STROBE-MR: Guidelines for strengthening the reporting of Mendelian randomization studies

Smith, George Davey; Davies, Neil M; Dimou, Niki; Egger, Matthias; Gallo, Valentina; Golub, Robert M.; Higgins, Julian P. T.; Langenberg, Claudia; Loder, Elizabeth; Richards, J. Brent; Richmond, Rebecca C; Skrivankova, Veronika; Swanson, Sonja A.; Timpson, Nicholas J.; Tybjærg‐Hansen, Anne; VanderWeele, Tyler J.; Woolf, Benjamin; Yarmolinsky, James

doi:10.7287/peerj.preprints.27857v1

Cited by 71 publications

(61 citation statements)

References 4 publications

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“…This study was conducted in accordance with the guidelines for Strengthening the Reporting of Observational Studies in Epidemiology– Mendelian randomization (STROBE-MR). 21 All data were derived from studies that had already obtained ethical review board approvals.…”

Section: Methodsmentioning

confidence: 99%

Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes

Georgakis¹,

Gill²,

Webb

et al. 2020

Neurology

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ObjectiveWe employed Mendelian randomization to explore whether the effects of blood pressure (BP) and BP-lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology.MethodsWe selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH).ResultsGenetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic phenotype of WMH.ConclusionsThis study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP-lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.

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Section: Methodsmentioning

confidence: 99%

Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes

Georgakis¹,

Gill²,

Webb

et al. 2020

Neurology

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show abstract

“…This MR study was performed in accordance with the STROBE-MR criteria. 22 All statistical analyses were undertaken using R (v3.5.0; The R Foundation for Statistical Computing).…”

Section: Methodsmentioning

confidence: 99%

Genetically Predicted Blood Pressure Across the Lifespan

Georgakis¹,

Malik²,

Protogerou

et al. 2020

Hypertension

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Hypertension is the leading risk factor for stroke. Yet, it remains unknown whether blood pressure pulsatility (pulse pressure [PP]) causally affects stroke risk independently of the steady pressure component (mean arterial pressure [MAP]). It is further unknown how the effects of MAP and PP on stroke risk vary with age and stroke cause. Using data from UK Biobank (N=408 228; 38–71 years), we selected genetic variants as instruments for MAP and PP at age ≤55 and >55 years and across age deciles. We applied multivariable Mendelian randomization analyses to explore associations with ischemic stroke, intracerebral hemorrhage, and their subtypes. Higher genetically predicted MAP was associated with higher risk of ischemic stroke and intracerebral hemorrhage across the examined age spectrum. Independent of MAP, higher genetically predicted PP only at age >55 years was further associated with higher risk of ischemic stroke (odds ratio per-SD-increment, 1.23 [95% CI, 1.13–1.34]). Among subtypes, the effect of genetically predicted MAP on large artery stroke was attenuated, whereas the effect of genetically predicted PP was augmented with increasing age. Genetically predicted MAP, but not PP, was associated with small vessel stroke and deep intracerebral hemorrhage homogeneously across age deciles. Neither genetically predicted MAP nor PP were associated with lobar intracerebral hemorrhage. Beyond an effect of high MAP at any age on ischemic and hemorrhagic stroke, our results support an independent causal effect of high PP at older ages on large artery stroke. This finding warrants further investigation for the development of stroke preventive strategies targeting pulsatility in later life.

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“…This study is reported according to the preprint guideline for reporting of MR studies, STRO-BE-MR (S1 Checklist) [25] and the STROBE guideline for cohort studies (S2 Checklist) [26]. The Trøndelag Health Study (HUNT) is a series of cross-sectional surveys carried out in Nord-Trøndelag County, Norway.…”

Section: Methodsmentioning

confidence: 99%

Body mass index and risk of dying from a bloodstream infection: A Mendelian randomization study

et al. 2020

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Background In observational studies of the general population, higher body mass index (BMI) has been associated with increased incidence of and mortality from bloodstream infection (BSI) and sepsis. On the other hand, higher BMI has been observed to be apparently protective among patients with infection and sepsis. We aimed to evaluate the causal association of BMI with risk of and mortality from BSI. Methods and findings We used a population-based cohort in Norway followed from 1995 to 2017 (the Trøndelag Health Study [HUNT]), and carried out linear and nonlinear Mendelian randomization analyses. Among 55,908 participants, the mean age at enrollment was 48.3 years, 26,324 (47.1%) were men, and mean BMI was 26.3 kg/m2. During a median 21 years of follow-up, 2,547 (4.6%) participants experienced a BSI, and 451 (0.8%) died from BSI. Compared with a genetically predicted BMI of 25 kg/m2, a genetically predicted BMI of 30 kg/m2 was associated with a hazard ratio for BSI incidence of 1.78 (95% CI: 1.40 to 2.27; p < 0.001) and for BSI mortality of 2.56 (95% CI: 1.31 to 4.99; p = 0.006) in the general population, and a hazard ratio for BSI mortality of 2.34 (95% CI: 1.11 to 4.94; p = 0.025) in an inverse-probability-weighted analysis of patients with BSI. Limitations of this study include a risk of pleiotropic effects that may affect causal inference, and that only participants of European ancestry were considered. Conclusions Supportive of a causal relationship, genetically predicted BMI was positively associated with BSI incidence and mortality in this cohort. Our findings contradict the “obesity paradox,” where previous traditional epidemiological studies have found increased BMI to be apparently protective in terms of mortality for patients with BSI or sepsis.

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STROBE-MR: Guidelines for strengthening the reporting of Mendelian randomization studies

Cited by 71 publications

References 4 publications

Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes

Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes

Genetically Predicted Blood Pressure Across the Lifespan

Body mass index and risk of dying from a bloodstream infection: A Mendelian randomization study

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