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1.
Lancet Psychiatry ; 7(2): 208-216, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31759900

RESUMO

Nutritional psychiatry is a growing area of research, with several nutritional factors implicated in the cause of psychiatric ill-health. However, nutritional research is highly complex, with multiple potential factors involved, highly confounded exposures and small effect sizes for individual nutrients. This Personal View considers whether Mendelian randomisation provides a solution to these difficulties, by investigating causality in a low-risk and low-cost way. We reviewed studies using Mendelian randomisation in nutritional psychiatry, along with the potential opportunities and challenges of using this approach for investigating the causal effects of nutritional exposures. Several studies have identified nutritional exposures that are potentially causal by using Mendelian randomisation in psychiatry, offering opportunities for further mechanistic research, intervention development, and replication. The use of Mendelian randomisation as a foundation for intervention development facilitates the best use of resources in an emerging discipline in which opportunities are rich, but resources are often poor.


Assuntos
Análise da Randomização Mendeliana , Transtornos Mentais , Fenômenos Fisiológicos da Nutrição , Psiquiatria , Humanos , Análise da Randomização Mendeliana/métodos , Análise da Randomização Mendeliana/normas , Transtornos Mentais/dietoterapia , Transtornos Mentais/epidemiologia , Transtornos Mentais/etiologia , Transtornos Mentais/prevenção & controle , Psiquiatria/métodos , Psiquiatria/normas
2.
Hum Genet ; 139(1): 121-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31134333

RESUMO

In the current era, with increasing availability of results from genetic association studies, finding genetic instruments for inferring causality in observational epidemiology has become apparently simple. Mendelian randomisation (MR) analyses are hence growing in popularity and, in particular, methods that can incorporate multiple instruments are being rapidly developed for these applications. Such analyses have enormous potential, but they all rely on strong, different, and inherently untestable assumptions. These have to be clearly stated and carefully justified for every application in order to avoid conclusions that cannot be replicated. In this article, we review the instrumental variable assumptions and discuss the popular linear additive structural model. We advocate the use of tests for the null hypothesis of 'no causal effect' and calculation of the bounds for a causal effect, whenever possible, as these do not rely on parametric modelling assumptions. We clarify the difference between a randomised trial and an MR study and we comment on the importance of validating instruments, especially when considering them for joint use in an analysis. We urge researchers to stand by their convictions, if satisfied that the relevant assumptions hold, and to interpret their results causally since that is the only reason for performing an MR analysis in the first place.


Assuntos
Variação Genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana/métodos , Epidemiologia Molecular/métodos , Humanos
3.
PLoS Med ; 16(12): e1002982, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31821322

RESUMO

BACKGROUND: Lifestyle interventions to reduce body mass index (BMI) are critical public health strategies for type 2 diabetes prevention. While weight loss interventions have shown demonstrable benefit for high-risk and prediabetic individuals, we aimed to determine whether the same benefits apply to those at lower risk. METHODS AND FINDINGS: We performed a multi-stratum Mendelian randomization study of the effect size of BMI on diabetes odds in 287,394 unrelated individuals of self-reported white British ancestry in the UK Biobank, who were recruited from across the United Kingdom from 2006 to 2010 when they were between the ages of 40 and 69 years. Individuals were stratified on the following diabetes risk factors: BMI, diabetes family history, and genome-wide diabetes polygenic risk score. The main outcome measure was the odds ratio of diabetes per 1-kg/m2 BMI reduction, in the full cohort and in each stratum. Diabetes prevalence increased sharply with BMI, family history of diabetes, and genetic risk. Conversely, predicted risk reduction from weight loss was strikingly similar across BMI and genetic risk categories. Weight loss was predicted to substantially reduce diabetes odds even among lower-risk individuals: for instance, a 1-kg/m2 BMI reduction was associated with a 1.37-fold reduction (95% CI 1.12-1.68) in diabetes odds among non-overweight individuals (BMI < 25 kg/m2) without a family history of diabetes, similar to that in obese individuals (BMI ≥ 30 kg/m2) with a family history (1.21-fold reduction, 95% CI 1.13-1.29). A key limitation of this analysis is that the BMI-altering DNA sequence polymorphisms it studies represent cumulative predisposition over an individual's entire lifetime, and may consequently incorrectly estimate the risk modification potential of weight loss interventions later in life. CONCLUSIONS: In a population-scale cohort, lower BMI was consistently associated with reduced diabetes risk across BMI, family history, and genetic risk categories, suggesting all individuals can substantially reduce their diabetes risk through weight loss. Our results support the broad deployment of weight loss interventions to individuals at all levels of diabetes risk.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Herança Multifatorial/genética , Obesidade/epidemiologia , Adulto , Idoso , Bancos de Espécimes Biológicos/estatística & dados numéricos , Índice de Massa Corporal , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido/epidemiologia
4.
PLoS Genet ; 15(10): e1008353, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31671092

RESUMO

Mendelian randomization (MR) is an established approach to evaluate the effect of an exposure on an outcome. The gene-by-environment (GxE) study design can be used to determine whether the genetic instrument affects the outcome through pathways other than via the exposure of interest (horizontal pleiotropy). MR phenome-wide association studies (MR-pheWAS) search for the effects of an exposure, and can be conducted in UK Biobank using the PHESANT package. In this proof-of-principle study, we introduce the novel GxE MR-pheWAS approach, that combines MR-pheWAS with the use of GxE interactions. This method aims to identify the presence of effects of an exposure while simultaneously investigating horizontal pleiotropy. We systematically test for the presence of causal effects of smoking heaviness-stratifying on smoking status (ever versus never)-as an exemplar. If a genetic variant is associated with smoking heaviness (but not smoking initiation), and this variant affects an outcome (at least partially) via tobacco intake, we would expect the effect of the variant on the outcome to differ in ever versus never smokers. We used PHESANT to test for the presence of effects of smoking heaviness, instrumented by genetic variant rs16969968, among never and ever smokers respectively, in UK Biobank. We ranked results by the strength of interaction between ever and never smokers. We replicated previously established effects of smoking heaviness, including detrimental effects on lung function. Novel results included a detrimental effect of heavier smoking on facial aging. We have demonstrated how GxE MR-pheWAS can be used to identify potential effects of an exposure, while simultaneously assessing whether results may be biased by horizontal pleiotropy.


Assuntos
Fumar Cigarros/epidemiologia , Biologia Computacional/métodos , Análise da Randomização Mendeliana/métodos , Envelhecimento da Pele/efeitos dos fármacos , Bancos de Espécimes Biológicos , Fumar Cigarros/efeitos adversos , Fumar Cigarros/genética , Interação Gene-Ambiente , Pleiotropia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudo de Prova de Conceito , Reino Unido/epidemiologia
5.
Neurology ; 93(15): e1412-e1424, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31527283

RESUMO

OBJECTIVE: To examine causal associations between risky behavior phenotypes and Parkinson disease using a mendelian randomization approach. METHODS: We used 2-sample mendelian randomization to generate unconfounded estimates using summary statistics from 2 independent, large meta-analyses of genome-wide association studies on risk-taking behaviors (n = 370,771-939,908) and Parkinson disease (cases n = 9,581, controls n = 33,245). We used the inverse variance weighted method as the main method for judging causality. RESULTS: Our results support a strong protective association between the tendency to smoke and Parkinson disease (odds ratio [OR] 0.714 per log odds of ever smoking, 95% confidence interval [CI] 0.568-0.897, p = 0.0041, Cochran Q test p = 0.238; I 2 index 6.3%). Furthermore, we observed risk association trends between automobile speed propensity and the number of sexual partners and Parkinson disease after removal of overlapping loci with other risky traits (OR 1.986 for each 1-SD increase in normalized automobile speed propensity, 95% CI 1.215-3.243, p = 0.0066; OR 1.635 for each 1-SD increase in number of sexual partners, 95% CI 1.165-2.293, p = 0.0049). CONCLUSION: These findings provide support for a causal relationship between general risk tolerance and Parkinson disease and may provide new insights into the pathogenic mechanisms leading to the development of Parkinson disease.


Assuntos
Predisposição Genética para Doença , Análise da Randomização Mendeliana , Doença de Parkinson/genética , Doença de Parkinson/terapia , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
6.
Eur J Endocrinol ; 181(4): 429-438, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325907

RESUMO

Objective: The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD). Design and methods: Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses). Results: In the two prospective nested case-control studies, logistic regression adjusting for sex, age, BMI, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR: 1.28 per 1 SD higher cortisol, 95% CI: 1.06-1.54). In the meta-analysis of prospective studies, the equivalent result was OR: 1.18, 95% CI: 1.06-1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR: 1.06, 95% CI: 0.98-1.15. Conclusions: All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together, these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Variação Genética/fisiologia , Hidrocortisona/sangue , Análise da Randomização Mendeliana/métodos , Idoso , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Ritmo Circadiano/fisiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
7.
PLoS Med ; 16(6): e1002833, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31220083

RESUMO

BACKGROUND: Iron is integral to many physiological processes, and variations in its levels, even within the normal range, can have implications for health. The objective of this study was to explore the broad clinical effects of varying iron status. METHODS AND FINDINGS: Genome-wide association study (GWAS) summary data obtained from 48,972 European individuals (55% female) across 19 cohorts in the Genetics of Iron Status Consortium were used to identify 3 genetic variants (rs1800562 and rs1799945 in the hemochromatosis gene [HFE] and rs855791 in the transmembrane protease serine 6 gene [TMPRSS6]) that associate with increased serum iron, ferritin, and transferrin saturation and decreased transferrin levels, thus serving as instruments for systemic iron status. Phenome-wide association study (PheWAS) of these instruments was performed on 424,439 European individuals (54% female) in the UK Biobank who were aged 40-69 years when recruited from 2006 to 2010, with their genetic data linked to Hospital Episode Statistics (HES) from April, 1995 to March, 2016. Two-sample summary data mendelian randomization (MR) analysis was performed to investigate the effect of varying iron status on outcomes across the human phenome. MR-PheWAS analysis for the 3 iron status genetic instruments was performed separately and then pooled by meta-analysis. Correction was made for testing of multiple correlated phenotypes using a 5% false discovery rate (FDR) threshold. Heterogeneity between MR estimates for different instruments was used to indicate possible bias due to effects of the genetic variants through pathways unrelated to iron status. There were 904 distinct phenotypes included in the MR-PheWAS analyses. After correcting for multiple testing, the 3 genetic instruments for systemic iron status demonstrated consistent evidence of a causal effect of higher iron status on decreasing risk of traits related to anemia (iron deficiency anemia: odds ratio [OR] scaled to a standard deviation [SD] increase in genetically determined serum iron levels 0.72, 95% confidence interval [CI] 0.64-0.81, P = 4 × 10-8) and hypercholesterolemia (hypercholesterolemia: OR 0.88, 95% CI 0.83-0.93, P = 2 × 10-5) and increasing risk of traits related to infection of the skin and related structures (cellulitis and abscess of the leg: OR 1.25, 95% CI 1.10-1.42, P = 6 × 10-4). The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and misclassification of diagnoses in the HES data. Furthermore, this work only investigated participants with European ancestry, and the findings may not be applicable to other ethnic groups. CONCLUSIONS: Our findings offer novel, to our knowledge, insight into previously unreported effects of iron status, highlighting a potential protective effect of higher iron status on hypercholesterolemia and a detrimental role on risk of skin and skin structure infections. Given the modifiable and variable nature of iron status, these findings warrant further investigation.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Ferro/sangue , Análise da Randomização Mendeliana/métodos , Fenótipo , Adulto , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
8.
PLoS Med ; 16(6): e1002828, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31211782

RESUMO

BACKGROUND: Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight. METHODS AND FINDINGS: We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g [95% CI -2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15-9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g [95% CI -44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121-236 g, p = 1.43 × 10-9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy. CONCLUSIONS: Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments.


Assuntos
Peso ao Nascer/fisiologia , Cálcio/sangue , Estudo de Associação Genômica Ampla/métodos , Análise da Randomização Mendeliana/métodos , Vitamina D/análogos & derivados , Adulto , Biomarcadores/sangue , Feminino , Variação Genética/genética , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Saúde Materna , Gravidez , Vitamina D/sangue , Vitamina D/genética
9.
JAMA Netw Open ; 2(5): e193447, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31050786

RESUMO

Importance: There is a well-established negative association of educational attainment (EA) and other traits related to cognitive ability with posttraumatic stress disorder (PTSD), but the underlying mechanisms are poorly understood. Objectives: To investigate the association of PTSD with traits related to EA. Design, Setting, and Participants: Genetic correlation, polygenic risk scoring, and mendelian randomization (MR) were conducted including 23 185 individuals with PTSD and 151 309 control participants from the Psychiatric Genomics Consortium for PTSD and up to 1 131 881 individuals assessed for EA and related traits from UK Biobank, 23andMe, and the Social Science Genetic Association Consortium. Data were analyzed from July 3 through November 19, 2018. Main Outcomes and Measures: Genetic correlation obtained from linkage disequilibrium score regression, phenotypic variance explained by polygenic risk scores, and association estimates from MR. Results: Summary association data from multiple genome-wide association studies were available for a total of 1 180 352 participants (634 391 [53.7%] women). Posttraumatic stress disorder showed negative genetic correlations with EA (rg = -0.26; SE = 0.05; P = 4.60 × 10-8). Mendelian randomization analysis, conducting considering a random-effects inverse-variance weighted method, indicated that EA has a negative association with PTSD (ß = -0.23; 95% CI, -0.07 to -0.39; P = .004). Investigating potential mediators of the EA-PTSD association, propensity for trauma exposure and risk-taking behaviors were observed as risk factors for PTSD independent of EA (trauma exposure: ß = 0.37; 95% CI, 0.19 to 0.52; P = 2.57 × 10-5; risk-taking: ß = 0.76; 95% CI, 0.38 to 1.13; P = 1.13 × 10-4), while income may mediate the association of EA with PSTD (MR income: ß = -0.18; 95% CI, -0.29 to -0.07; P = .001; MR EA: ß = -0.23; 95% CI, -0.39 to -0.07; P = .004; multivariable MR income: ß = -0.32; 95% CI, -0.57 to 0.07; P = .02; multivariable MR EA: ß = -0.04; 95% CI, -0.29 to 0.21; SE, 0.13; P = .79). Conclusions and Relevance: Large-scale genomic data sets add further evidence to the negative association of EA with PTSD, also supporting the role of economic status as a mediator in the association observed.


Assuntos
Cognição/fisiologia , Status Econômico , Escolaridade , Análise da Randomização Mendeliana/métodos , Transtornos de Estresse Pós-Traumáticos/psicologia , Estudos Transversais , Humanos , Polimorfismo de Nucleotídeo Único , Assunção de Riscos , Transtornos de Estresse Pós-Traumáticos/genética
10.
Evid Based Ment Health ; 22(2): 67-71, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30979719

RESUMO

OBJECTIVE: Mendelian randomisation (MR) is a technique that aims to assess causal effects of exposures on disease outcomes. The paper aims to present the main assumptions that underlie MR, the statistical methods used to estimate causal effects and how to account for potential violations of the key assumptions. METHODS: We discuss the key assumptions that should be satisfied in an MR setting. We list the statistical methodologies used in two-sample MR when summary data are available to estimate causal effects (ie, Wald ratio estimator, inverse-variance weighted and maximum likelihood method) and identify/adjust for potential violations of MR assumptions (ie, MR-Egger regression and weighted Median approach). We also present statistical methods and graphical tools used to evaluate the presence of heterogeneity. RESULTS: We use as an illustrative example of a published two-sample MR study, investigating the causal association of body mass index with three psychiatric disorders (ie, bipolar disorder, schizophrenia and major depressive disorder). We highlight the importance of assessing the results of all available methods rather than each method alone. We also demonstrate the impact of heterogeneity in the estimation of the causal effects. CONCLUSIONS: MR is a useful tool to assess causality of risk factors in medical research. Assessment of the key assumptions underlying MR is crucial for a valid interpretation of the results.


Assuntos
Índice de Massa Corporal , Causalidade , Análise da Randomização Mendeliana/métodos , Transtornos Mentais , Estudos Observacionais como Assunto/métodos , Humanos , Transtornos Mentais/etiologia , Transtornos Mentais/genética
11.
BMC Med ; 17(1): 61, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30866921

RESUMO

BACKGROUND: The role of n-6 polyunsaturated fatty acids (PUFAs) in ischemic heart disease (IHD) is controversial, and dietary guidelines vary. Observationally, lower saturated fat intake and higher intake of vegetable oils rich in linoleic acid (LA), the main n-6 PUFA, is associated with lower IHD and diabetes; however, randomized controlled trials have not fully corroborated these benefits. We assessed how genetically predicted LA affected IHD and its risk factors, including diabetes, lipids, and blood pressure. We also assessed the role of LA in reticulocyte count, the red blood cell precursor, which has recently been identified as a possible causal factor in IHD. METHODS: Two-sample instrumental variable analysis with genetic instruments, i.e., Mendelian randomization, was used to obtain unconfounded estimates using genetic variants strongly (p value < 5 × 10-8) and solely associated with LA, applied to an IHD case (n ≤ 76,014)-control (n ≤ 264,785) study (mainly based on the meta-analysis of CARDIoGRAMplusC4D 1000 Genomes and UK Biobank CAD SOFT GWAS), the DIAbetes Genetics Replication And Meta-analysis diabetes case (n = 26,676)-control (n = 132,532) study, lipids from the Global Lipids Genetics Consortium Results (n = 196,475), and reticulocyte count and blood pressure from the UK Biobank (n ≤ 361,194). A weighted median and Mendelian randomization Egger were used for sensitivity analysis. RESULTS: Genetically predicted LA was not associated with IHD or systolic blood pressure. Genetically predicted higher serum LA was associated with lower diabetes (odds ratio (OR) 0.97 per percentage in total fatty acid increase in LA, 95% confidence interval (CI) 0.96 to 0.99) and lower lipids (low-density lipoprotein, high-density lipoprotein, and total cholesterol), but may be associated with higher diastolic blood pressure. The findings were robust to different single nucleotide polymorphism (SNP) selections, analytic methods, and correction for multiple testing. CONCLUSIONS: Our novel study suggests a benefit of LA for diabetes and lipids but no benefit for IHD, blood pressure, or reticulocyte count. Explicating these paradoxical findings would facilitate identification of effective new interventions for diabetes and IHD.


Assuntos
Ácido Linoleico/efeitos adversos , Análise da Randomização Mendeliana/métodos , Isquemia Miocárdica/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
12.
Ann Neurol ; 85(4): 470-481, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30723964

RESUMO

OBJECTIVE: To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). METHODS: Linkage disequilibrium score regression and Mendelian randomization were applied in a large-scale, data-driven manner to explore genetic correlations and causal relationships between >700 phenotypic traits and ALS. Exposures consisted of publicly available genome-wide association studies (GWASes) summary statistics from MR Base and LD-hub. The outcome data came from the recently published ALS GWAS involving 20,806 cases and 59,804 controls. Multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses were also performed. RESULTS: We have shown, by linkage disequilibrium score regression, that ALS shares polygenic risk genetic factors with a number of traits and conditions, including positive correlations with smoking status and moderate levels of physical activity, and negative correlations with higher cognitive performance, higher educational attainment, and light levels of physical activity. Using Mendelian randomization, we found evidence that hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest. INTERPRETATION: Here, we have developed a public resource (https://lng-nia.shinyapps.io/mrshiny) which we hope will become a valuable tool for the ALS community, and that will be expanded and updated as new data become available. Shared polygenic risk exists between ALS and educational attainment, physical activity, smoking, and tenseness/restlessness. We also found evidence that elevated low-desnity lipoprotein cholesterol is a causal risk factor for ALS. Future randomized controlled trials should be considered as a proof of causality. Ann Neurol 2019;85:470-481.


Assuntos
Esclerose Amiotrófica Lateral/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Análise da Randomização Mendeliana/métodos , Herança Multifatorial/genética , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/epidemiologia , Exercício/fisiologia , Predisposição Genética para Doença/epidemiologia , Humanos
13.
Ann Neurol ; 85(4): 482-484, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30786056

RESUMO

In this study, we examined the potential causal effect of smoking on amyotrophic lateral sclerosis (ALS) using the Project MinE data involving 12,577 patients with ALS and 23,475 controls in a Mendelian randomization (MR) framework. The MR approach has the potential to investigate a causal relationship between a risk factor and a disease, avoiding confounding and information bias that often present in conventional epidemiological studies. We found that smokers had a higher risk of ALS compared to never smokers. Our study thus provides evidence for a causal relationship between smoking and ALS. Ann Neurol 2019;85:482-484.


Assuntos
Esclerose Amiotrófica Lateral/epidemiologia , Esclerose Amiotrófica Lateral/genética , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único/genética , Fumar/epidemiologia , Fumar/genética , Estudos de Coortes , Humanos , Estudos Prospectivos , Fatores de Risco
14.
Ann Neurol ; 85(4): 495-501, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30785218

RESUMO

OBJECTIVE: Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization. METHODS: We used summary statistics data for single-nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B6 (n = 1), and vitamin B12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases). RESULTS: Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13-1.58; p = 6.7 × 10-4 ) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B6 levels were 0.49 (95% CI, 0.34-0.71; p = 1.3 × 10-4 ) and 0.70 (95% CI, 0.52-0.94; p = 0.02), respectively. Genetically higher vitamin B12 levels were not associated with any stroke subtype. INTERPRETATION: These findings suggest that any effect of homocysteine-lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495-501.


Assuntos
Isquemia Encefálica/genética , Homocisteína/genética , Análise da Randomização Mendeliana/métodos , Acidente Vascular Cerebral/genética , Isquemia Encefálica/sangue , Isquemia Encefálica/prevenção & controle , Homocisteína/antagonistas & inibidores , Homocisteína/sangue , Humanos , Microvasos/patologia , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/prevenção & controle , Vitamina B 12/uso terapêutico
15.
Gastroenterology ; 156(8): 2254-2265.e3, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30779925

RESUMO

BACKGROUND & AIMS: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. METHODS: We obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. RESULTS: We identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. CONCLUSIONS: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.


Assuntos
Doença de Crohn/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana/métodos , Adolescente , Fatores Etários , Estudos de Casos e Controles , Criança , Pré-Escolar , Doença de Crohn/sangue , Progressão da Doença , Feminino , Seguimentos , Genótipo , Humanos , Lactente , Inflamação/genética , Masculino , América do Norte , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais
16.
Genome Med ; 11(1): 6, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704512

RESUMO

BACKGROUND: The extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analysis pipeline that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the causal pathway from a genetic variant to a complex trait. METHODS: We undertook an expression quantitative trait loci-wide association study to uncover genetic variants associated with both nearby gene expression and cardiovascular traits. Fine-mapping was performed to prioritize possible causal variants for detected associations. Two-sample Mendelian randomization (MR) was then applied using findings from genome-wide association studies (GWAS) to investigate whether changes in gene expression within certain tissue types may influence cardiovascular trait variation. We subsequently used Bayesian multiple-trait colocalization to further interrogate the findings and also gain insight into whether DNA methylation, as well as gene expression, may play a role in disease susceptibility. Finally, we applied our analysis pipeline genome-wide using summary statistics from large-scale GWAS. RESULTS: Eight genetic loci were associated with changes in gene expression and measures of cardiovascular function. Our MR analysis provided evidence of tissue-specific effects at multiple loci, of which the effects at the ADCY3 and FADS1 loci for body mass index and cholesterol, respectively, were particularly insightful. Multiple-trait colocalization uncovered evidence which suggested that changes in DNA methylation at the promoter region upstream of FADS1/TMEM258 may also affect cardiovascular trait variation along with gene expression. Furthermore, colocalization analyses uncovered evidence of tissue specificity between gene expression in liver tissue and cholesterol levels. Applying our pipeline genome-wide using summary statistics from GWAS uncovered 233 association signals at loci which represent promising candidates for further evaluation. CONCLUSIONS: Disease susceptibility can be influenced by differential changes in tissue-specific gene expression and DNA methylation. The approach undertaken in our study can be used to elucidate mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. Future studies which continue to uncover quantitative trait loci for molecular traits across various tissue and cell types will further improve our capability to understand and prevent disease.


Assuntos
Doenças Cardiovasculares/genética , Predisposição Genética para Doença , Análise da Randomização Mendeliana/métodos , Criança , Metilação de DNA , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Fígado/metabolismo , Masculino , Especificidade de Órgãos , Regiões Promotoras Genéticas
17.
Genet Epidemiol ; 43(4): 373-401, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30635941

RESUMO

In Mendelian randomization (MR), inference about causal relationship between a phenotype of interest and a response or disease outcome can be obtained by constructing instrumental variables from genetic variants. However, MR inference requires three assumptions, one of which is that the genetic variants only influence the outcome through phenotype of interest. Pleiotropy, that is, the situation in which some genetic variants affect more than one phenotype, can invalidate these genetic variants for use as instrumental variables; thus a naive analysis will give biased estimates of the causal relation. Here, we present new methods (constrained instrumental variable [CIV] methods) to construct valid instrumental variables and perform adjusted causal effect estimation when pleiotropy exists and when the pleiotropic phenotypes are available. We demonstrate that a smoothed version of CIV performs approximate selection of genetic variants that are valid instruments, and provides unbiased estimates of the causal effects. We provide details on a number of existing methods, together with a comparison of their performance in a large series of simulations. CIV performs robustly across different pleiotropic violations of the MR assumptions. We also analyzed the data from the Alzheimer's disease (AD) neuroimaging initiative (ADNI; Mueller et al., 2005. Alzheimer's Dementia, 11(1), 55-66) to disentangle causal relationships of several biomarkers with AD progression.


Assuntos
Pleiotropia Genética/fisiologia , Análise da Randomização Mendeliana/métodos , Algoritmos , Estudos de Associação Genética , Variação Genética , Humanos , Modelos Genéticos , Fenótipo
18.
Curr Protoc Hum Genet ; 101(1): e82, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30645041

RESUMO

Mendelian randomization (MR) is defined as the utilization of genetic variants as instrumental variables to assess the causal relationship between an exposure and an outcome. By leveraging genetic polymorphisms as proxy for an exposure, the causal effect of an exposure on an outcome can be assessed while addressing susceptibility to biases prone to conventional observational studies, including confounding and reverse causation, where the outcome causes the exposure. Analogous to a randomized controlled trial where patients are randomly assigned to subgroups based on different treatments, in an MR analysis, the random allocation of alleles during meiosis from parent to offspring assigns individuals to different subgroups based on genetic variants. Recent methods use summary statistics from genome-wide association studies to perform MR, bypassing the need for individual-level data. Here, we provide a straightforward protocol for using summary-level data to perform MR and provide guidance for utilizing available software. © 2019 by John Wiley & Sons, Inc.


Assuntos
Análise da Randomização Mendeliana/métodos , Modelos Estatísticos , Polimorfismo Genético/genética , Software , Alelos , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos
19.
JAMA Cardiol ; 4(2): 144-152, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30673084

RESUMO

Importance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear. Objective: To evaluate the potential direct involvement of thyroid traits on AF. Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry. Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data. Main Outcomes and Measures: Prevalent and incident AF. Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045). Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.


Assuntos
Fibrilação Atrial/genética , Análise da Randomização Mendeliana/métodos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Hipertireoidismo/sangue , Hipertireoidismo/epidemiologia , Hipertireoidismo/genética , Hipotireoidismo/sangue , Hipotireoidismo/epidemiologia , Hipotireoidismo/genética , Iodeto Peroxidase/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Testes de Função Tireóidea/métodos , Glândula Tireoide/fisiopatologia , Tireotropina/sangue , Tireotropina/genética , Tiroxina/sangue , Tiroxina/genética , Tri-Iodotironina/sangue , Tri-Iodotironina/genética
20.
Ophthalmic Physiol Opt ; 39(1): 11-25, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30628743

RESUMO

PURPOSE: Randomised controlled trials (RCTs) allow reliable causal inferences to be drawn regarding the effectiveness of specific interventions. However, they are expensive to carry out, and not all exposure-outcome relationships can be tested in an RCT framework: for example, it would be unethical to deliberately expose participants to a putative risk factor, or the time-scale involved may be prohibitive. Mendelian randomisation (MR) has been proposed as an alternative approach for drawing causal inferences, with the major advantage that the method can often be applied to existing, cross-sectional study datasets. Therefore, results from an MR study can be obtained much more quickly and cheaply than through an RCT. RECENT FINDINGS: The validity of causal inferences from an MR study are dependent on two key assumptions, neither of which can be tested fully. Nevertheless, several approaches have been proposed in the last 3 years that either highlight questionable results, or provide valid causal inference if the necessary assumptions are met only in part. Compared to certain other areas of clinical practice, the ophthalmic research community has been slow to adopt MR. SUMMARY: An MR study cannot match an RCT in its strength of evidence for a claim of causality. However, MR still has much to offer. In some circumstances, an MR study can provide causal insight into research questions that cannot be addressed by an RCT, while more generally, an MR study can be used to evaluate the supporting evidence before deciding to embark on a lengthy and costly RCT.


Assuntos
Oftalmopatias/genética , Análise da Randomização Mendeliana/métodos , Estudos Observacionais como Assunto/métodos , Genótipo , Humanos , Reprodutibilidade dos Testes
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