Mendelian randomization: how genetics is pushing the boundaries of epidemiology to identify new causes of heart disease.

Published on Jan 1, 2013in Canadian Journal of Cardiology5.592
· DOI :10.1016/j.cjca.2012.09.014
George Thanassoulis30
Estimated H-index: 30
(MUHC: McGill University Health Centre)
Abstract The past 10 years have seen a remarkable revolution in the genetics of cardiovascular (CV) disease. Although much work remains to bring these discoveries to the bedside, genetics has opened up remarkable possibilities in understanding the causes of CV disease through a relatively novel study design known as "Mendelian randomization." Akin to a randomized trial, Mendelian randomization is a genetic study design that takes advantage of the "randomization" of genetic information at birth to evaluate a potential causal relationship between a genetically determined biomarker and an outcome. By providing evidence for causal relationships, Mendelian randomization can improve our understanding of fundamental mechanisms in human disease, potentially accelerate the identification of bona fide drug targets, and ultimately improve the care of patients with CV disease. This review describes the concept and design of Mendelian randomization genetic studies, discusses their strengths and weaknesses, and presents recent examples of Mendelian randomization studies in the CV literature that have helped clarify the causal role of selected biomarkers in CV medicine.
  • References (29)
  • Citations (13)
📖 Papers frequently viewed together
1 Author (Sarah J. Lewis)
3 Citations
10 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Svati H. ShahH-Index: 49
#2William E. KrausH-Index: 79
Last. Christopher B. NewgardH-Index: 98
view all 3 authors...
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, but their molecular etiology remains poorly understood, in part because they develop slowly as a result of a mixture of genetic and environmental factors. Given the complex nature of CVD, molecular profiling of processes more “proximal” to the disease than genetic markers may have great promise in revealing both “form” (novel biomarkers with clinical potential) and “function” (mechanisms of disease development) of CVD. CVD ...
10 CitationsSource
#1Svati H. ShahH-Index: 49
#2William E. KrausH-Index: 79
Last. Christopher B. NewgardH-Index: 98
view all 3 authors...
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, but their molecular etiology remains poorly understood, in part because they develop slowly as a result of a mixture of genetic and environmental factors. Given the complex nature of CVD, molecular profiling of processes more “proximal” to the disease than genetic markers may have great promise in revealing both “form” (novel biomarkers with clinical potential) and “function” (mechanisms of disease development) of CVD. CVD ...
159 CitationsSource
#1Benjamin F. Voight (UPenn: University of Pennsylvania)H-Index: 74
#2Gina M. Peloso (BU: Boston University)H-Index: 43
Last. Sekar KathiresanH-Index: 106
view all 126 authors...
Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive con...
1,298 CitationsSource
#1Tom M. Palmer (UoB: University of Bristol)H-Index: 31
#2Debbie A. Lawlor (UoB: University of Bristol)H-Index: 118
Last. Jonathan A C Sterne (UoB: University of Bristol)H-Index: 91
view all 8 authors...
Mendelian randomisation analyses use genetic variants as instrumental variables (IVs) to estimate causal effects of modifiable risk factors on disease outcomes. Genetic variants typically explain a small proportion of the variability in risk factors; hence Mendelian randomisation analyses can require large sample sizes. However, an increasing number of genetic variants have been found to be robustly associated with disease-related outcomes in genome-wide association studies. Use of multiple inst...
194 CitationsSource
#1Nadeem Sarwar (University of Cambridge)H-Index: 21
#2Adam S. Butterworth (University of Cambridge)H-Index: 46
Last. John Danesh (University of Cambridge)H-Index: 106
view all 96 authors...
Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk fac...
344 CitationsSource
#2Daniel I. Swerdlow (UCL: University College London)H-Index: 17
#3Michael V. HolmesH-Index: 32
Last. Juan P. Casas (Lond: University of London)H-Index: 69
view all 116 authors...
Findings In 40 studies including up to 133 449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34–10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31–9·38) and fi brinogen concentrations (decrease per allele 0·85%, 95% CI 0·60–1·10). This pattern of eff ects was consistent with IL6R blockade from infusi...
477 CitationsSource
#1Robert Clarke (Clinical Trial Service Unit)H-Index: 135
#2David A. Bennett (Clinical Trial Service Unit)H-Index: 160
Last. Richard Peto (Clinical Trial Service Unit)H-Index: 164
view all 31 authors...
Background: Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so ‘‘Mendelian randomization’’ studies using this variant as an instrumental variable could help test causality. Methods and Findings: Nineteen unpublished...
129 CitationsSource
#1Elizabeth G. Nabel (Brigham and Women's Hospital)H-Index: 74
#2Eugene Braunwald (Brigham and Women's Hospital)H-Index: 212
In this review of heart disease, Nabel and Braunwald focus on two themes — coronary artery disease and myocardial infarction — and explain how our understanding has evolved over the past two centuries. The authors consider therapies that have led to improved survival.
502 CitationsSource
#1David N. Reshef (University of Oxford)H-Index: 8
#2Yakir A. Reshef (Broad Institute)H-Index: 13
Last. Pardis C. Sabeti (Broad Institute)H-Index: 59
view all 9 authors...
Identifying interesting relationships between pairs of variables in large data sets is increasingly important. Here, we present a measure of dependence for two-variable relationships: the maximal information coefficient (MIC). MIC captures a wide range of associations both functional and not, and for functional relationships provides a score that roughly equals the coefficient of determination ( R 2 ) of the data relative to the regression function. MIC belongs to a larger class of maximal infor...
1,039 CitationsSource
#1John F. Peden (Wellcome Trust Centre for Human Genetics)H-Index: 42
#2Martin Farrall (Wellcome Trust Centre for Human Genetics)H-Index: 91
Coronary artery disease (CAD) is the leading cause of death worldwide. Affected individuals cluster in families in patterns that reflect the sharing of numerous susceptibility genes. Genome-wide and large-scale gene-centric genotyping studies that involve tens of thousands of cases and controls have now mapped common disease variants to 34 distinct loci. Some coronary disease common variants show allelic heterogeneity or copy number variation. Some of the loci include candidate genes that imply ...
108 CitationsSource
Cited By13
Mendelian randomization implemented through instrumental variable analysis is frequently discussed in causality and recently the number of applications on real data is increasing. However, there are very few discussions to address modern biomedical questions such as the integration of large scale omics in causality. While in the age of large omics, we face several hundred or thousands of components with little knowledge about the underlying structures, the focus of the field is on small scales a...
Calcific aortic stenosis (AS) is the most common form of valve disease in the Western world and affects over 2.5 million individuals in North America. Despite the large burden of disease, there are no medical treatments to slow the development of AS, due at least in part to our incomplete understanding of its causes. The Cohorts for Heart and Aging Research in Genetic Epidemiology extra-coronary calcium consortium reported a genome-wide association study demonstrating that genetic variants in LP...
34 CitationsSource
#1Natasja Koks (Erasmus University Medical Center)H-Index: 1
#2Akhgar Ghassabian (NIH: National Institutes of Health)H-Index: 6
Last. Henning Tiemeier (Erasmus University Medical Center)H-Index: 80
view all 7 authors...
Background Exposure to elevated levels of inflammatory markers during pregnancy has been suggested as possible aetiologic factor in the occurrence of autism spectrum disorder (ASD). In this study, we investigated the prospective relation between maternal C-reactive protein (CRP) during early pregnancy and children's autistic traits in the general population. Methods In a large population-based cohort in the Netherlands, we measured maternal CRP levels before 18 weeks of gestation (N = 4165). Par...
9 CitationsSource
#1Khanh N. Vu (University of Texas Health Science Center at Houston)H-Index: 1
#2Christie M. Ballantyne (BCM: Baylor College of Medicine)H-Index: 100
Last. Alanna C. Morrison (University of Texas Health Science Center at Houston)H-Index: 44
view all 7 authors...
Introduction Health benefits of low-to-moderate alcohol consumption may operate through an improved lipid profile. A Mendelian randomization (MR) approach was used to examine whether alcohol consumption causally affects lipid levels. Methods This analysis involved 10,893 European Americans (EA) from the Atherosclerosis Risk in Communities (ARIC) study. Common and rare variants in alcohol dehydrogenase and acetaldehyde dehydrogenase genes were evaluated for MR assumptions. Five variants, residing...
21 CitationsSource
#1Ajay Thankamony (UCPH: University of Copenhagen)H-Index: 11
#2Vickie PasterskiH-Index: 18
Last. Ieuan A. Hughes (University of Cambridge)H-Index: 50
view all 5 authors...
The CBGS studies referred to in this review were supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), the Newlife Foundation, the Mothercare Foundation, the Evelyn Trust and the NIHR Cambridge Biomedical Research Centre.
57 CitationsSource
#1Daniel F. Kripke (UCSD: University of California, San Diego)H-Index: 70
Abstract Sleeping pills, more formally defined as hypnotics, are sedatives used to induce and maintain sleep. In a review of publications for the past 30 years, descriptive epidemiologic studies were identified that examined the mortality risk of hypnotics and related sedative–anxiolytics. Of the 34 studies estimating risk ratios, odds ratios, or hazard ratios, excess mortality associated with hypnotics was significant (p
21 CitationsSource
#1Ricardo Ladeiras-Lopes (University of Porto)H-Index: 11
#2Stefan Agewall (Oslo University Hospital)H-Index: 42
Last. Wolfgang Koenig (TUM: Technische Universität München)H-Index: 102
view all 9 authors...
Abstract Mortality from cardiovascular diseases (CVD) represents the primary cause of death worldwide. Prevention or treatment of atherosclerosis and its clinical sequelae is a central goal in the management of patients with established vascular disease or those at high-risk for vascular events. This paper provides a review of the contemporary pharmacological armamentarium targeting atherosclerosis and also highlights strategies to support future clinical trial design. Powering future trials tar...
26 CitationsSource
#1Shusuke Numata (University of Tokushima)H-Index: 23
#2Makoto Kinoshita (University of Tokushima)H-Index: 35
Last. Tetsuro Ohmori (University of Tokushima)H-Index: 29
view all 6 authors...
Background The results of meta-analyses conducted by previous association studies between total homocysteine and schizophrenia suggest that an elevated total homocysteine level is a risk factor for schizophrenia. However, observational studies have potential limitations, such as confounding and reverse causation. In the present study, we evaluated a causal relationship between plasma total homocysteine and schizophrenia by conducting a Mendelian randomization analysis.
12 CitationsSource
#1Bernhard M. Kaess (TUM: Technische Universität München)H-Index: 17
#2Sarah R. Preis (BU: Boston University)H-Index: 24
Last. Ramachandran S. Vasan (BU: Boston University)H-Index: 150
view all 11 authors...
Background Brain‐derived neurotrophic factor (BDNF) is a pleiotropic peptide involved in maintaining endothelial integrity. It is unknown if circulating BDNF levels are associated with risk of cardiovascular disease (CVD). Methods and Results We prospectively investigated the association of circulating BDNF levels with cardiovascular events and mortality in 3687 participants (mean age 65 years, 2068 women) from the Framingham Heart Study (FHS). Using a common nonsynonomous single nucleotide poly...
46 CitationsSource
It has recently been appreciated that atherosclerosis is predominantly an inflammatory process. Atherosclerosis begins with a fatty streak, which is made up almost entirely of monocyte-derived macrophages. The development of an atheroma continues as T-cells, mast cells, and other inflammatory cells
127 CitationsSource