genome-wide association meta-analysis comprising 24 cohorts and the UK Biobank including a total of 76 549 cases and 470 164 controls, who, on average, also had calcium levels in the normal range was then performed. RESULTS: A standard deviation increase in genetically derived serum calcium (0.13 mmol/L or 0.51 mg/dL) was not associated with increased estimated bone mineral density (0.003 g/cm2, 95% confidence interval -0.059 to 0.066; P=0.92) or a reduced risk of fractures (odds ratio 1.01, 95% confidence interval 0.89 to 1.15; P=0.85) in inverse-variance weighted mendelian randomisation analyses. Sensitivity analyses did not provide evidence of pleiotropic effects. CONCLUSIONS: Genetic predisposition to increased serum calcium levels in individuals with normal calcium levels is not associated with an increase in estimated bone mineral density and does not provide clinically relevant protection against fracture. Whether such predisposition mimics the effect of short term calcium supplementation is not known. Given that the same genetically derived increase in serum calcium is associated with an increased risk of coronary artery disease, widespread calcium supplementation in the general population could provide more risk than benefit.


Assuntos
Densidade Óssea/genética , Cálcio/sangue , Predisposição Genética para Doença , Fraturas por Osteoporose/sangue , Fraturas por Osteoporose/genética , Adenosina Trifosfatases/genética , Diacilglicerol Quinase/genética , Feminino , Fator de Transcrição GATA3/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Receptores de Detecção de Cálcio/genética , Medição de Risco , Vitamina D3 24-Hidroxilase/genética , Vitamina K Epóxido Redutases/genética
2.
Nat Commun ; 10(1): 2949, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270314

RESUMO

Recent analyses have shown educational attainment to be associated with a number of health outcomes. This association may, in part, be due to an effect of educational attainment on smoking behaviour. In this study, we apply a multivariable Mendelian randomisation design to determine whether the effect of educational attainment on smoking behaviour is due to educational attainment or general cognitive ability. We use individual data from the UK Biobank study (N = 120,050) and summary data from large GWA studies of educational attainment, cognitive ability and smoking behaviour. Our results show that more years of education are associated with a reduced likelihood of smoking that is not due to an effect of general cognitive ability on smoking behaviour. Given the considerable physical harms associated with smoking, the effect of educational attainment on smoking is likely to contribute to the health inequalities associated with differences in educational attainment.


Assuntos
Cognição/fisiologia , Escolaridade , Análise da Randomização Mendeliana , Fumar/genética , Viés , Estudo de Associação Genômica Ampla , Humanos , Razão de Chances
3.
Epidemiol Health ; 41: e2019034, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31319653

RESUMO

OBJECTIVES: Bilirubin is an endogenous antioxidant that protects cells against oxidative stress. Increased plasma levels of bilirubin have been associated with a reduced risk of ischemic heart disease (IHD) in previous studies. Nonetheless, whether those associations reflect a true protective effect of bilirubin on IHD, rather than confounding or reverse causation, remains unknown. Therefore, we applied two-sample Mendelian randomization to evaluate the causal association between bilirubin levels and IHD risk in a Korean population. METHODS: A total of 5 genetic variants-TRPM8 (rs10490012), USP40 (rs12993249), ATG16L1 (rs2119503), SLCO1B1 (rs4149014), and SLCO1B3 (rs73233620)-were selected as genetic instruments for serum bilirubin levels using a communitybased cohort, the Korean Genome and Epidemiology Study, comprising 33,598 subjects. We then evaluated their impact on IHD using the Korean Cancer Prevention Study-II cohort. RESULTS: Among the 5 instrumental variables that showed significant associations with serum bilirubin levels, rs12993249 (USP40) showed the most significant association (p<2.36×10-105). However, we found no significant association between serum bilirubin levels and IHD. Sensitivity analyses demonstrated a consistent association, suggesting that our observations were robust. CONCLUSIONS: Using two-sample Mendelian randomization, we found no association between serum bilirubin levels and IHD. Further studies that confirm the observed interactions among other ethnicities are warranted.


Assuntos
Bilirrubina/sangue , Isquemia Miocárdica/epidemiologia , Causalidade , Estudos de Coortes , Feminino , Variação Genética , Humanos , Masculino , Análise da Randomização Mendeliana , Isquemia Miocárdica/sangue , Isquemia Miocárdica/genética , República da Coreia/epidemiologia
8.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(7): 839-843, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31357808

RESUMO

Objective: To assess the casual effect of childhood obesity on adulthood coronary artery disease (CAD) using Mendelian randomization (MR) method. Methods: Data on BMI of children aged 2-10 years in 2015 were downloaded from Early Growth Genetics Consortium and Genetic Investigation of Anthropometric Traits Consortium. Twenty-seven genetic variants related to children's BMI were selected as instrumental variables (IVs), and the associations between IVs and CAD were extracted from a Meta-analysis of the genome-wide association study of CAD cases published in UK Biobank 2015. We used MR-Egger regression to test whether there was the pleiotropy of the selected SNPs. In the present MR methods, we conducted MR analyses by using mode-based estimate method as primary method for summary-level of associations to estimate the causal association between childhood obesity and CAD. Results: The intercept term estimated for CAD from MR-Egger method suggested that the selected SNPs don't exert pleiotropy with a 95%CI including the null (-0.008-0.018). In addition, we found evidence that support the effect of childhood obesity on CAD risk: a 1 s increase in children BMI (kg/m(2)), and the risk of suffering from CAD in adulthood increased by an average of 37% (OR=1.37, 95%CI: 1.09-1.72). Conclusion: This study provides a causal association between childhood obesity and CAD risk.


Assuntos
Doença da Artéria Coronariana/epidemiologia , Obesidade Pediátrica/epidemiologia , Criança , Pré-Escolar , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Metanálise como Assunto , Obesidade Pediátrica/genética , Polimorfismo de Nucleotídeo Único
9.
Zhonghua Yu Fang Yi Xue Za Zhi ; 53(6): 619-624, 2019 Jun 06.
Artigo em Chinês | MEDLINE | ID: mdl-31177761

RESUMO

Mendelian randomization (MR) approach follows the Mendel's law of inheritance, which is called "Parental alleles randomly assigned to the offspring", and refers to use genetic variants as an instrumental variable to develop causal inference between the exposure factor and the outcome from observational study. In recent years, with the rapid development of genome-wide association study (GWAS) and various omics data,the disclosure of a large number of aggregated data provides an opportunity for the wide application of MR approach in causal inference. We introduce three methods widely used in MR and then apply them to explore causal relationship between blood metabolites and depressive. The advantages and disadvantages of three methods in causal inference are compared in order to provide reference for the application of MR in observational studies.


Assuntos
Causalidade , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Estudos Observacionais como Assunto , Alelos , Distribuição Aleatória , Projetos de Pesquisa
10.
BMJ ; 365: l2327, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243001

RESUMO

OBJECTIVE: To examine whether sleep traits have a causal effect on risk of breast cancer. DESIGN: Mendelian randomisation study. SETTING: UK Biobank prospective cohort study and Breast Cancer Association Consortium (BCAC) case-control genome-wide association study. PARTICIPANTS: 156 848 women in the multivariable regression and one sample mendelian randomisation (MR) analysis in UK Biobank (7784 with a breast cancer diagnosis) and 122 977 breast cancer cases and 105 974 controls from BCAC in the two sample MR analysis. EXPOSURES: Self reported chronotype (morning or evening preference), insomnia symptoms, and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits. MAIN OUTCOME MEASURE: Breast cancer diagnosis. RESULTS: In multivariable regression analysis using UK Biobank data on breast cancer incidence, morning preference was inversely associated with breast cancer (hazard ratio 0.95, 95% confidence interval 0.93 to 0.98 per category increase), whereas there was little evidence for an association between sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated with sleep duration, and 57 SNPs associated with insomnia symptoms, one sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (0.85, 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two sample MR using data from BCAC supported findings for a protective effect of morning preference (inverse variance weighted odds ratio 0.88, 95% confidence interval 0.82 to 0.93 per category increase) and adverse effect of increased sleep duration (1.19, 1.02 to 1.39 per hour increase) on breast cancer risk (both oestrogen receptor positive and oestrogen receptor negative), whereas evidence for insomnia symptoms was inconsistent. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy. CONCLUSIONS: Findings showed consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of increased sleep duration on breast cancer risk.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Sono , Adulto , Idoso , Estudos de Casos e Controles , Ritmo Circadiano , Comorbidade , Fatores de Confusão (Epidemiologia) , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Fatores de Risco , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Fatores de Tempo , Reino Unido/epidemiologia
12.
Nat Commun ; 10(1): 2773, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235808

RESUMO

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.


Assuntos
Cárie Dentária/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Periodontite/genética , Cárie Dentária/epidemiologia , Genômica , Hereditariedade , Humanos , Análise da Randomização Mendeliana , Periodontite/epidemiologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Autorrelato/estatística & dados numéricos
14.
BMJ ; 365: l1855, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31122926

RESUMO

OBJECTIVES: To investigate the role of body mass index (BMI), systolic blood pressure, and smoking behaviour in explaining the effect of education on the risk of cardiovascular disease outcomes. DESIGN: Mendelian randomisation study. SETTING: UK Biobank and international genome-wide association study data. PARTICIPANTS: Predominantly participants of European ancestry. EXPOSURE: Educational attainment, BMI, systolic blood pressure, and smoking behaviour in observational analysis, and randomly allocated genetic variants to instrument these traits in mendelian randomisation. MAIN OUTCOMES MEASURE: The risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease (all subtypes; all measured in odds ratio), and the degree to which this is mediated through BMI, systolic blood pressure, and smoking behaviour respectively. RESULTS: Each additional standard deviation of education (3.6 years) was associated with a 13% lower risk of coronary heart disease (odds ratio 0.86, 95% confidence interval 0.84 to 0.89) in observational analysis and a 37% lower risk (0.63, 0.60 to 0.67) in mendelian randomisation analysis. As a proportion of the total risk reduction, BMI was estimated to mediate 15% (95% confidence interval 13% to 17%) and 18% (14% to 23%) in the observational and mendelian randomisation estimates, respectively. Corresponding estimates were 11% (9% to 13%) and 21% (15% to 27%) for systolic blood pressure and 19% (15% to 22%) and 34% (17% to 50%) for smoking behaviour. All three risk factors combined were estimated to mediate 42% (36% to 48%) and 36% (5% to 68%) of the effect of education on coronary heart disease in observational and mendelian randomisation analyses, respectively. Similar results were obtained when investigating the risk of stroke, myocardial infarction, and cardiovascular disease. CONCLUSIONS: BMI, systolic blood pressure, and smoking behaviour mediate a substantial proportion of the protective effect of education on the risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of cardiovascular disease attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.


Assuntos
Doenças Cardiovasculares/etiologia , Escolaridade , Adulto , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Fatores de Risco , Fumar/efeitos adversos , Fatores Socioeconômicos , Reino Unido
15.
BMJ ; 364: l1042, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30957776

RESUMO

OBJECTIVE: To investigate the shape of the causal relation between body mass index (BMI) and mortality. DESIGN: Linear and non-linear mendelian randomisation analyses. SETTING: Nord-Trøndelag Health (HUNT) Study (Norway) and UK Biobank (United Kingdom). PARTICIPANTS: Middle to early late aged participants of European descent: 56 150 from the HUNT Study and 366 385 from UK Biobank. MAIN OUTCOME MEASURES: All cause and cause specific (cardiovascular, cancer, and non-cardiovascular non-cancer) mortality. RESULTS: 12 015 and 10 344 participants died during a median of 18.5 and 7.0 years of follow-up in the HUNT Study and UK Biobank, respectively. Linear mendelian randomisation analyses indicated an overall positive association between genetically predicted BMI and the risk of all cause mortality. An increase of 1 unit in genetically predicted BMI led to a 5% (95% confidence interval 1% to 8%) higher risk of mortality in overweight participants (BMI 25.0-29.9) and a 9% (4% to 14%) higher risk of mortality in obese participants (BMI ≥30.0) but a 34% (16% to 48%) lower risk in underweight (BMI <18.5) and a 14% (-1% to 27%) lower risk in low normal weight participants (BMI 18.5-19.9). Non-linear mendelian randomisation indicated a J shaped relation between genetically predicted BMI and the risk of all cause mortality, with the lowest risk at a BMI of around 22-25 for the overall sample. Subgroup analyses by smoking status, however, suggested an always-increasing relation of BMI with mortality in never smokers and a J shaped relation in ever smokers. CONCLUSIONS: The previously observed J shaped relation between BMI and risk of all cause mortality appears to have a causal basis, but subgroup analyses by smoking status revealed that the BMI-mortality relation is likely comprised of at least two distinct curves, rather than one J shaped relation. An increased risk of mortality for being underweight was only evident in ever smokers.


Assuntos
Índice de Massa Corporal , Causas de Morte , Adulto , Idoso , Doenças Cardiovasculares/mortalidade , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Neoplasias/mortalidade , Noruega/epidemiologia , Obesidade/mortalidade , Fatores de Risco , Distribuição por Sexo , Magreza/mortalidade , Reino Unido/epidemiologia
16.
Acta Diabetol ; 56(9): 1037-1044, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30989380

RESUMO

AIMS: Observational studies indicated that resting heart rate (RHR) was associated with diabetes mellitus (DM) risk; however, it remains unclear whether the association between RHR and DM is causal. We aimed to examine whether there was causal association of RHR with DM risk. METHODS: A prospective study including 16,201 middle-aged and older Chinese (7031 males and 9170 females) derived from the Dongfeng-Tongji cohort was performed. Cox proportional hazard regression models were conducted to estimate the associations between RHR and incident DM risk. In 7481 participants, 65 single nucleotide polymorphisms related to RHR were genotyped. A genetic risk score (GRS) of RHR was calculated based on the RHR-associated variants. The causal associations of RHR with DM risk were investigated by Mendelian randomization analysis. RESULTS: During a mean (SD) follow-up of 4.5 (0.5) years, 1110 diabetes were identified. Compared with the referential RHR group (≤ 60 beats per minute [bpm]), individuals with RHR > 80 bpm have a higher incident diabetes risk, with a hazard ratio of 1.40 (95% confidence interval [CI], 1.05-1.88). With per SD increase in the weighted genetic risk score, the resting heart rate increased by 0.71 bpm (95% CI 0.49-0.93). By using the GRS to estimate the unconfounded effect, we found that higher resting heart rate did not have a causal effect on diabetes risk (OR 1.00 [95% CI 0.95-1.05]). CONCLUSIONS: The present study supported a positive but not a causal association of RHR with incident diabetes risk. More studies are needed to verify our findings.


Assuntos
Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatologia , Frequência Cardíaca/genética , Polimorfismo de Nucleotídeo Único , Descanso/fisiologia , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , China/epidemiologia , Estudos de Coortes , Feminino , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença/epidemiologia , Genótipo , Humanos , Incidência , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
17.
Nat Commun ; 10(1): 1941, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028273

RESUMO

Mendelian randomization (MR) has emerged as a major tool for the investigation of causal relationship among traits, utilizing results from large-scale genome-wide association studies. Bias due to horizontal pleiotropy, however, remains a major concern. We propose a novel approach for robust and efficient MR analysis using large number of genetic instruments, based on a novel spike-detection algorithm under a normal-mixture model for underlying effect-size distributions. Simulations show that the new method, MRMix, provides nearly unbiased or/and less biased estimates of causal effects compared to alternative methods and can achieve higher efficiency than comparably robust estimators. Application of MRMix to publicly available datasets leads to notable observations, including identification of causal effects of BMI and age-at-menarche on the risk of breast cancer; no causal effect of HDL and triglycerides on the risk of coronary artery disease; a strong detrimental effect of BMI on the risk of major depressive disorder.


Assuntos
Algoritmos , Neoplasias da Mama/genética , Doença da Artéria Coronariana/genética , Transtorno Depressivo Maior/genética , Genoma Humano , Análise da Randomização Mendeliana/estatística & dados numéricos , Fatores Etários , Índice de Massa Corporal , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etiologia , HDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Conjuntos de Dados como Assunto , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/etiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Menarca/sangue , Menarca/genética , Característica Quantitativa Herdável , Fatores de Risco , Triglicerídeos/sangue
20.
Diabetes Care ; 42(7): 1284-1289, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30894365

RESUMO

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has demonstrated the major role of hyperglycemia as a risk factor for clinical cardiovascular outcomes in type 1 diabetes (T1D). We assessed whether and to what extent the effect of glycemia is mediated by other established cardiovascular disease (CVD) risk factors. RESEARCH DESIGN AND METHODS: In the DCCT, 1,441 participants were randomized to receive either intensive or conventional diabetes therapy. The EDIC observational follow-up study enrolled 96% of the surviving DCCT cohort with 94% of the survivors still actively participating after more than 27 years of follow-up. Mediation of the effect of glycemia, as captured by HbA1c, on the subsequent CVD risk was quantified using the relative change in the CVD risk associated with HbA1c between models without and with the potential mediator. RESULTS: Adjusted for age, only a few factors (e.g., pulse, triglycerides, albumin excretion rate) explained more than 10% of the effect of glycemia on CVD risk when considered individually. In multivariable models, these traditional risk factors together mediated up to ∼50% of the effect of glycemia on the risk of CVD. However, the association between HbA1c and the risk of CVD remained highly significant even after adjustment for these risk factors. CONCLUSIONS: While HbA1c is associated with many traditional CVD risk factors, its association with these factors alone cannot explain its effects on risk of CVD. Consequently, aggressive management of traditional nonglycemic CVD risk factors, coupled with aggressive glycemic management, is indicated for individuals with type 1 diabetes.


Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus Tipo 1 , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Análise da Randomização Mendeliana , Fatores de Risco
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