A robust and efficient method for Mendelian randomization with hundreds of genetic variants: unravelling mechanisms linking HDL-cholesterol and coronary heart disease

Mendelian randomization (MR) investigations with large numbers of genetic variants are becoming increasingly common. However, the reliability of findings from a MR investigation is dependent on the validity of the genetic variants as instrumental variables. We developed a method to identify groups of genetic variants with similar causal effect estimates, which may represent distinct mechanisms by which the risk factor influences the outcome. Our contamination mixture method is a robust and efficient method for valid MR in the presence of invalid IVs. Compared to other robust methods, our method had the lowest mean squared error across a range of realistic scenarios. The method is fast and efficient, and can perform analysis with hundreds of variants in a fraction of a second. In a MR analysis for high-density lipoprotein (HDL) cholesterol and coronary heart disease (CHD) risk, the method identified 11 variants associated with increased HDL-cholesterol, decreased triglyceride levels, and decreased CHD risk that had the same directions of associations with platelet distribution width and other blood cell traits, suggesting a shared mechanism linking lipids and CHD risk relating to platelet aggregation.

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Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis

10.2337/figshare.13135781 ◽

2020 ◽

Author(s):

Tricia M. Peters ◽

Michael V. Holmes ◽

J. Brent Richards ◽

Tom Palmer ◽

Vincenzo Forgetta ◽

...

Keyword(s):

Type 2 Diabetes ◽

Coronary Heart Disease ◽

Heart Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Sensitivity Analyses ◽

Chd Risk ◽

Unit Increase

Objective: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding. Methods: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (N=251,420 women and 212,049 men). Weighted-median, MR Egger, MR-PRESSO and radial MR from summary-level analyses were used for pleiotropy assessment. Results: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.08-1.18 per 1-log unit increase in odds of type 2 diabetes) and men (OR 1.21, 95% CI 1.17-1.26 per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy, however, results were similar after correction for outlier SNPs. Conclusions: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.

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The role of glycaemic and lipid risk factors in mediating the effect of BMI on coronary heart disease: A two-step, two-sample Mendelian randomization study

10.1101/118133 ◽

2017 ◽

Cited By ~ 1

Author(s):

Lin Xu ◽

Maria Carolina Borges ◽

Gibran Hemani ◽

Deborah A Lawlor

Keyword(s):

Risk Factors ◽

Coronary Heart Disease ◽

Heart Disease ◽

Research Council ◽

Mendelian Randomization ◽

Fasting Glucose ◽

Causal Effect ◽

Hdl Cholesterol

AbstractBackgroundThe extent to which effects of BMI on coronary heart disease (CHD) are mediated by gylcaemic and lipid risk factors is unclear.MethodsWe used two-sample Mendelian randomization to determine the causal effect of: (i) BMI on CHD (60,801 cases; 123, 504 controls), type 2 diabetes (T2DM; 34,840 cases; 114,981 controls), fasting glucose (n=46,186), insulin (n=38,238), HbA1c (n=46,368), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and triglycerides (n=188,577); (ii) glycaemic and lipids traits on CHD; and (iii) extent to which these traits mediated any effect of BMI on CHD.FindingsOne standard deviation (SD) increase in BMI (~ 4.5kg/m2) increased CHD (odds ratio=1.45 (95% confidence interval (CI): 1.27, 1.66)) and T2DM (1.96 (1.35, 2.83)), and levels of fasting glucose (0.07mmol/l (95%CI 0.03, 0.11)), HbA1c (0.05% (95%CI 0.01, 0.08)), fasting insulin (0.18log pmol/l (95%CI 0.14, 0.22)) and triglycerides (0.20 SD (95%CI 0.14, 0.26)), and lowered levels of HDL-C (−0.23 SD (95%CI −0.32, −0.15)). BMI was not causally related to LDL-C. After accounting for potential pleiotropy, triglycerides, HbA1c and T2DM were causally related to CHD. The BMI-CHD effect reduced from 1.45 to 1.16 (95%CI 0.99, 1.36) and to 1.36 (95%CI 1.19, 1.57) with genetic adjustment for triglycerides or HbA1c respectively, and to 1.09 (95%CI 0.94, 1.27) with adjustment for both.InterpretationIncreased triglyceride levels and poor glycaemic control appear to mediate much of the effect of BMI on CHD.FundingEuropean Research Council (669545), European Union (733206), China Medical Board (CMB_2015/16), Conselho Nacional de Desenvolvimento Científico e Tecnológico and UK Medical Research Council (MC_UU_12013/5).

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Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis

10.2337/figshare.13135781.v1 ◽

2020 ◽

Author(s):

Tricia M. Peters ◽

Michael V. Holmes ◽

J. Brent Richards ◽

Tom Palmer ◽

Vincenzo Forgetta ◽

...

Keyword(s):

Type 2 Diabetes ◽

Coronary Heart Disease ◽

Heart Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Sensitivity Analyses ◽

Chd Risk ◽

Unit Increase

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Mendelian Randomization evaluation of causal effects of fibrinogen on incident coronary heart disease

10.1101/448381 ◽

2018 ◽

Author(s):

Cavin K. Ward-Caviness ◽

Paul S. de Vries ◽

Kerri L. Wiggins, MS ◽

Jennifer E. Huffman ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Mendelian Randomization ◽

Causal Effect ◽

Genome Wide Association ◽

European Ancestry ◽

Sample Sizes ◽

Genome Wide ◽

Myocardial Infraction ◽

Incident Cases

AbstractBackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.Methods and FindingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score incorporated data from 11 European-ancestry prospective cohorts to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI).In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.ConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.Author SummaryInitial Mendelian Randomization (MR) analyses of the causal effect of fibrinogen on coronary heart disease (CHD) utilized single variants and did not take advantage of modern, multivariant approaches. This manuscript provides an important update to these initial analyses by incorporating larger sample sizes and employing multiple, modern multi-variant MR approaches to account for pleiotropy. We used incident cases to perform a MR study of the causal effect of fibrinogen on incident CHD and the nested outcome of myocardial infarction (MI) using an allele score approach. Then using data from a case-control genome-wide association study for CHD and MI we performed two sample MR analyses with multiple, pleiotropy robust approaches. Overall, the results indicated that associations between fibrinogen and CHD in observational studies are likely upwardly biased from any underlying causal effect. Single variant MR approaches show little evidence of a causal effect of fibrinogen on CHD or MI. Multi-variant MR analyses of fibrinogen on CHD indicate there may be a small positive effect, however this result needs to be interpreted carefully as the 95% confidence intervals were still consistent with a null effect. Multi-variant MR approaches did not suggest evidence of even a small causal effect of fibrinogen on MI.

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Milk intake and incident stroke and coronary heart disease in populations of European descent: A Mendelian Randomization study

British Journal Of Nutrition ◽

10.1017/s0007114521004244 ◽

2021 ◽

pp. 1-25

Author(s):

L.E.T. Vissers ◽

I. Sluijs ◽

S. Burgess ◽

N.G. Forouhi ◽

H. Freisling ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Mendelian Randomization ◽

Cox Regression ◽

Milk Intake ◽

Outcome Analysis ◽

Milk Consumption ◽

Uk Biobank ◽

Chd Risk ◽

Residual Confounding

Abstract Higher milk intake has been associated with a lower stroke risk, but not with risk of coronary heart disease (CHD). Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29,328 participants (4,611 stroke; 9,828 CHD) of the EPIC-CVD (8 European countries) and EPIC-NL case-cohort studies. rs4988235, a lactase persistence (LP) single nucleotide polymorphism which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777,024 participants (50,804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483,966 participants (61,612 cases) from CARDIoGRAM, UK Biobank and EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (β=13.7 g/day; 95%CI: 8.4-19.1) and EPIC-NL (36.8 g/day; 20.0-53.5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/day 1.05; 95%CI: 0.94-1.16) or CHD (1.02; 0.96-1.08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (odds ratios 1.02; 0.99-1.05) or CHD (0.99; 0.95-1.03). Current Mendelian Randomization analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.

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The Assessment of Interleukin-18 on the Risk of Coronary Heart Disease

Medicinal Chemistry ◽

10.2174/1573406415666191004115128 ◽

2020 ◽

Vol 16 (5) ◽

pp. 626-634 ◽

Cited By ~ 6

Author(s):

Weiju Sun ◽

Ying Han ◽

Shuo Yang ◽

He Zhuang ◽

Jingwen Zhang ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Robust Regression ◽

Mendelian Randomization ◽

Causal Effect ◽

Meta Analysis ◽

Penalized Regression ◽

P Value ◽

Interleukin 18 ◽

Allele Difference

Background: Observational studies support the inflammation hypothesis in coronary heart disease (CHD). As a pleiotropic proinflammatory cytokine, Interleukin-18 (IL-18), has also been found to be associated with the risk of CHD. However, to our knowledge, the method of Mendelian Randomization has not been used to explore the causal effect of IL-18 on CHD. Objective: To assess the causal effect of IL-18 on the risk of CHD. Methods and Results: Genetic variant instruments for IL-18 were obtained from information of the CHS and InCHIANTI cohort, and consisted of the per-allele difference in mean IL-18 for 16 independent variants that reached genome-wide significance. The per-allele difference in log-odds of CHD for each of these variants was estimated from CARDIoGRAMplusC4D, a two-stage meta -analysis. Two-sample Mendelian Randomization (MR) was then performed. Various MR analyses were used, including weighted inverse-variance, MR-Egger regression, robust regression, and penalized regression. The OR of elevated IL-18 associated with CHD was only 0.005 (95%CI -0.105~0.095; P-value=0.927). Similar results were obtained with the use of MR-Egger regression, suggesting that directional pleiotropy was unlikely biasing these results (intercept -0.050, P-value=0.220). Moreover, results from the robust regression and penalized regression analyses also revealed essentially similar findings. Conclusions: Our findings indicate that, by itself, IL-18 is unlikely to represent even a modest causal factor for CHD risk.

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Abstract 19: Dietary Lipophilic Load and Dietary Lipophilic Index with Risk of Coronary Heart Disease in Middle-Aged Women: Beyond Conventional Fat Classifications

Circulation ◽

10.1161/circ.131.suppl_1.19 ◽

2015 ◽

Vol 131 (suppl_1) ◽

Author(s):

Eric L Ding ◽

Katerina M De Vito ◽

Hongyu Wu ◽

Qi Sun ◽

An Pan ◽

...

Keyword(s):

Risk Factors ◽

Coronary Heart Disease ◽

Heart Disease ◽

Dietary Fat ◽

Hdl Cholesterol ◽

Health Study ◽

Chd Risk ◽

Increased Risk ◽

Total Fat ◽

Traditional Risk Factors

Introduction: Studies indicate dietary types of fats are associated with risk of coronary heart disease (CHD). Traditional broad classifications may incompletely capture the diversity of fatty acids on CHD. The novel lipid index Dietary Lipophilic Load (DLL) reflects a unique combination of fatty acid fluidity, intermolecular attraction, plus relative fat quantity, while Dietary Lipophilic Index (DLI) is a measure of average fat fluidity, regardless of fat quantity. Thus, we evaluated the association, DLL and DLI, with risk of incident CHD. METHODS: Participants included 30,932 women in the Women’s Health Study (WHS), who were free of major chronic diseases at baseline. DLL was calculated by weighted summation of the multiplicative product of each fatty acid’s intakes (g/day) and its melting points (Celcius); DLI was calculated by dividing DLL by total fat intake (g/day). Hazard ratios (HRs) were adjusted for established risk factors, with updated dietary data, and potential mediators. We also investigated hypothesized interactions with C-Reactive Protein (CRP). RESULTS: There were 1137 cases of incident CHD in 525,828 person-years over 19 years follow-up. At baseline in over 27,000 women with blood samples, DLL and DLI were not correlated with serum cholesterol, triglyceride, HbA1c, ICAM-1, or CRP biomarkers (r<0.02 for all). In overall multivariate analysis, DLL was associated with higher risk of CHD (extreme quintile HR=1.40, 95%CI: 1.11-1.76, P trend=0.0002), while DLI was not (HR=0.83, 95%CI: 0.67-1.03, P trend=0.75). DLL results were independent beyond adjustment for dietary trans, saturated, monounsaturated, and polyunsaturated fats, nor their aggregate adjustment or the P:S ratio. DLL effects persisted even adjusting for CRP (HR=1.29, P-trend=1 mg/dL for DLL (extreme quintile HR=1.38, 1.02-1.88), than among individuals with low CRP <1 mg/dl for DLL (HR=1.08, 0.68-1.72), with P-interaction<0.0001. Furthermore, CRP also modified DLI, where effects again diverged among higher CRP (HR=0.98, 0.73-1.31) versus low CRP (HR=0.45, 0.27-0.74), with P-interaction<0.0001. Moreover, adjustment of triglycerides, HbA1c, ICAM-1, LDL or HDL cholesterol also did not materially affect overall results. CONCLUSION: Results indicate that DLL is associated with increased risk of incident CHD, independent of traditional risk factors, conventional dietary fat classifications, and major CHD biomarkers. Effects of DLL and DLI appear to be modified by levels of CRP. DLL appears to be an important novel dietary fat index that captures additional CHD risk information beyond biomarkers and traditional dietary fat categories. Further studies are warranted.

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Risk for coronary heart disease in people with severe mental illness

The British Journal of Psychiatry ◽

10.1192/bjp.bp.104.008060 ◽

2006 ◽

Vol 188 (3) ◽

pp. 271-277 ◽

Cited By ~ 81

Author(s):

David P. J. Osborn ◽

Irwin Nazareth ◽

Michael B. King

Keyword(s):

Risk Factors ◽

Coronary Heart Disease ◽

Mental Illness ◽

Heart Disease ◽

Severe Mental Illness ◽

Hdl Cholesterol ◽

Risk Scores ◽

Systematic Research ◽

Chd Risk ◽

Chd Risk Factors

BackgroundDespite concern about the incidence of coronary heart disease (CHD) in people with severe mental illness (SMI), there is little systematic research on CHD risk factors in this population.AimsTo compare the main risk factors for CHD in people with and without SMI in primary care, to investigate the role of socio-economic variables, and to examine any association between antipsychotic medication and CHD risk.MethodCross-sectional screening.ResultsIn total, 75 of 182 general practice patients with SMI and 150 of 313 such patients without SMI attended the interview. SMI was associated with: raised 10-year CHD risk scores (OR= 1.8, 95% CI 1.0–3.1); high-density-lipoprotein (HDL)-cholesterol levels <l.0 mmol/l (OR=4.0, 95% CI 1.5–10.7); raised cholesterol/HDL-cholesterol ratios (OR=1.8, 95% CI 1.0–3.2); diabetes mellitus (OR=3.8, 95% CI 1.1–13.3) and smoking (OR=3.0, 95% CI 1.7–3.4). These associations varied significantly with age. Adjustment for unemployment did not fully explain the associations.ConclusionsExcess risk factors for CHD are not wholly accounted for by medication or socio-economic deprivation. There is an urgent need for CHD screening and for relevant interventions for smoking cessation and diabetes, as well as advice on diet and exercise, in patients with SMI.

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Apolipoprotein B underlies the causal relationship of circulating blood lipids with coronary heart disease

10.1101/19004895 ◽

2019 ◽

Cited By ~ 3

Author(s):

Tom G Richardson ◽

Eleanor Sanderson ◽

Tom M. Palmer ◽

Mika Ala-Korpela ◽

Brian A Ference ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Apolipoprotein B ◽

Blood Lipids ◽

Ldl Cholesterol ◽

Mendelian Randomization ◽

Hdl Cholesterol ◽

Blood Lipid ◽

Apolipoprotein A ◽

Relationship Of

AbstractBackgroundCirculating blood lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. We sought to explore the causal relationships of blood lipid traits with risk of CHD using multivariable Mendelian randomization.MethodsWe conducted GWAS of circulating blood lipid traits in UK Biobank (up to n=440,546) for LDL cholesterol, triglycerides and apolipoprotein B to identify lipid-associated SNPs. Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable Mendelian randomization (MR) analyses. Similar analyses were conducted for HDL cholesterol and apolipoprotein A-I.FindingsGWAS identified multiple independent SNPs associated at P<5×10−8 for LDL cholesterol (220), apolipoprotein B (n=255), triglycerides (440), HDL cholesterol (534) and apolipoprotein AI (440). Between 56-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWAS. Almost half (46%) of these SNPs were associated at P<5×10−8 with more than one lipid related trait. Assessed individually using MR, each of LDL cholesterol (OR 1.66 per 1 standard deviation higher trait; 95%CI: 1.49; 1.86; P=2.4×10−19), triglycerides (OR 1.34; 95%CI: 1.25, 1.44; P=9.1×10−16) and apolipoprotein B (OR 1.73; 95%CI: 1.56, 1.91; P=1.5×10−25) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95%CI: 1.31, 2.81; P=7.5×10−4) retained a robust effect with the estimate for LDL cholesterol (OR 0.85; 95%CI: 0.57; 1.27; P=0.44) reversing and that of triglycerides (OR 1.12; 95%CI: 1.02, 1.23; P=0.01) becoming markedly weaker.Individual MR analyses showed a 1-SD higher HDL-C (OR 0.80; 95%CI: 0.75, 0.86; P=1.7×10−10) and apolipoprotein A-I (OR 0.83; 95%CI: 0.77, 0.89; P=1.0×10−6) to lower the risk of CHD but these effect estimates weakened to include the null on accounting for apolipoprotein B.ConclusionsApolipoprotein B is of fundamental causal relevance in the aetiology of CHD, and underlies the relationship of LDL cholesterol and triglycerides with CHD.

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Association of high sensitive C-reactive protein with coronary heart disease: a Mendelian randomization study

BMC Medical Genetics ◽

10.1186/s12881-019-0910-z ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 2

Author(s):

Qian Zhuang ◽

Chong Shen ◽

Yanchun Chen ◽

Xianghai Zhao ◽

Pengfei Wei ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Regression Model ◽

Mendelian Randomization ◽

Cox Regression ◽

Causal Effect ◽

C Reactive Protein ◽

Reactive Protein ◽

Hs Crp

Abstract Objectives Whether high sensitivity C-reactive protein (hs-CRP) has a causal effect on coronary heart disease (CHD) is unclear. This study investigated the causal effect of hs-CRP on CHD risk using Mendelian Randomization (MR) analysis. Methods A total of 3802 subjects were recruited in the follow-up study. Linear regression model was used to evaluate the relationship between CRP polymorphisms and hs-CRP. Survival receiver operator characteristic curve method was used to explore the cut-off of hs-CRP on CHD incidence. Cox regression model was applied to detect the association of hs-CRP with CHD by calculating the hazard ratio (HR) and 95% confidence interval (CI). Rs1205 and rs876537 in CRP were selected as instrumental variables in MR analysis. Results During a median follow-up time of 5.01 years, 98 CHD incidence was identified (47.03/104 person-years). Hs-CRP was significantly increased among rs1205 and rs876537 genotypes with r values of 0.064 and 0.066, respectively. Hs-CRP 1.08 mg/L was identified as the cut-off value with a maximum value of sensitivity and specificity on prediction of CHD. Participants with ≥1.08 mg/L of hs-CRP has a higher risk of CHD incidence than that of participants with < 1.08 mg/L, the adjusted HR (95% CI) was 1.69 (1.11–2.60) with a P value of 0.016. No significant casual association was observed between hs-CRP and CHD with a P value of 0.777. Conclusions The association between hs-CRP and CHD is unlikely to be causal, hs-CRP might be a predictor for incidence of CHD in general population.

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