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Using Mendelian Randomisation methods to understand whether diurnal preference is causally related to mental health.

ABSTRACT: Late diurnal preference has been linked to poorer mental health outcomes, but the understanding of the causal role of diurnal preference on mental health and wellbeing is currently limited. Late diurnal preference is often associated with circadian misalignment (a mismatch between the timing of the endogenous circadian system and behavioural rhythms), so that evening people live more frequently against their internal clock. This study aims to quantify the causal contribution of diurnal preference on mental health outcomes, including anxiety, depression and general wellbeing and test the hypothesis that more misaligned individuals have poorer mental health and wellbeing using an actigraphy-based measure of circadian misalignment. Multiple Mendelian Randomisation (MR) approaches were used to test causal pathways between diurnal preference and seven well-validated mental health and wellbeing outcomes in up to 451,025 individuals. In addition, observational analyses tested the association between a novel, objective measure of behavioural misalignment (Composite Phase Deviation, CPD) and seven mental health and wellbeing outcomes. Using genetic instruments identified in the largest GWAS for diurnal preference, we provide robust evidence that early diurnal preference is protective for depression and improves wellbeing. For example, using one-sample MR, a twofold higher genetic liability of morningness was associated with lower odds of depressive symptoms (OR: 0.92, 95% CI: 0.88, 0.97). It is possible that behavioural factors including circadian misalignment may contribute in the chronotype depression relationship, but further work is needed to confirm these findings.

SUBMITTER: O'Loughlin J

PROVIDER: S-EPMC8760058 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Using Mendelian Randomisation methods to understand whether diurnal preference is causally related to mental health.

O'Loughlin Jessica J Casanova Francesco F Jones Samuel E SE Hagenaars Saskia P SP Beaumont Robin N RN Freathy Rachel M RM Watkins Edward R ER Vetter Céline C Rutter Martin K MK Cain Sean W SW Phillips Andrew J K AJK Windred Daniel P DP Wood Andrew R AR Weedon Michael N MN Tyrrell Jessica J

Molecular psychiatry 20210608 11

Late diurnal preference has been linked to poorer mental health outcomes, but the understanding of the causal role of diurnal preference on mental health and wellbeing is currently limited. Late diurnal preference is often associated with circadian misalignment (a mismatch between the timing of the endogenous circadian system and behavioural rhythms), so that evening people live more frequently against their internal clock. This study aims to quantify the causal contribution of diurnal preferenc ...[more]

PMID: 34099873

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Project description:BackgroundPoor dietary choices may underlie known associations between having an evening diurnal preference and cardiometabolic diseases. Assessing causal links between diurnal preference and food intake is now possible in Mendelian randomization (MR) analyses.ObjectivesWe aimed to use a 2-sample MR to determine potential causal effects of genetic liability to a morning preference on food intake. We also examined potential causal effects of a morning preference on objectively captured response performances to email-administered 24-h diet recalls.MethodsWe used genetic variants associated with a morning preference from a published genome-wide association meta-analysis. Our outcomes included 61 food items with estimates from a food-frequency questionnaire in the UK Biobank (n = 361,194). For significant findings, we repeated the analysis using intake estimates from modified 24-h diet recalls in a subset of overlapping participants (n = 146,086). In addition, we examined 7 response performance outcomes, including the time and duration of responses to 24-h diet recalls (n = 123,035). MR effects were estimated using an inverse-variance weighted analysis.ResultsGenetic liability to a morning preference was associated with increased intake of 6 food items (fresh fruit, alcohol with meals, bran cereal, cereals, dried fruit, and water), decreased intake of 4 food items (beer plus cider, processed meat, other cereals [e.g., corn or frosted flakes], and full cream milk), increased temperature of hot drinks, and decreased variation in diet (PFalse Discovery Rate < 0.05). There was no evidence for an effect on coffee or tea intake. Findings for fresh fruit, beer plus cider, bran cereal, and cereal were consistent when intakes were estimated by 24-h diet recalls (P < 0.05). We also identified potential causal links between a morning preference with earlier timing and a shorter duration for completing email-administered 24-h diet recalls.ConclusionsOur findings provide evidence for a potentially causal effect of a morning preference with the increased intake of foods known to constitute a healthy diet, suggesting possible health benefits of adopting a more morning diurnal preference.

Project description:Aims/hypothesisThe aim of this study was to identify differentially expressed long non-coding RNAs (lncRNAs) and mRNAs in whole blood of people with type 2 diabetes across five different clusters: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), mild diabetes (MD) and mild diabetes with high HDL-cholesterol (MDH). This was to increase our understanding of different molecular mechanisms underlying the five putative clusters of type 2 diabetes.MethodsParticipants in the Hoorn Diabetes Care System (DCS) cohort were clustered based on age, BMI, HbA1c, C-peptide and HDL-cholesterol. Whole blood RNA-seq was used to identify differentially expressed lncRNAs and mRNAs in a cluster compared with all others. Differentially expressed genes were validated in the Innovative Medicines Initiative DIabetes REsearCh on patient straTification (IMI DIRECT) study. Expression quantitative trait loci (eQTLs) for differentially expressed RNAs were obtained from a publicly available dataset. To estimate the causal effects of RNAs on traits, a two-sample Mendelian randomisation analysis was performed using public genome-wide association study (GWAS) data.ResultsEleven lncRNAs and 175 mRNAs were differentially expressed in the MOD cluster, the lncRNA AL354696.2 was upregulated in the SIDD cluster and GPR15 mRNA was downregulated in the MDH cluster. mRNAs and lncRNAs that were differentially expressed in the MOD cluster were correlated among each other. Six lncRNAs and 120 mRNAs validated in the IMI DIRECT study. Using two-sample Mendelian randomisation, we found 52 mRNAs to have a causal effect on anthropometric traits (n=23) and lipid metabolism traits (n=10). GPR146 showed a causal effect on plasma HDL-cholesterol levels (p = 2×10-15), without evidence for reverse causality.Conclusions/interpretationMultiple lncRNAs and mRNAs were found to be differentially expressed among clusters and particularly in the MOD cluster. mRNAs in the MOD cluster showed a possible causal effect on anthropometric traits, lipid metabolism traits and blood cell fractions. Together, our results show that individuals in the MOD cluster show aberrant RNA expression of genes that have a suggested causal role on multiple diabetes-relevant traits.

Project description:BackgroundAn increasing number of observational studies have reported associations between frailty and mental disorders, but the causality remains ambiguous.AimsTo assess the bidirectional causal relationship between frailty and nine mental disorders.MethodWe conducted a bidirectional two-sample Mendelian randomisation on genome-wide association study summary data, to investigate causality between frailty and nine mental disorders. Causal effects were primarily estimated using inverse variance weighted method. Several secondary analyses were applied to verify the results. Cochran's Q-test and Mendelian randomisation Egger intercept were applied to evaluate heterogeneity and pleiotropy.ResultsGenetically determined frailty was significantly associated with increased risk of major depressive disorder (MDD) (odds ratio 1.86, 95% CI 1.36-2.53, P = 8.1 × 10-5), anxiety (odds ratio 2.76, 95% CI 1.56-4.90, P = 5.0 × 10-4), post-traumatic stress disorder (PTSD) (odds ratio 2.56, 95% CI 1.69-3.87, P = 9.9 × 10-6), neuroticism (β = 0.25, 95% CI 0.11-0.38, P = 3.3 × 10-4) and insomnia (β = 0.50, 95% CI 0.25-0.75, P = 1.1 × 10-4). Conversely, genetic liability to MDD, neuroticism, insomnia and suicide attempt significantly increased risk of frailty (MDD: β = 0.071, 95% CI 0.033-0.110, P = 2.8 × 10-4; neuroticism: β = 0.269, 95% CI 0.173-0.365, P = 3.4 × 10-8; insomnia: β = 0.160, 95% CI 0.141-0.179, P = 3.2 × 10-61; suicide attempt: β = 0.056, 95% CI 0.029-0.084, P = 3.4 × 10-5). There was a suggestive detrimental association of frailty on suicide attempt and an inverse relationship of subjective well-being on frailty.ConclusionsOur findings show bidirectional causal associations between frailty and MDD, insomnia and neuroticism. Additionally, higher frailty levels are associated with anxiety and PTSD, and suicide attempts are correlated with increased frailty. Understanding these associations is crucial for the effective management of frailty and improvement of mental disorders.

Project description:ObjectiveTo use mendelian randomisation to investigate whether 25-hydroxyvitamin D concentration has a causal effect on gestational hypertension or pre-eclampsia.DesignOne and two sample mendelian randomisation analyses.SettingTwo European pregnancy cohorts (Avon Longitudinal Study of Parents and Children, and Generation R Study), and two case-control studies (subgroup nested within the Norwegian Mother and Child Cohort Study, and the UK Genetics of Pre-eclampsia Study).Participants7389 women in a one sample mendelian randomisation analysis (751 with gestational hypertension and 135 with pre-eclampsia), and 3388 pre-eclampsia cases and 6059 controls in a two sample mendelian randomisation analysis.ExposuresSingle nucleotide polymorphisms in genes associated with vitamin D synthesis (rs10741657 and rs12785878) and metabolism (rs6013897 and rs2282679) were used as instrumental variables.Main outcome measuresGestational hypertension and pre-eclampsia defined according to the International Society for the Study of Hypertension in Pregnancy.ResultsIn the conventional multivariable analysis, the relative risk for pre-eclampsia was 1.03 (95% confidence interval 1.00 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, and 2.04 (1.02 to 4.07) for 25-hydroxyvitamin D levels <25 nmol/L compared with ≥75 nmol/L. No association was found for gestational hypertension. The one sample mendelian randomisation analysis using the total genetic risk score as an instrument did not provide strong evidence of a linear effect of 25-hydroxyvitamin D on the risk of gestational hypertension or pre-eclampsia: odds ratio 0.90 (95% confidence interval 0.78 to 1.03) and 1.19 (0.92 to 1.52) per 10% decrease, respectively. The two sample mendelian randomisation estimate gave an odds ratio for pre-eclampsia of 0.98 (0.89 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, an odds ratio of 0.96 (0.80 to 1.15) per unit increase in the log(odds) of 25-hydroxyvitamin D level <75 nmol/L, and an odds ratio of 0.93 (0.73 to 1.19) per unit increase in the log(odds) of 25-hydroxyvitamin D levels <50 nmol/L.ConclusionsNo strong evidence was found to support a causal effect of vitamin D status on gestational hypertension or pre-eclampsia. Future mendelian randomisation studies with a larger number of women with pre-eclampsia or more genetic instruments that would increase the proportion of 25-hydroxyvitamin D levels explained by the instrument are needed.

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Using Mendelian Randomisation methods to understand whether diurnal preference is causally related to mental health.

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Using Mendelian Randomisation methods to understand whether diurnal preference is causally related to mental health.

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