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Concept: Mendelian randomization

19

Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date.

Concepts: Gene, Genetics, Epidemiology, Allele, Serum iron, Mendelian randomization

13

Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.

Concepts: Genetics, Epidemiology, Cancer, Breast cancer, Menopause, Estrogen, Body mass index, Mendelian randomization

3

Understanding mediation is useful for identifying intermediates lying between an exposure and an outcome which, when intervened upon, will remove (some of) the causal pathway between the exposure and outcome. Mediation approaches used in conventional epidemiology have been adapted to understanding the role of molecular intermediates in situations of high-dimensional omics data with varying degrees of success. In particular, the limitations of observational epidemiological study including confounding, reverse causation and measurement error can afflict conventional mediation approaches and may lead to incorrect conclusions regarding causal effects. Solutions to analysing mediation which overcome these problems include the use of instrumental variable methods such as Mendelian randomization, which may be applied to evaluate causality in increasingly complex networks of omics data.

Concepts: Genetics, Epidemiology, Causality, Measurement, Philosophy of science, Knowledge, Metaphysics, Mendelian randomization

1

Despite epidemiologic data showing an increased stroke incidence in African ancestry populations, genetic studies in this group have so far been limited, and there has been little characterization of the genetic contribution to stroke liability in this population, particularly for stroke subtypes.

Concepts: Genetics, Epidemiology, Biology, Demography, English American, London, United States Census Bureau, Mendelian randomization

1

Instrumental variable (IV) methods are often used to identify ‘local’ causal effects in a subgroup of the population of interest. Such ‘local’ effects may not be ideal for informing clinical or policy decision making. When the instrument is non-causal, additional difficulties arise for interpreting ‘local’ effects. Little attention has been paid to these difficulties, even though commonly proposed instruments in epidemiology are non-causal (e.g. proxies for physician’s preference; genetic variants in some Mendelian randomization studies).

Concepts: Genetics, Epidemiology, Biology, Econometrics, Decision theory, Unsolved problems in neuroscience, Generalized method of moments, Mendelian randomization

1

Human epidemiologic and genetic evidence using the Mendelian randomization approach in large-scale studies now strongly support that elevated lipoprotein(a) (Lp(a)) is a causal risk factor for cardiovascular disease, that is, for myocardial infarction, atherosclerotic stenosis, and aortic valve stenosis. The Mendelian randomization approach used to infer causality is generally not affected by confounding and reverse causation, the major problems of observational epidemiology. This approach is particularly valuable to study causality of Lp(a), as single genetic variants exist that explain 27-28% of all variation in plasma Lp(a). The most important genetic variant likely is the kringle IV type 2(KIV-2) copy number variant, as the apolipoprotein(a)(apo(a)) product of this variant influences fibrinolysis and thereby thrombosis, as opposed to the Lp(a) particle per se. We speculate that the physiological role of KIV-2 in Lp(a) could be through wound healing during childbirth, infections and injury, a role that in addition could lead to more blood clots promoting stenosis of arteries and the aortic valve, and myocardial infarction. Randomized placebo-controlled trials of Lp(a) reduction in individuals with very high concentrations to reduce cardiovascular disease are awaited. Recent genetic evidence document elevated Lp(a) as a cause of myocardial infarction, atherosclerotic stenosis, and aortic valve stenosis.

Concepts: Gene, Genetics, Epidemiology, Causality, Myocardial infarction, Atherosclerosis, Stroke, Mendelian randomization

1

Much of the genetic basis of complex traits is present on current genotyping products, but the individual variants that affect the traits have largely not been identified. Several traditional problems in genetic epidemiology have recently been addressed by assuming a polygenic basis for disease and treating it as a single entity. Here I briefly review some of these applications, which collectively may be termed polygenic epidemiology. Methodologies in this area include polygenic scoring, linear mixed models, and linkage disequilibrium scoring. They have been used to establish a polygenic effect, estimate genetic correlation between traits, estimate how many variants affect a trait, stratify cases into subphenotypes, predict individual disease risks, and infer causal effects using Mendelian randomization. Polygenic epidemiology will continue to yield useful applications even while much of the specific variation underlying complex traits remains undiscovered.

Concepts: Genetics, Epidemiology, Effect, Affect, Genetic linkage, Randomness, Linkage disequilibrium, Mendelian randomization

1

Observational epidemiological studies are prone to confounding, reverse causation and various biases and have generated findings that have proved to be unreliable indicators of the causal effects of modifiable exposures on disease outcomes. Mendelian randomization (MR) is a method that utilizes genetic variants that are robustly associated with such modifiable exposures to generate more reliable evidence regarding which interventions should produce health benefits. The approach is being widely applied, and various ways to strengthen inference given the known potential limitations of MR are now available. Developments of MR, including two-sample MR, bidirectional MR, network MR, two-step MR, factorial MR and multiphenotype MR, are outlined in this review. The integration of genetic information into population-based epidemiological studies presents translational opportunities, which capitalize on the investment in genomic discovery research.

Concepts: Scientific method, Gene, Genetics, Epidemiology, Critical thinking, Causality, Evidence, Mendelian randomization

0

The etiology of multiple sclerosis (MS) involves a complex interplay of genetic and environmental factors. Epidemiologic studies have furthered our understanding of these risk factors but remain limited by residual confounding and potential for reverse causation, particularly in MS where time of disease onset is not known. Mendelian randomization (MR) uses genetic variants to study the causal effect of modifiable exposures on an outcome. This method avoids some of the limitations of classical epidemiology and can strengthen causal inference. Here, we introduce the basic concepts of MR and review its contributions to the field of MS. Indeed, several studies using MR have now provided support for a causal role for low vitamin D level and obesity in the development of MS.

Concepts: Vitamin D, Genetics, Epidemiology, Cancer, Disease, Causality, Multiple sclerosis, Mendelian randomization

0

Mitochondrial disease can present as a movement disorder. Data on this entity’s epidemiology, genetics, and underlying pathophysiology, however, is scarce.

Concepts: DNA, Genetics, Cell, Genetic disorder, Bacteria, Biology, Neurology, Mendelian randomization