scholarly journals Investigating causal relationships between sleep traits and risk of breast cancer: a Mendelian randomization study

2018 ◽  
Author(s):  
Rebecca C. Richmond ◽  
Emma L. Anderson ◽  
Hassan S. Dashti ◽  
Samuel E. Jones ◽  
Jacqueline M. Lane ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Effect ◽  
Protective Effect ◽  
Sleep Duration ◽  
Mendelian Randomization ◽  
Uk Biobank ◽  
Multivariable Regression ◽  
Using Data ◽  
Randomization Analysis ◽  
Insomnia Symptoms

AbstractObjectiveTo examine whether sleep traits have a causal effect on risk of breast cancer.DesignMultivariable regression, one- and two-sample Mendelian randomization.SettingThe UK Biobank prospective cohort study and the Breast Cancer Association Consortium (BCAC) case-control genome-wide association study.Participants156,848 women in the multivariable regression and one-sample Mendelian randomization analysis in UK Biobank (7,784 with a breast cancer diagnosis) and 122,977 breast cancer cases and 105,974 controls from BCAC in the two-sample Mendelian randomization analysis.ExposuresSelf-reported chronotype (morning/evening preference), insomnia symptoms and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits.Main outcome measuresBreast cancer (prevalent and incident cases in UK Biobank, prevalent cases only in BCAC).ResultsIn multivariable regression analysis using data on breast cancer incidence in UK Biobank, morning preference was inversely associated with breast cancer (HR 0.95, 95% CI 0.93, 0.98 per category increase) while there was little evidence for an association with sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated sleep duration and 57 SNPs associated with insomnia symptoms, one-sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (HR 0.85, 95% 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two-sample MR using data from BCAC supported findings for a protective effect of morning preference (OR 0.88, 95% CI 0.82, 0.93 per category increase) and adverse effect of increased sleep duration (OR 1.19, 95% CI 1.02, 1.39 per hour increase) on breast cancer (both estrogen receptor positive and negative), while there was inconsistent evidence for insomnia symptoms. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy.ConclusionsWe found consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of sleep duration on breast cancer risk.

scholarly journals Investigating causal relations between sleep traits and risk of breast cancer in women: mendelian randomisation study

BMJ ◽  
2019 ◽  
pp. l2327 ◽  
Author(s):  
Rebecca C Richmond ◽  
Emma L Anderson ◽  
Hassan S Dashti ◽  
Samuel E Jones ◽  
Jacqueline M Lane ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Protective Effect ◽  
Sleep Duration ◽  
Breast Cancer Diagnosis ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
Multivariable Regression ◽  
Insomnia Symptoms

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

scholarly journals Factorial Mendelian randomization: using genetic variants to assess interactions

2019 ◽  
Vol 49 (4) ◽  
pp. 1147-1158 ◽  
Author(s):  
Jessica M B Rees ◽  
Christopher N Foley ◽  
Stephen Burgess
Keyword(s):  
Risk Factors ◽  
Instrumental Variables ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Real Data ◽  
Uk Biobank ◽  
Pharmacological Interventions ◽  
Natural Break ◽  
Using Data ◽  
Randomization Analysis

Abstract Background Factorial Mendelian randomization is the use of genetic variants to answer questions about interactions. Although the approach has been used in applied investigations, little methodological advice is available on how to design or perform a factorial Mendelian randomization analysis. Previous analyses have employed a 2 × 2 approach, using dichotomized genetic scores to divide the population into four subgroups as in a factorial randomized trial. Methods We describe two distinct contexts for factorial Mendelian randomization: investigating interactions between risk factors, and investigating interactions between pharmacological interventions on risk factors. We propose two-stage least squares methods using all available genetic variants and their interactions as instrumental variables, and using continuous genetic scores as instrumental variables rather than dichotomized scores. We illustrate our methods using data from UK Biobank to investigate the interaction between body mass index and alcohol consumption on systolic blood pressure. Results Simulated and real data show that efficiency is maximized using the full set of interactions between genetic variants as instruments. In the applied example, between 4- and 10-fold improvement in efficiency is demonstrated over the 2 × 2 approach. Analyses using continuous genetic scores are more efficient than those using dichotomized scores. Efficiency is improved by finding genetic variants that divide the population at a natural break in the distribution of the risk factor, or else divide the population into more equal-sized groups. Conclusions Previous factorial Mendelian randomization analyses may have been underpowered. Efficiency can be improved by using all genetic variants and their interactions as instrumental variables, rather than the 2 × 2 approach.

scholarly journals Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Maxime M. Bos ◽  
Neil J. Goulding ◽  
Matthew A. Lee ◽  
Amy Hofman ◽  
Mariska Bot ◽  
...  
Keyword(s):  
Sleep Duration ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Multivariable Regression ◽  
Artery Disease ◽  
Insomnia Symptoms

Abstract Background Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD)[95% confidence interval (CI) − 0.12, − 0.03] in AMV and − 0.03SD [− 0.07, − 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (− 0.04SD [− 0.08, 0.00] in AMV and − 0.05SD [− 0.09, − 0.02] in MR), and lower phospholipids in very large HDL particles (− 0.04SD [− 0.08, 0.002] in AMV and − 0.05SD [− 0.08, − 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. Conclusions Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

scholarly journals Investigating the relationships between unfavorable sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses

2020 ◽  
Author(s):  
Maxime M Bos ◽  
Neil J Goulding ◽  
Matthew A Lee ◽  
Amy Hofman ◽  
Mariska Bot ◽  
...  
Keyword(s):  
Sleep Duration ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Multivariable Regression ◽  
Artery Disease ◽  
Insomnia Symptoms

Background: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods: We used AMV (N=17,370) combined with two-sample MR (N=38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (-0.08 standard deviation (SD)[95% confidence interval (CI): -0.12, -0.03] in AMV and -0.03SD [-0.07, -0.003] in MR), higher glycoprotein acetyls (0.08SD [95%CI: 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (-0.04SD [-0.08, 0.00] in AMV and -0.05SD [-0.09, -0.02] in MR) and lower phospholipids in very large HDL particles (-0.04SD [-0.08, 0.002] in AMV and -0.05SD [-0.08, -0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1-hour [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. Conclusions: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

scholarly journals 454Relationships between sleep traits and metabolic profiles: evidence from multivariable regression and Mendelian randomization analyses

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Neil Goulding ◽  
Maxime Bos ◽  
Diana van Heemst ◽  
Raymond Noordam ◽  
Deborah Lawlor
Keyword(s):  
Sleep Duration ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Inflammatory Marker ◽  
Genome Wide Association Studies ◽  
Inverse Variance ◽  
Multivariable Regression ◽  
Multivariable Analyses ◽  
Insomnia Symptoms

Abstract Background Sleep traits are associated with cardiometabolic disease. The aim of this study was to explore the causal effect of sleep traits (duration and insomnia) on multiple metabolic traits. Methods We used age, sex and BMI adjusted multivariable regression (N = 17,370) and two-sample summary statistic Mendelian randomization (MR) to examine effects of sleep duration and insomnia symptoms on ∼150 NMR metabolites. Multivariable analyses were conducted on data from nine European cohorts and meta-analysed. MR analyses utilised summary statistics from published genome-wide association studies (GWAS) of self-reported sleep traits (sample 1; N = 446,118 to 1,331,010) and from GWAS on NMR serum metabolites (sample 2; N = 38,618). We used inverse-variance weighted (IVW) for the main MR analyses and weighed median (WM) and MR-Egger to explore bias due to pleiotropy. Results MR IVW and multivariable analyses both suggest a positive effect of insomnia symptoms on glycoprotein acetyls (MR: 0.06 s.d. increase in mean concentration comparing any symptoms to none; p = 5.9e-4) and between total sleep duration and creatinine (MR: 0.16 s.d. increase per additional hour; p = 0.03). WM and MR-Egger analyses show consistent results. There was evidence for thirteen and eight effects of insomnia and duration in multivariable only and three and one, respectively, in MR only. Conclusions Insomnia symptoms lead to higher levels of an inflammatory marker (glycoprotein acetyls) and longer sleep duration leads to higher creatinine levels. Key messages We found no evidence of widespread metabolic disruption by sleep traits.

Adiposity and cancer: a Mendelian randomization analysis in the UK biobank

2021 ◽  
Author(s):  
Muktar Ahmed ◽  
Anwar Mulugeta ◽  
S. Hong Lee ◽  
Ville-Petteri Mäkinen ◽  
Terry Boyle ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Uk Biobank ◽  
Mendelian Randomization Analysis ◽  
The Uk ◽  
Randomization Analysis

scholarly journals Sleep Duration and Stroke

Stroke ◽  
2020 ◽  
Vol 51 (11) ◽  
pp. 3279-3285
Author(s):  
Olga E. Titova ◽  
Karl Michaëlsson ◽  
Susanna C. Larsson
Keyword(s):  
Ischemic Stroke ◽  
Intracerebral Hemorrhage ◽  
Prospective Study ◽  
Sleep Duration ◽  
Mendelian Randomization ◽  
Short Sleep ◽  
Mendelian Randomization Analysis ◽  
Increased Risk ◽  
Long Sleep ◽  
Randomization Analysis

Background and Purpose: Studies of sleep duration in relation to specific types of stroke are scarce. Moreover, the results are inconclusive and causality remains unclear. Our objective was to investigate whether sleep duration is associated with risk of stroke and its types using observational and Mendelian randomization designs. Methods: The prospective study included 79 881 women and men (45–79 years of age) who were followed up for incident stroke or death over a mean follow-up of 14.6 years (1 164 646 person-years) through linkage to Swedish Registers. For the Mendelian randomization study, single-nucleotide polymorphisms associated with sleep duration were identified from a genome-wide association study. Summarized data for genetic associations with stroke were obtained from publicly available data of the MEGASTROKE and the International Stroke Genetics Consortia. Results: Compared with normal sleep duration, long sleep (≥9 hours per day) was associated with increased risk of total and ischemic stroke (hazard ratios [95% CI], 1.12 [1.03–1.22] and 1.14 [1.03–1.24], respectively), whereas short sleep (<7 h/d) was linked to higher risk of intracerebral hemorrhage (hazard ratio [95% CI], 1.21 [1.03–1.41]). The 2-sample Mendelian randomization analysis supported no causal association of short or long sleep duration with ischemic stroke as a whole. Conclusions: In a prospective study, long sleep duration was associated with increased risk of total and ischemic stroke, whereas short sleep was linked to increased risk of intracerebral hemorrhage. However, the Mendelian randomization analysis did not show a significant detrimental effect of short or long sleep duration on the risk of total stroke or stroke types.

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