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1.
BMC Med Genomics ; 14(1): 38, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536004

RESUMO

BACKGROUND: Lifestyle factors including obesity and smoking are suggested to be correlated with increased risk of COVID-19 severe illness or related death. However, whether these relationships are causal is not well known; neither for the relationships between COVID-19 severe illness and other common lifestyle factors, such as physical activity and alcohol consumption. METHODS: Genome-wide significant genetic variants associated with body mass index (BMI), lifetime smoking, physical activity and alcohol consumption identified by large-scale genome-wide association studies (GWAS) of up to 941,280 individuals were selected as instrumental variables. Summary statistics of the genetic variants on severe illness of COVID-19 were obtained from GWAS analyses of up to 6492 cases and 1,012,809 controls. Two-sample Mendelian randomisation analyses were conducted. RESULTS: Both per-standard deviation (SD) increase in genetically predicted BMI and lifetime smoking were associated with about two-fold increased risks of severe respiratory COVID-19 and COVID-19 hospitalization (all P < 0.05). Per-SD increase in genetically predicted physical activity was associated with decreased risks of severe respiratory COVID-19 (odds ratio [OR] = 0.19; 95% confidence interval [CI], 0.05, 0.74; P = 0.02), but not with COVID-19 hospitalization (OR = 0.44; 95% CI 0.18, 1.07; P = 0.07). No evidence of association was found for genetically predicted alcohol consumption. Similar results were found across robust Mendelian randomisation methods. CONCLUSIONS: Evidence is found that BMI and smoking causally increase and physical activity might causally decrease the risk of COVID-19 severe illness. This study highlights the importance of maintaining a healthy lifestyle in protecting from COVID-19 severe illness and its public health value in fighting against COVID-19 pandemic.


Assuntos
/diagnóstico , Estilo de Vida , Análise da Randomização Mendeliana/métodos , Consumo de Bebidas Alcoólicas , Índice de Massa Corporal , /virologia , Exercício Físico , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Razão de Chances , Fatores de Risco , Índice de Gravidade de Doença , Fumar
2.
Cancer Sci ; 112(4): 1579-1588, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33506574

RESUMO

Traditional observational studies have reported a positive association between higher body mass index (BMI) and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between BMI and CRC is sparse. A two-sample Mendelian randomization (MR) study was undertaken using 68 single nucleotide polymorphisms (SNPs) from the Japanese genome-wide association study (GWAS) and 654 SNPs from the GWAS catalogue for BMI as sets of instrumental variables. For the analysis of SNP-BMI associations, we undertook a meta-analysis with 36 303 participants in the Japanese Consortium of Genetic Epidemiology studies (J-CGE), comprising normal populations. For the analysis of SNP-CRC associations, we utilized 7636 CRC cases and 37 141 controls from five studies in Japan, and undertook a meta-analysis. Mendelian randomization analysis of inverse-variance weighted method indicated that a one-unit (kg/m2 ) increase in genetically predicted BMI was associated with an odds ratio of 1.13 (95% confidence interval, 1.06-1.20; P value <.001) for CRC using the set of 68 SNPs, and an odds ratio of 1.07 (1.03-1.11, 0.001) for CRC using the set of 654 SNPs. Sensitivity analyses robustly showed increased odds ratios for CRC for every one-unit increase in genetically predicted BMI. Our MR analyses strongly support the evidence that higher BMI influences the risk of CRC. Although Asians are generally leaner than Europeans and North Americans, avoiding higher BMI seems to be important for the prevention of CRC in Asian populations.


Assuntos
Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Japão , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
3.
Nat Commun ; 12(1): 350, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441555

RESUMO

Causal inference via Mendelian randomization requires making strong assumptions about horizontal pleiotropy, where genetic instruments are connected to the outcome not only through the exposure. Here, we present causal Graphical Analysis Using Genetics (cGAUGE), a pipeline that overcomes these limitations using instrument filters with provable properties. This is achievable by identifying conditional independencies while examining multiple traits. cGAUGE also uses ExSep (Exposure-based Separation), a novel test for the existence of causal pathways that does not require selecting instruments. In simulated data we illustrate how cGAUGE can reduce the empirical false discovery rate by up to 30%, while retaining the majority of true discoveries. On 96 complex traits from 337,198 subjects from the UK Biobank, our results cover expected causal links and many new ones that were previously suggested by correlation-based observational studies. Notably, we identify multiple risk factors for cardiovascular disease, including red blood cell distribution width.


Assuntos
Bancos de Espécimes Biológicos , Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Doenças Cardiovasculares/genética , Causalidade , Simulação por Computador , Redes Reguladoras de Genes , Variação Genética , Genótipo , Humanos , Análise da Randomização Mendeliana/métodos , Modelos Teóricos , Fenótipo , Fatores de Risco
4.
PLoS Med ; 17(9): e1003302, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32915777

RESUMO

BACKGROUND: A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR). METHODS AND FINDINGS: Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study. CONCLUSIONS: We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.


Assuntos
Neoplasias da Mama/genética , Lipídeos/análise , Lipídeos/sangue , Adulto , Neoplasias da Mama/metabolismo , Colesterol/análise , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Triglicerídeos/sangue
5.
PLoS Med ; 17(7): e1003178, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32701947

RESUMO

BACKGROUND: Smoking is a well-established cause of lung cancer and there is strong evidence that smoking also increases the risk of several other cancers. Alcohol consumption has been inconsistently associated with cancer risk in observational studies. This mendelian randomisation (MR) study sought to investigate associations in support of a causal relationship between smoking and alcohol consumption and 19 site-specific cancers. METHODS AND FINDINGS: We used summary-level data for genetic variants associated with smoking initiation (ever smoked regularly) and alcohol consumption, and the corresponding associations with lung, breast, ovarian, and prostate cancer from genome-wide association studies consortia, including participants of European ancestry. We additionally estimated genetic associations with 19 site-specific cancers among 367,643 individuals of European descent in UK Biobank who were 37 to 73 years of age when recruited from 2006 to 2010. Associations were considered statistically significant at a Bonferroni corrected p-value below 0.0013. Genetic predisposition to smoking initiation was associated with statistically significant higher odds of lung cancer in the International Lung Cancer Consortium (odds ratio [OR] 1.80; 95% confidence interval [CI] 1.59-2.03; p = 2.26 × 10-21) and UK Biobank (OR 2.26; 95% CI 1.92-2.65; p = 1.17 × 10-22). Additionally, genetic predisposition to smoking was associated with statistically significant higher odds of cancer of the oesophagus (OR 1.83; 95% CI 1.34-2.49; p = 1.31 × 10-4), cervix (OR 1.55; 95% CI 1.27-1.88; p = 1.24 × 10-5), and bladder (OR 1.40; 95% CI 1.92-2.65; p = 9.40 × 10-5) and with statistically nonsignificant higher odds of head and neck (OR 1.40; 95% CI 1.13-1.74; p = 0.002) and stomach cancer (OR 1.46; 95% CI 1.05-2.03; p = 0.024). In contrast, there was an inverse association between genetic predisposition to smoking and prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (OR 0.90; 95% CI 0.83-0.98; p = 0.011) and in UK Biobank (OR 0.90; 95% CI 0.80-1.02; p = 0.104), but the associations did not reach statistical significance. We found no statistically significant association between genetically predicted alcohol consumption and overall cancer (n = 75,037 cases; OR 0.95; 95% CI 0.84-1.07; p = 0.376). Genetically predicted alcohol consumption was statistically significantly associated with lung cancer in the International Lung Cancer Consortium (OR 1.94; 95% CI 1.41-2.68; p = 4.68 × 10-5) but not in UK Biobank (OR 1.12; 95% CI 0.65-1.93; p = 0.686). There was no statistically significant association between alcohol consumption and any other site-specific cancer. The main limitation of this study is that precision was low in some analyses, particularly for analyses of alcohol consumption and site-specific cancers. CONCLUSIONS: Our findings support the well-established relationship between smoking and lung cancer and suggest that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Análise da Randomização Mendeliana/métodos , Neoplasias/etiologia , Fumar/genética , Bancos de Espécimes Biológicos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Reino Unido
6.
Nat Commun ; 11(1): 3368, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632093

RESUMO

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (Ncases/Ncontrols = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, rg = 0.11, P = 3.56 × 10-06) and systolic BP (SBP, rg = 0.06, P = 0.01), but not pulse pressure (PP, rg = -0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10-08), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15-1.25]/10 mmHg; P = 5.57 × 10-25) on migraine than SBP (1.05 [1.03-1.07]/10 mmHg; P = 2.60 × 10-07) and a corresponding opposite effect for PP (0.92 [0.88-0.95]/10 mmHg; P = 3.65 × 10-07). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine.


Assuntos
Pressão Sanguínea/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Metanálise como Assunto , Transtornos de Enxaqueca/genética , Polimorfismo de Nucleotídeo Único , Humanos , Hipertensão/genética , Cadeias beta de Integrinas/genética , Análise da Randomização Mendeliana/métodos , Proteínas/genética , Receptores Adrenérgicos alfa 2/genética , Fatores de Risco , Telomerase/genética
7.
Nat Commun ; 11(1): 3519, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665587

RESUMO

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.


Assuntos
Análise da Randomização Mendeliana/métodos , Índice de Massa Corporal , Epidemiologia , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
8.
PLoS One ; 15(6): e0234488, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32542040

RESUMO

There is substantial variation in the timing of significant reproductive life events such as menarche and first sexual intercourse. Life history theory explains this variation as an adaptive response to an individual's environment and it is important to examine how traits within life history strategies affect each other. Here we applied Mendelian randomization (MR) methods to investigate whether there is a causal effect of variation in age at menarche and age at first sexual intercourse (markers or results of exposure to early life adversity) on outcomes related to reproduction, education and risky behaviour in UK Biobank (N = 114 883-181 255). Our results suggest that earlier age at menarche affects some traits that characterize life history strategies including earlier age at first and last birth, decreased educational attainment, and decreased age at leaving education (for example, we found evidence for a 0.26 year decrease in age at first birth per year decrease in age at menarche, 95% confidence interval: -0.34 to -0.17; p < 0.001). We find no clear evidence of effects of age at menarche on other outcomes, such as risk taking behaviour. Age at first sexual intercourse was also related to many life history outcomes, although there was evidence of horizontal pleiotropy which violates an assumption of MR and we therefore cannot infer causality from this analysis. Taken together, these results highlight how MR can be applied to test predictions of life history theory and to better understand determinants of health and social behaviour.


Assuntos
Coito , Escolaridade , Menarca/genética , Análise da Randomização Mendeliana/métodos , Reprodução , Assunção de Riscos , Fatores Etários , Feminino , Humanos , Traços de História de Vida , Masculino , Pessoa de Meia-Idade , Gravidez , Reino Unido
9.
Eur J Epidemiol ; 35(7): 685-697, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32383070

RESUMO

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (ß = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (ß = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (ß = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.


Assuntos
Peso ao Nascer , Pressão Sanguínea/genética , Hipertensão/epidemiologia , Hipertensão/genética , Análise da Randomização Mendeliana/métodos , Adulto , Peso ao Nascer/genética , Peso ao Nascer/fisiologia , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo Único/genética
10.
Nat Genet ; 52(7): 740-747, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32451458

RESUMO

Mendelian randomization (MR) is a valuable tool for detecting causal effects by using genetic variant associations. Opportunities to apply MR are growing rapidly with the increasing number of genome-wide association studies (GWAS). However, existing MR methods rely on strong assumptions that are often violated, leading to false positives. Correlated horizontal pleiotropy, which arises when variants affect both traits through a heritable shared factor, remains a particularly challenging problem. We propose a new MR method, Causal Analysis Using Summary Effect estimates (CAUSE), that accounts for correlated and uncorrelated horizontal pleiotropic effects. We demonstrate, in simulations, that CAUSE avoids more false positives induced by correlated horizontal pleiotropy than other methods. Applied to traits studied in recent GWAS studies, we find that CAUSE detects causal relationships that have strong literature support and avoids identifying most unlikely relationships. Our results suggest that shared heritable factors are common and may lead to many false positives using alternative methods.


Assuntos
Pleiotropia Genética , Análise da Randomização Mendeliana/métodos , Causalidade , Simulação por Computador , Doença , Reações Falso-Positivas , Genoma , Modelos Estatísticos , Fatores de Risco
11.
J Cancer Res Clin Oncol ; 146(8): 1933-1940, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32462299

RESUMO

PURPOSE: Few studies have investigated the relationship between vitiligo and risks of various types of cancers, especially those other than skin cancer. Conventional observational studies are susceptible to potential confounders and inverse causation. With a Mendelian randomization approach, we were able to evaluate the causality between vitiligo and different cancer risks. METHODS: 37 vitiligo-related single-nucleotide polymorphisms identified by the published genome-wide association studies were used as instrumental variables in our study. Summary data of individual-level genetic information were obtained from corresponding studies and cancer consortia. A total of 246,706 cases and 1,021,154 controls were included. The inverse variance-weighted method was applied to estimate the causation between vitiligo and different cancers. RESULTS: The results revealed that vitiligo patients were at lower risks of lung cancer [odds ratio (OR) 0.9513; 95% confidence interval (CI) 0.9174-0.9864; p = 0.0070], breast cancer (OR 0.9827; 95% CI 0.9659-0.9997; p = 0.0468), ovarian cancer (OR 0.9474; 95% CI 0.9271-0.9682; p < 0.001), melanoma (OR 0.9983; 95% CI 0.9976-0.9990; p < 0.001), non-melanoma skin cancer (OR 0.9997; 95% CI 0.9995-0.9999; p < 0.001), kidney cancer (OR 0.9998; 95% CI 0.9996-1.0000; p = 0.0212), and liver cancer (OR 0.9999; 95% CI 0.9999-1.0000; p = 0.0441), while no correlation was observed for other cancer types. CONCLUSIONS: Vitiligo was causally associated with reduced risks of several cancers, suggesting that vitiligo-associated autoimmune process might play a role in the suppression of cancer.


Assuntos
Neoplasias/epidemiologia , Neoplasias/genética , Vitiligo/epidemiologia , Vitiligo/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único , Risco
12.
PLoS One ; 15(4): e0230555, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275720

RESUMO

This study uses a Mendelian randomization approach to resolve the difficulties of identifying the causal relationship between height and earnings by using a unique sample of 3,427 respondents from mainland China with sociodemographic information linked to individual genotyping data. Exploiting genetic variations to create instrumental variables for observed height, we find that while OLS regressions yield that an additional centimeter in height is associated with a 10-13% increase in one's annual earnings, IV estimates reveal only an insubstantial causal effect of height. Further analyses suggest that the observed height premium is likely to pick up the impacts of several cognitive/noncognitive skills on earnings confounded in previous studies, such as mental health, risk preference, and personality factors. Our study is the first empirical study that employs genetic IVs in developing countries, and our results contribute to the recent debate on the mechanism of height premium.


Assuntos
Estatura/genética , Renda , China , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana/métodos
13.
Genet Epidemiol ; 44(4): 313-329, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249995

RESUMO

The number of Mendelian randomization (MR) analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire to obtain more precise estimates of causal effects. Since it is unlikely that all genetic variants will be valid instrumental variables, several robust methods have been proposed. We compare nine robust methods for MR based on summary data that can be implemented using standard statistical software. Methods were compared in three ways: by reviewing their theoretical properties, in an extensive simulation study, and in an empirical example. In the simulation study, the best method, judged by mean squared error was the contamination mixture method. This method had well-controlled Type 1 error rates with up to 50% invalid instruments across a range of scenarios. Other methods performed well according to different metrics. Outlier-robust methods had the narrowest confidence intervals in the empirical example. With isolated exceptions, all methods performed badly when over 50% of the variants were invalid instruments. Our recommendation for investigators is to perform a variety of robust methods that operate in different ways and rely on different assumptions for valid inferences to assess the reliability of MR analyses.


Assuntos
Análise da Randomização Mendeliana/métodos , Índice de Massa Corporal , Doença da Artéria Coronariana/patologia , Estudos de Associação Genética , Pleiotropia Genética , Humanos , Razão de Chances , Fatores de Risco
14.
PLoS Genet ; 16(3): e1008198, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32119656

RESUMO

Mendelian randomization (MR) implemented through instrumental variables analysis is an increasingly popular causal inference tool used in genetic epidemiology. But it can have limitations for evaluating simultaneous causal relationships in complex data sets that include, for example, multiple genetic predictors and multiple potential risk factors associated with the same genetic variant. Here we use real and simulated data to investigate Bayesian network analysis (BN) with the incorporation of directed arcs, representing genetic anchors, as an alternative approach. A Bayesian network describes the conditional dependencies/independencies of variables using a graphical model (a directed acyclic graph) with an accompanying joint probability. In real data, we found BN could be used to infer simultaneous causal relationships that confirmed the individual causal relationships suggested by bi-directional MR, while allowing for the existence of potential horizontal pleiotropy (that would violate MR assumptions). In simulated data, BN with two directional anchors (mimicking genetic instruments) had greater power for a fixed type 1 error than bi-directional MR, while BN with a single directional anchor performed better than or as well as bi-directional MR. Both BN and MR could be adversely affected by violations of their underlying assumptions (such as genetic confounding due to unmeasured horizontal pleiotropy). BN with no directional anchor generated inference that was no better than by chance, emphasizing the importance of directional anchors in BN (as in MR). Under highly pleiotropic simulated scenarios, BN outperformed both MR (and its recent extensions) and two recently-proposed alternative approaches: a multi-SNP mediation intersection-union test (SMUT) and a latent causal variable (LCV) test. We conclude that BN incorporating genetic anchors is a useful complementary method to conventional MR for exploring causal relationships in complex data sets such as those generated from modern "omics" technologies.


Assuntos
Pleiotropia Genética/genética , Polimorfismo de Nucleotídeo Único/genética , Teorema de Bayes , Humanos , Análise da Randomização Mendeliana/métodos , Fatores de Risco
15.
Neurobiol Aging ; 91: 167.e11-167.e19, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32204957

RESUMO

With the steadily increasing prevalence of Alzheimer's disease (AD) and great difficulties encountered for AD drug development presently, much interest has been devoted to identifying modifiable risk factors to lower the risk of AD, while the causal associations between risk factors and AD remain inconclusive. The present study conducted a comprehensive evaluation of the causal associations between risk factors and AD development by taking the recent advancements of Mendelian randomization (MR). Inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode were used for complementary calculation. A total of 45 risk factors and corresponding studies were covered in the study. This two-sample MR (2SMR) analysis provided a suggestive association between genetically predicted higher years of schooling and reduced risks of AD, and each standard deviation (3.71 years) increased in years of schooling was associated with a 41% reduction in the risk of AD (IVW, OR: 0.59, 95% CI: 0.45-0.77). At the same time, it was genetically predicted that urate might be a risk factor in AD, and it was found that each standard deviation increase in urate levels (1.33 mg/dL) was associated with a 0.09-fold increase in the risk of AD (IVW, OR: 1.09, 95% CI: 1.01-1.18). To summarize, the 2SMR analysis indicated a suggestive association between genetically predicted higher years of schooling and reduced risks of AD, and between genetically predicted higher urate levels and increased risks of AD. The findings provide useful clues to help combat AD and warrants future studies.


Assuntos
Doença de Alzheimer/etiologia , Escolaridade , Análise da Randomização Mendeliana/métodos , Ácido Úrico/sangue , Doença de Alzheimer/genética , Estatura , Cobre/sangue , Estudo de Associação Genômica Ampla , Hipocampo/patologia , Humanos , Ácido Linoleico/sangue , Tamanho do Órgão , Polimorfismo de Nucleotídeo Único , Fatores de Risco
16.
Eur J Epidemiol ; 35(2): 99-111, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32207040

RESUMO

We respond to criticisms of Mendelian randomization (MR) by Mukamal, Stampfer and Rimm (MSR). MSR consider that MR is receiving too much attention and should be renamed. We explain how MR links to Mendel's laws, the origin of the name and our lack of concern regarding nomenclature. We address MSR's substantive points regarding MR of alcohol and cardiovascular disease, an issue on which they dispute the MR findings. We demonstrate that their strictures with respect to population stratification, confounding, weak instrument bias, pleiotropy and confounding have been addressed, and summarise how the field has advanced in relation to the issues they raise. We agree with MSR that "the hard problem of conducting high-quality, reproducible epidemiology" should be addressed by epidemiologists. However we see more evidence of confrontation of this issue within MR, as opposed to conventional observational epidemiology, within which the same methods that have demonstrably failed in the past are simply rolled out into new areas, leaving their previous failures unexamined.


Assuntos
Pleiotropia Genética , Variação Genética/genética , Análise da Randomização Mendeliana/métodos , Doenças Cardiovasculares , Humanos , Epidemiologia Molecular
17.
BMC Med ; 18(1): 71, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32200763

RESUMO

BACKGROUND: Age at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner. METHODS: We conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations. RESULTS: Of the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null. CONCLUSIONS: The genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Menarca/fisiologia , Análise da Randomização Mendeliana/métodos , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Am J Hum Genet ; 106(3): 315-326, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084330

RESUMO

Whether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We first investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in 1 s (FEV1) in UK Biobank (n = 321,047) by using two-sample Mendelian randomization (MR) and then replicated this investigation in the SpiroMeta Consortium (n = 79,055). Second, we used two-step MR to investigate whether DNA methylation mediates the effect of smoking on FEV1. Lastly, we evaluated the presence of horizontal pleiotropy and assessed whether there is any evidence for shared causal genetic variants between lung function, DNA methylation, and gene expression by using a multiple-trait colocalization ("moloc") framework. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p < 1.2 × 10-4). Replication analysis supported a causal effect at three CpGs (cg21201401 [LIME1 and ZGPAT], cg19758448 [PGAP3], and cg12616487 [EML3 and AHNAK] [p < 0.0028]). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites might influence lung function via effects on smoking. By using "moloc", we found evidence of shared causal variants between lung function, gene expression, and DNA methylation. These findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although larger, tissue-specific datasets are required to confirm these results.


Assuntos
Metilação de DNA , Pulmão/fisiologia , Análise da Randomização Mendeliana/métodos , Fumar , Ilhas de CpG , Volume Expiratório Forçado , Pleiotropia Genética , Humanos
19.
Clin Interv Aging ; 15: 185-193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32103921

RESUMO

Background: Alzheimer's disease is a devastating neurodegenerative disorder. Its worldwide prevalence is over 24 million and is expected to double by 2040. Finding ways to prevent its cognitive decline is urgent. Methods: A two-sample Mendelian randomization study was performed instrumenting glutamine, which is abundant in blood, capable of crossing the blood-brain barrier, and involved in a metabolic cycle with glutamate in the brain. Results: The results reveal a protective effect of circulating glutamine against Alzheimer's disease (inverse-variance weighted method, odds ratio per 1-standard deviation increase in circulating glutamine = 0.83; 95% CI 0.71, 0.97; P = 0.02). Conclusion: These findings lend credence to the emerging story supporting the modifiability of glutamine/glutamate metabolism for the prevention of cognitive decline. More circulating glutamine might mean that more substrate is available during times of stress, acting as a neuroprotectant. Modifications to exogenous glutamine may be worth exploring in future efforts to prevent and/or treat Alzheimer's disease.


Assuntos
Doença de Alzheimer , Barreira Hematoencefálica/fisiologia , Encéfalo/metabolismo , Disfunção Cognitiva/prevenção & controle , Glutamina , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Cognição/fisiologia , Feminino , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Glutamina/sangue , Glutamina/genética , Glutamina/metabolismo , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Fármacos Neuroprotetores/metabolismo , Receptores de Glutamato/metabolismo
20.
Stroke ; 51(4): 1290-1293, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32106772

RESUMO

Background and Purpose- Mendelian stroke confers a high lifetime risk for mutation carriers; however, ethnicity-specific prevalence estimates have been difficult to establish. Methods- Eighteen genes responsible for Mendelian stroke were investigated using the Genome Aggregation Database. Genome Aggregation Database participants belonged to 1 of 7 populations: African/African-American, Latino/Admixed American, Ashkenazi Jewish, East Asian, Finnish European, non-Finnish European, and South Asian. Rare nonsynonymous variants from 101 635 participants free of neurological disease were examined for each ethnicity. Mutations were categorized according to 3 nested classes: pathogenic clinical variants, likely damaging variants based on in silico prediction, and all nonsynonymous variants. Results- ABCC6, KRIT1, CECR1, COL3A1, COL4A1, COL4A2, COLGALT1, GLA, HTRA1, NOTCH3, RNF213, and TREX1 harbored pathogenic clinical variants in Genome Aggregation Database. Across all 18 genes, total nonsynonymous carrier frequency was found to be high in 5 ethnicities (African/African-American, Latino/Admixed American, East Asian, non-Finnish European, and South Asian; 28.5%-37.5%) while lower total frequencies were estimated for in silico-predicted likely damaging variants (14.9%-19.7%) and pathogenic clinical variants (0.7%-2.8%). Overall, East Asian exhibited the highest total pathogenic clinical mutation carrier frequency (2.8%). ABCC6 pathogenic clinical variants were most prevalent among East Asian (0.8%). Pathogenic NOTCH3 variants, causal for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, were most frequent among East Asian (1.1%) and South Asian (1.2%). East Asian also demonstrated the highest carrier rate for RNF213 (0.8%). Finnish European exhibited the greatest HTRA1 frequency (0.2%), while COL4A1 pathogenic variants were most prevalent in African/African-American (0.3%). Conclusions- Especially, among pathogenic clinical variants, Mendelian stroke genetic prevalence differed significantly between populations. These prevalence estimates may serve as guides for screening and risk profiling in patients worldwide, particularly for understudied non-European populations.


Assuntos
Grupos Étnicos/genética , Variação Genética/genética , Análise da Randomização Mendeliana/métodos , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/genética , Bases de Dados Genéticas/tendências , Feminino , Saúde Global , Humanos , Masculino , Prevalência , Acidente Vascular Cerebral/diagnóstico
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