Mendelian randomization

Nature Reviews Methods Primers, Год журнала: 2022, Номер 2(1)

Опубликована: Фев. 10, 2022

Язык: Английский

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Statistical methods for Mendelian randomization in genome-wide association studies: A review

Computational and Structural Biotechnology Journal, Год журнала: 2022, Номер 20, С. 2338 - 2351

Опубликована: Янв. 1, 2022

Genome-wide association studies have yielded thousands of associations for many common diseases and disease-related complex traits. The identified made it possible to identify the causal risk factors underlying investigate relationships among traits through Mendelian randomization. randomization is a form instrumental variable analysis that uses SNP from genome-wide as instruments study uncover between By leveraging genotypes variables, or proxies, exposure trait, investigators can tease out effects observational data, provided necessary assumptions are satisfied. We discuss below development methods in parallel with growth studies. argue recent availability GWAS summary statistics diverse has motivated new relaxed causality this area continues offer opportunities robust biological discoveries.

Язык: Английский

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Using Mendelian Randomization to Improve the Design of Randomized Trials

Cold Spring Harbor Perspectives in Medicine, Год журнала: 2021, Номер unknown, С. a040980 - a040980

Опубликована: Янв. 11, 2021

Randomized controlled trials and Mendelian randomization studies are two study designs that provide randomized evidence in human biological medical research. Both exploit the power of to unconfounded estimates causal effect. However, have very different scientific objectives. As a result, despite sometimes being referred as "nature's trial," cannot be used replace trial but instead provides complementary information. In this review, we explain similarities differences between studies, suggest several ways can directly inform improve design illustrated with practical examples. We conclude by describing how employ principles framed "naturally trials" template for future evaluating therapies directed against genetically validated targets.

Язык: Английский

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Psychiatric diagnosis and treatment in the 21st century: paradigm shifts versus incremental integration

World Psychiatry, Год журнала: 2022, Номер 21(3), С. 393 - 414

Опубликована: Сен. 8, 2022

Psychiatry has always been characterized by a range of different models and approaches to mental disorder, which have sometimes brought progress in clinical practice, but often also accompanied critique from within without the field. Psychiatric nosology particular focus debate recent decades; successive editions DSM ICD strongly influenced both psychiatric practice research, led assertions that psychiatry is crisis, advocacy for entirely new paradigms diagnosis assessment. When thinking about etiology, many researchers currently refer biopsychosocial model, this approach received significant critique, being considered some observers overly eclectic vague. Despite development evidence-based pharmacotherapies psychotherapies, current evidence points treatment gap research-practice health. In paper, after considering we discuss proposed novel perspectives recently achieved prominence may significantly impact research future: neuroscience personalized pharmacotherapy; statistical nosology, assessment research; deinstitutionalization community health care; scale-up psychotherapy; digital phenotyping therapies; global task-sharing approaches. We consider extent transitions practices reflect hype or hope. Our review indicates each contributes important insights allow hope future, provides only partial view, any promise paradigm shift field not well grounded. conclude there crucial advances that, despite progress, considerable need further improvements intervention; such will likely be specific shifts rather incremental iterative integration.

Язык: Английский

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Causal relationship between physical activity, leisure sedentary behaviors and COVID-19 risk: a Mendelian randomization study

Journal of Translational Medicine, Год журнала: 2022, Номер 20(1)

Опубликована: Май 13, 2022

Abstract Background The 2019 coronavirus disease pandemic (COVID-19) poses an enormous threat to public health worldwide, and the ensuing management of social isolation has greatly decreased opportunities for physical activity (PA) increased leisure sedentary behaviors (LSB). Given that both PA LSB have been established as major influencing factors obesity, diabetes cardiometabolic syndrome, whether PA/LSB in turn affects susceptibility COVID-19 by disrupting metabolic homeostasis remains be explored. In this study, we aimed systematically evaluate causal relationship between susceptibility, hospitalization severity using a Mendelian randomization study. Methods Data were obtained from large-scale dataset (N = 377,000), 422,218) Host Genetics Initiative 2,586,691). effects estimated with inverse variance weighted, MR-Egger, weighted median MR-PRESSO. Sensitivity analyses implemented Cochran’s Q test, MR-Egger intercept MR-PRESSO, leave-one-out analysis funnel plot. Risk factor further conducted investigate potential mediators. Results Genetically predicted accelerometer-assessed risk (OR 0.93, 95% CI 0.88–0.97; P 0.002), while television watching significantly 1.55, 1.29–1.88; 4.68 × 10 –6 ) 1.85, 1.33–2.56; 0.0002) after Bonferroni correction. No self-reported moderate vigorous (MVPA), accelerometer fraction accelerations > 425 milligravities, computer use or driving on progression observed. indicated above associations might mediated several factors, including smoking, high body mass index, elevated serum triglyceride levels, insulin resistance occurrence type 2 diabetes. Conclusion Our findings supported effect reduced well severity, which was potentially obesity diabetes-related phenotypes. Particular attention should given reducing encouraging proper exercise during quarantine COVID-19.

Язык: Английский

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Causal inference with observational data: the need for triangulation of evidence

Psychological Medicine, Год журнала: 2021, Номер 51(4), С. 563 - 578

Опубликована: Март 1, 2021

Abstract The goal of much observational research is to identify risk factors that have a causal effect on health and social outcomes. However, data are subject biases from confounding, selection measurement, which can result in an underestimate or overestimate the interest. Various advanced statistical approaches exist offer certain advantages terms addressing these potential biases. although different underlying assumptions, practice they cannot always completely remove key sources bias; therefore, using design-based improve inference also important. Here it design study addresses problem bias – either by ensuring not present (under assumptions) comparing results across methods with direction bias. distinction between absolute one, but provides framework for triangulation thoughtful application multiple (e.g. based), each their own strengths weaknesses, particular directions It unlikely any single method provide definite answer question, evidence provided stronger basis inference. Triangulation be considered part wider efforts transparency robustness scientific research, infrastructure system incentives.

Язык: Английский

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Mendelian randomization study reveals a causal relationship between rheumatoid arthritis and risk for pre-eclampsia

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Дек. 12, 2022

Epidemiological observational studies have investigated the relationship between rheumatoid arthritis(RA) and pre-eclampsia, but no consistent conclusions were obtained due to various limitations. Hence, we conducted a two-sample mendelian randomization analysis evaluate potential causal effect of RA on pre-eclampsia.Summary-level statistics for derived from large-scale meta-analysis datasets genome-wide association studies(GWAS) which involved 14,361 cases 43,923 controls. Moreover, summary pre-eclampsia or eclampsia sourced Finn biobank contained 3,903 114,735 The inverse variance weighting (IVW) as well other four effective methods including MR-Egger, weighted median, mode, simple mode applied deduce relationships comprehensively.The MR suggested strong pre-eclampsia[OR,1.05;95%CI, 1.01-1.09;p<0.05]. OR estimates mode[OR,1.09;95%CI,1.03-1.15;p<0.01] median[OR,1.07;95%CI, 1.01-1.14;p<0.05] similar those IVW method, there was significant observed in Egger analysis.This provides evidence positive genetically. Our findings highlight importance more intensive prenatal care early intervention among pregnant women with prevent adverse obstetric outcomes. our study clues risk factor identification prediction pre-eclampsia.

Язык: Английский

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Genetically predicted 486 blood metabolites in relation to risk of colorectal cancer: A Mendelian randomization study

Cancer Medicine, Год журнала: 2023, Номер 12(12), С. 13784 - 13799

Опубликована: Май 3, 2023

Metabolic disorders are a hallmark feature of cancer. However, the evidence for causality circulating metabolites to promote or prevent colorectal cancer (CRC) is still lacking. We performed two-sample Mendelian randomization (MR) analysis assess from genetically proxied 486 blood CRC.Genome-wide association study (GWAS) data exposures were extracted 7824 Europeans GWAS on metabolite levels. CRC catalog database GCST012879 used preliminary analysis. The random inverse variance weighted (IVW) primary while MR-Egger and median as complementary analyses. Cochran Q test, intercept MR-PRESSO, Radial MR, leave-one-out sensitivity For significant associations, additional independent GCST012880 replication meta-analysis. final identification metabolites, Steiger linkage disequilibrium score regression, colocalization further evaluation. Multivariable MR was direct effect CRC.The results this indicated associations between six pyruvate (odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.32-0.77, p = 0.002), 1,6-anhydroglucose (OR: 1.33, CI: 1.11-1.59, nonadecanoate (19:0) 0.40, C I:0.4-0.68, 0.0008), 1-linoleoylglycerophosphoethanolamine 0.47, 0.30-0.75, 0.001), 2-hydroxystearate 0.39, 0.23-0.67, 0.0007), gamma-glutamylthreonine 2.14, 1.02-4.50, 0.040) CRC. MVMR revealed that predicted pyruvate, can directly influence independently other metabolites.The current work provides support new perspective exploration biological mechanisms by combining genomics metabolomics. These findings contribute screening, prevention treatment

Язык: Английский

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Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

JAMA Network Open, Год журнала: 2023, Номер 6(5), С. e2313734 - e2313734

Опубликована: Май 17, 2023

Importance An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most these lacking. Effective interventions should target in causal pathway to dementia. Objective To comprehensively disentangle aspects modifiable Alzheimer disease (AD) inspire new drug targeting and improved prevention. Design, Setting, Participants This genetic association study was conducted using 2-sample univariable multivariable mendelian randomization. Independent variants associated with were selected as instrumental variables from genomic consortia. Outcome data AD obtained European &amp;amp; Dementia Biobank (EADB), generated on August 31, 2021. Main analyses EADB clinically diagnosed end point data. All performed between April October 27, 2022. Exposures Genetically determined factors. Outcomes Measures Odds ratios (ORs) 95% CIs calculated per 1-unit change genetically Results The EADB-diagnosed cohort included 39 106 participants 401 577 control without AD. mean age ranged 72 83 years 51 80 participants. Among AD, 54% 75% female, among participants, 48% 60% female. high-density lipoprotein (HDL) cholesterol concentrations increased odds (OR 1-SD increase, 1.10 [95% CI, 1.05-1.16]). high systolic blood pressure after adjusting diastolic 10–mm Hg 1.22 1.02-1.46]). In a second analysis minimize bias due sample overlap, entire UK excluded consortium; similar HDL unit 1.08 1.02-1.15]) 1.23 1.01-1.50]). Conclusions Relevance found novel associations higher These findings may prevention implementation.

Язык: Английский

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Genetic analyses identify brain structures related to cognitive impairment associated with elevated blood pressure

European Heart Journal, Год журнала: 2023, Номер 44(23), С. 2114 - 2125

Опубликована: Март 27, 2023

Abstract Background and aims Observational studies have linked elevated blood pressure (BP) to impaired cognitive function. However, the functional structural changes in brain that mediate relationship between BP elevation impairment remain unknown. Using observational genetic data from large consortia, this study aimed identify structures potentially associated with values Methods results Data on were integrated 3935 magnetic resonance imaging-derived phenotypes (IDPs) function defined by fluid intelligence score. analyses performed UK Biobank a prospective validation cohort. Mendelian randomisation (MR) used derived Biobank, International Consortium for Blood Pressure, COGENT consortium. analysis identified adverse causal effect of higher systolic [−0.044 standard deviation (SD); 95% confidence interval (CI) −0.066, −0.021] MR estimate strengthening (−0.087 SD; CI −0.132, −0.042), when further adjusted diastolic BP. found 242, 168, 68 IDPs showing significant (false discovery rate P &lt; 0.05) association BP, pulse pressure, respectively. Most these inversely showed concordant effects relationships nine BP-associated IDPs, including anterior thalamic radiation, corona radiata, or external capsule. Conclusion Complementary which may be responsible hypertension performance.

Язык: Английский

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