Causal relationships between blood lipids and depression phenotypes: a Mendelian randomisation analysis

2020 ◽  
pp. 1-13 ◽  
Author(s):  
Hon-Cheong So ◽  
Carlos Kwan-long Chau ◽  
Yu-ying Cheng ◽  
Pak C. Sham
Keyword(s):  
Causal Relationship ◽  
Large Scale ◽  
Blood Lipids ◽  
Blood Lipid ◽  
Lipid Lowering ◽  
Mendelian Randomisation ◽  
Causal Relationships ◽  
Low Mood ◽  
Moderate Evidence ◽  
Mechanistic Basis

Abstract Background The etiology of depression remains poorly understood. Changes in blood lipid levels were reported to be associated with depression and suicide, however study findings were mixed. Methods We performed a two-sample Mendelian randomisation (MR) analysis to investigate the causal relationship between blood lipids and depression phenotypes, based on large-scale GWAS summary statistics (N = 188 577/480 359 for lipid/depression traits respectively). Five depression-related phenotypes were included, namely major depression (MD; from PGC), depressive symptoms (DS; from SSGAC), longest duration and number of episodes of low mood, and history of deliberate self-harm (DSH)/suicide (from UK Biobank). MR was conducted with inverse-variance weighted (MR-IVW), Egger and Generalised Summary-data-based MR (GSMR) methods. Results There was consistent evidence that triglyceride (TG) is causally associated with DS (MR-IVW β for one-s.d. increase in TG = 0.0346, 95% CI 0.0114–0.0578), supported by MR-IVW and GSMR and multiple r2 clumping thresholds. We also observed relatively consistent associations of TG with DSH/suicide (MR-Egger OR = 2.514, CI 1.579–4.003). There was moderate evidence for positive associations of TG with MD and the number of episodes of low mood. For HDL-c, we observed moderate evidence for causal associations with DS and MD. LDL-c and TC did not show robust causal relationships with depression phenotypes, except for weak evidence that LDL-c is inversely related to DSH/suicide. We did not detect significant associations when depression phenotypes were treated as exposures. Conclusions This study provides evidence to a causal relationship between TG, and to a lesser extent, altered cholesterol levels with depression phenotypes. Further studies on its mechanistic basis and the effects of lipid-lowering therapies are warranted.

Causal relationships between blood lipids and depression phenotypes: A Mendelian randomization analysis

2018 ◽  
Author(s):  
Hon-Cheong So ◽  
Carlos Kwan-long Chau ◽  
Yu-ying Cheng ◽  
Pak C. Sham
Keyword(s):  
Causal Relationship ◽  
Large Scale ◽  
Blood Lipids ◽  
Mendelian Randomization ◽  
Blood Lipid ◽  
Lipid Lowering ◽  
Causal Relationships ◽  
Low Mood ◽  
Moderate Evidence ◽  
Mechanistic Basis

AbstractBackgroundThe etiology of depression remains poorly understood. Changes in blood lipid levels were reported to be associated with depression and suicide, however study findings were mixed.MethodsWe performed a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between blood lipids and depression phenotypes, based on large-scale GWAS summary statistics (N=188,577/480,359 for lipid/depression traits respectively). Five depression-related phenotypes were included, namely major depressive disorder (MDD; from PGC), depressive symptoms (DS; from SSGAC), longest duration and number of episodes of low mood, and history of deliberate self-harm (DSH)/suicide (from UK Biobank). MR was conducted with inverse-variance weighted (MR-IVW), Egger and Generalized Summary-data-based MR(GSMR) methods.ResultsThere was consistent evidence that triglyceride (TG) is causally associated with DS (MR-IVW beta for one-SD increase in TG=0.0346, 95% CI=0.0114-0.0578), supported by MR-IVW and GSMR and multiple r2 clumping thresholds. We also observed relatively consistent associations of TG with DSH/suicide (MR-Egger OR= 2.514, CI: 1.579-4.003). There was moderate evidence for positive associations of TG with MDD and the number of episodes of low mood. For HDL-c, we observed moderate evidence for causal associations with DS and MDD. LDL-c and TC did not show robust causal relationships with depression phenotypes, except for weak evidence that LDL-c is inversely related to DSH/suicide. We did not detect significant associations when depression phenotypes were treated as exposures.ConclusionsThis study provides evidence to a causal relationship between TG, and to a lesser extent, altered cholesterol levels with depression phenotypes. Further studies on its mechanistic basis and the effects of lipid-lowering therapies are warranted.

scholarly journals Is there a causal relationship between executive function and liability to mental health and substance use? A Mendelian randomisation approach

2022 ◽  
Author(s):  
Sabrina M.I Burton ◽  
Hannah M Sallis ◽  
Alexander S Hatoum ◽  
Marcus R Munafo ◽  
Zoe E Reed
Keyword(s):  
Mental Health ◽  
Substance Use ◽  
Executive Function ◽  
Alcohol Consumption ◽  
Causal Relationship ◽  
Causal Effect ◽  
Smoking Initiation ◽  
Mendelian Randomisation ◽  
P Value ◽  
Causal Relationships

Background: Executive function consists of several cognitive control processes that are able to regulate lower level processes. Poorer performance in tasks designed to test executive function is associated with a range of psychopathologies such as schizophrenia, major depressive disorder (MDD) and anxiety, as well as with smoking and alcohol consumption. Despite these well-documented associations, whether they reflect causal relationships, and if so in what direction, remains unclear. We aimed to establish whether there is a causal relationship between a latent factor for performance on multiple executive function tasks - which we refer to as common executive function (cEF) - and liability to schizophrenia, MDD, anxiety, smoking initiation, alcohol consumption, alcohol dependence and cannabis use disorder (CUD), and the directionality of any relationship observed. Methods: We used a two-sample bidirectional Mendelian randomisation (MR) approach using genome-wide association study (GWAS) summary data from large cohorts (N=17,310 to 848,460) to examine whether causal relationships exist, and if so in which direction. Results: We found evidence of a causal effect of increased cEF on reduced schizophrenia liability (IVW: OR=0.10; 95% CI 0.05 to 0.19; p-value=3.43x10-12), reduced MDD liability (IVW: OR=0.52; 95% CI 0.38 to 0.72; p-value=5.23x10-05), decreased drinks per week (IVW: β=-0.06; 95% CI -0.10 to -0.02; p-value=0.003), and reduced CUD liability (IVW: OR=0.27; 95% CI 0.12 to 0.61; p-value=1.58x10-03). We also found evidence of a causal effect of increased schizophrenia liability on decreased cEF (IVW: β=-0.04; 95% CI -0.04 to -0.03; p-value=3.25x10-27), as well as smoking initiation on decreased cEF (IVW: β=-0.06; 95%CI -0.09 to -0.03; p-value=6.11x10-05). Conclusion: Our results indicate a potential bidirectional causal relationship between a latent factor measure of executive function (cEF) and schizophrenia liability, a possible causal effect of increased cEF on reduced MDD liability, CUD liability, and alcohol consumption, and a possible causal effect of smoking initiation on decreased cEF. These results suggest that executive function should be considered as a potential risk factor for some mental health and substance use outcomes, and may also be impacted by mental health (particularly schizophrenia). Further studies are required to improve our understanding of the underlying mechanisms of these effects, but our results suggest that executive function may be a promising intervention target. These results may therefore inform the prioritisation of experimental medicine studies (e.g., of executive function interventions), for both mental health and substance use outcomes, to improve the likelihood of successful translation.

scholarly journals Longitudinal trajectories of blood lipid levels in an ageing population sample of Russian Western-Siberian urban population

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260229
Author(s):  
Jaroslav A. Hubacek ◽  
Yuri Nikitin ◽  
Yulia Ragino ◽  
Ekaterina Stakhneva ◽  
Hynek Pikhart ◽  
...  
Keyword(s):  
Blood Lipids ◽  
Population Sample ◽  
Age Groups ◽  
Serum Triglyceride ◽  
Blood Lipid ◽  
Lipid Lowering ◽  
Ageing Population ◽  
Mixed Effect ◽  
Over Time

This study investigated 12-year blood lipid trajectories and whether these trajectories are modified by smoking and lipid lowering treatment in older Russians. To do so, we analysed data on 9,218 Russian West-Siberian Caucasians aged 45–69 years at baseline participating in the international HAPIEE cohort study. Mixed-effect multilevel models were used to estimate individual level lipid trajectories across the baseline and two follow-up examinations (16,445 separate measurements over 12 years). In all age groups, we observed a reduction in serum total cholesterol (TC), LDL-C and non-HDL-C over time even after adjusting for sex, statin treatment, hypertension, diabetes, social factors and mortality (P<0.01). In contrast, serum triglyceride (TG) values increased over time in younger age groups, reached a plateau and decreased in older age groups (> 60 years at baseline). In smokers, TC, LDL-C, non-HDL-C and TG decreased less markedly than in non-smokers, while HDL-C decreased more rapidly while the LDL-C/HDL-C ratio increased. In subjects treated with lipid-lowering drugs, TC, LDL-C and non-HDL-C decreased more markedly and HDL-C less markedly than in untreated subjects while TG and LDL-C/HDL-C remained stable or increased in treatment naïve subjects. We conclude, that in this ageing population we observed marked changes in blood lipids over a 12 year follow up, with decreasing trajectories of TC, LDL-C and non-HDL-C and mixed trajectories of TG. The findings suggest that monitoring of age-related trajectories in blood lipids may improve prediction of CVD risk beyond single measurements.

scholarly journals Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pradeep Natarajan ◽  
◽  
Akhil Pampana ◽  
Sarah E. Graham ◽  
Sanni E. Ruotsalainen ◽  
...  
Keyword(s):  
X Chromosome ◽  
Blood Lipids ◽  
Ldl Cholesterol ◽  
Blood Lipid ◽  
Lipid Lowering ◽  
High Coverage ◽  
Abdominal Mri ◽  
Males And Females ◽  
Atherogenic Lipid

AbstractAutosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Effects of the Tibetan herbal preparation PADMA 28 on blood lipids and lipid oxidisability in subjects with mild hypercholesterolaemia

VASA ◽  
2005 ◽  
Vol 34 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Brunner-La Rocca ◽  
Schindler ◽  
Schlumpf ◽  
Saller ◽  
Suter
Keyword(s):  
Endothelial Dysfunction ◽  
Blood Lipids ◽  
Ex Vivo ◽  
Hdl Cholesterol ◽  
Blood Lipid ◽  
Tibetan Medicine ◽  
Double Blind ◽  
Intraarterial Infusion ◽  
Padma 28

Background: Previous studies showed an anti-atherosclerotic effect of PADMA 28, an herbal formula based on Tibetan medicine. As the mechanisms of action are not fully understood, we investigated whether PADMA 28 may lower blood lipids and lipid oxidisability, and affect early endothelial dysfunction. Patients and methods: Sixty otherwise healthy subjects with total cholesterol ≥5.2 mmol/l and < 8.0 mmol/l were randomly assigned to placebo or PADMA 28, 3 x 2 capsules daily, for 4 weeks (double-blind). Blood lipids (total, LDL-, and HDL-cholesterol, triglycerides, Apo-lipoprotein A1 and B) and ex vivo lipid oxidisability were measured before and after treatment. In a subset of 24 subjects, endothelial function was assessed using venous occlusion plethysmography with intraarterial infusion of acetylcholine. Isolated LDL and plasma both untreated and pre-treated with PADMA 28 extract were oxidised by the radical generator AAPH. Conjugated diene formation was measured at 245 nm. Results: Blood lipids did not change during the study in both groups. In contrast to previous reports in mild hypercholesterolaemia, no endothelial dysfunction was seen and, consequently, was not influenced by therapy. Ex vivo blood lipid oxidisability was significantly reduced with PADMA 28 (area under curve: 5.29 ± 1.62 to 4.99 ± 1.46, p = 0.01), and remained unchanged in the placebo group (5.33 ± 1.88 to 5.18 ± 1.78, p > 0.1). This effect persisted one week after cessation of medication. In vitro experiments confirmed the prevention of lipid peroxidation in the presence of PADMA 28 extracts. Persistent protection was also seen for LDL isolated from PADMA 28-pretreated blood after being subjected to rigorous purification. Conclusions: This study suggests that the inhibition of blood lipid oxidisability by PADMA 28 may play a role in its anti-atherosclerotic effect.

scholarly journals Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: a Mendelian randomisation analysis

2021 ◽  
Author(s):  
Richard Culliford ◽  
Alex J. Cornish ◽  
Philip J. Law ◽  
Susan M. Farrington ◽  
Kimmo Palin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Large Scale ◽  
Causal Effect ◽  
Gallstone Disease ◽  
Epidemiological Studies ◽  
Mendelian Randomisation ◽  
Linear Relationships ◽  
Potential Risk Factors ◽  
The Relationship ◽  
Circulating Levels

Abstract Background Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). Methods We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. Results No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96–1.03, P value = 0.90) with CRC was shown. Conclusions Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.

scholarly journals Examining the possible causal relationship between lung function, COPD and Alzheimer’s disease: a Mendelian randomisation study

2021 ◽  
Vol 8 (1) ◽  
pp. e000759
Author(s):  
Daniel Higbee ◽  
Raquel Granell ◽  
Esther Walton ◽  
Roxanna Korologou-Linden ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lung Function ◽  
Causal Relationship ◽  
Mendelian Randomisation ◽  
P Value ◽  
Unmeasured Confounding ◽  
Increased Risk ◽  
Shared Risk

RationaleLarge retrospective case-control studies have reported an association between chronic obstructive pulmonary disease (COPD), reduced lung function and an increased risk of Alzheimer’s disease. However, it remains unclear if these diseases are causally linked, or due to shared risk factors. Conventional observational epidemiology suffers from unmeasured confounding and reverse causation. Additional analyses addressing causality are required.ObjectivesTo examine a causal relationship between COPD, lung function and Alzheimer’s disease.MethodsUsing two-sample Mendelian randomisation, we used single nucleotide polymorphisms (SNPs) identified in a genome wide association study (GWAS) for lung function as instrumental variables (exposure). Additionally, we used SNPs discovered in a GWAS for COPD in those with moderate to very severe obstruction. The effect of these SNPs on Alzheimer’s disease (outcome) was taken from a GWAS based on a sample of 24 807 patients and 55 058 controls.ResultsWe found minimal evidence for an effect of either lung function (OR: 1.02 per SD; 95% CI 0.91 to 1.13; p value 0.68) or liability for COPD on Alzheimer’s disease (OR: 0.97 per SD; 95% CI 0.92 to 1.03; p value 0.40).ConclusionNeither reduced lung function nor liability COPD are likely to be causally associated with an increased risk of Alzheimer’s, any observed association is likely due to unmeasured confounding. Scientific attention and health prevention policy may be better focused on overlapping risk factors, rather than attempts to reduce risk of Alzheimer’s disease by targeting impaired lung function or COPD directly.

scholarly journals Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study

2014 ◽  
Vol 205 (1) ◽  
pp. 24-28 ◽  
Author(s):  
Chi-Fa Hung ◽  
Margarita Rivera ◽  
Nick Craddock ◽  
Michael J. Owen ◽  
Michael Gill ◽  
...  
Keyword(s):  
Major Depression ◽  
Causal Relationship ◽  
Instrumental Variable ◽  
Common Mental Disorders ◽  
Genetic Risk Score ◽  
Linear Regression Analysis ◽  
Mendelian Randomisation ◽  
Probit Regression ◽  
Reverse Causality ◽  
Increased Risk

BackgroundObesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMI) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue.AimsTo investigate whether higher BMI increases the risk of major depression.MethodTwo instrumental variable analyses were conducted to test the causal relationship between obesity and major depression in RADIANT, a large case–control study of major depression. We used a single nucleotide polymorphism (SNP) in FTO and a genetic risk score (GRS) based on 32 SNPs with well-established associations with BMI.ResultsLinear regression analysis, as expected, showed that individuals carrying more risk alleles of FTO or having higher score of GRS had a higher BMI. Probit regression suggested that higher BMI is associated with increased risk of major depression. However, our two instrumental variable analyses did not support a causal relationship between higher BMI and major depression (FTO genotype: coefficient −0.03, 95% CI −0.18 to 0.13, P = 0.73; GRS: coefficient −0.02, 95% CI −0.11 to 0.07, P = 0.62).ConclusionsOur instrumental variable analyses did not support a causal relationship between higher BMI and major depression. The positive associations of higher BMI with major depression in probit regression analyses might be explained by reverse causality and/or residual confounding.

Lipid-lowering treatment in hypercholesterolaemic patients: the CEPHEUS Pan-Asian survey

2011 ◽  
Vol 19 (4) ◽  
pp. 781-794 ◽  
Author(s):  
Jeong Euy Park ◽  
Chern-En Chiang ◽  
Muhammad Munawar ◽  
Gia Khai Pham ◽  
Apichard Sukonthasarn ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
High Risk ◽  
Large Scale ◽  
Goal Attainment ◽  
Density Lipoprotein ◽  
Final Analysis ◽  
Relevant Information ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Lipid Lowering Drugs

Background: Treatment of hypercholesterolaemia in Asia is rarely evaluated on a large scale, and data on treatment outcome are scarce. The Pan-Asian CEPHEUS study aimed to assess low-density lipoprotein cholesterol (LDL-C) goal attainment among patients on lipid-lowering therapy. Methods: This survey was conducted in eight Asian countries. Hypercholesterolaemic patients aged ≥18 years who had been on lipid-lowering treatment for ≥3 months (stable medication for ≥6 weeks) were recruited, and lipid concentrations were measured. Demographic and other clinically relevant information were collected, and the cardiovascular risk of each patient was determined. Definitions and criteria set by the updated 2004 National Cholesterol Education Program guidelines were applied. Results: In this survey, 501 physicians enrolled 8064 patients, of whom 7281 were included in the final analysis. The mean age was 61.0 years, 44.4% were female, and 85.1% were on statin monotherapy. LDL-C goal attainment was reported in 49.1% of patients overall, including 51.2% of primary and 48.7% of secondary prevention patients, and 36.6% of patients with familial hypercholesterolaemia. The LDL-C goal was attained in 75.4% of moderate risk, 55.4% of high risk, and only 34.9% of very high-risk patients. Goal attainment was directly related to age and inversely related to cardiovascular risk and baseline LDL-C. Conclusion: A large proportion of Asian hypercholesterolaemic patients on lipid-lowering drugs are not at recommended LDL-C levels and remain at risk for cardiovascular disease. Given the proven efficacy of lipid-lowering drugs in the reduction of LDL-C, there is room for further optimization of treatments to maximize benefits and improve outcomes.

Sign in / Sign up

Export Citation Format

Share Document