Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits

Graßmann, Felix; Kiel, Christina; Zimmermann, Martina E.; Kronenberg, Florian; Grassmann, Veronika; Stark, Klaus; Heid, Iris M.; Weber, Bernhard H. F.

doi:10.1186/s13073-017-0418-0

Cited by 56 publications

(57 citation statements)

References 119 publications

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“…Genetic pleiotropy between AMD and other complex diseases has been observed before. 39 The emerging question is, if there is such a commonality for these diseases in terms of their genetic makeup, what determines why one individual develops one and not all diseases? One reason may be that there are different polymorphisms in a single gene that create different risks for different diseases.…”

Section: Discussionmentioning

confidence: 99%

Repository of proposed pathways and protein–protein interaction networks in age-related macular degeneration

et al. 2020

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Age-related macular degeneration (AMD) is one of the commonest causes of sight loss in the elderly population and to date there is no intervention that slows or prevents early AMD disease progressing to blinding neovascularization or geographic atrophy. AMD is a complex disease and factors proposed to contribute to the development and progression of disease include aging, genetics, epigenetics, oxidative stress, pro-inflammatory state, and life-style factors such as smoking, alcohol, and high fat diet. Here, we generate a knowledge repository of pathways and protein-protein interaction (PPI) networks likely to be implicated in AMD pathogenesis, such as complement activation, lipid trafficking and metabolism, vitamin A cycle, oxidative stress, proteostasis, bioenergetics, autophagy/mitophagy, extracellular matrix (ECM) turnover, and choroidal vascular dropout. Two disctinct clusters ermerged from the networks for parainflamation and ECM homeostasis, which may represent two different disease modules underlying AMD pathology. Our analyses also suggest that the disease manifests primarily in RPE/choroid and less in neural retina. The use of standardized syntax when generating maps of these biological processes (SBGN standard) and networks (PSI standard) enables visualization of complex information in graphical programs such as CellDesigner and Cytoscape and enhances reusability and extension of data. The ability to focus onto subnetworks, multiple visualizations and simulation options will enable the AMD research community to computationally model subnetworks or to test experimentally new hypotheses arising from connectivities in the AMD pathway map.npj Aging and Mechanisms of Disease (2020) 6:2 ; https://doi.

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Section: Discussionmentioning

confidence: 99%

Repository of proposed pathways and protein–protein interaction networks in age-related macular degeneration

et al. 2020

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“…More than 30 million individuals worldwide are affected by vision loss from AMD (6). Mutations in more than 20 genes and loci have been associated with increased risk of AMD (7,8). However, age and smoking remain the two highest risk factors, which suggests that oxidative stress and reactive oxygen species production play a pivotal role in early disease progression (8).…”

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Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium

Kong

Wang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Retinal degenerative diseases are generally characterized by a permanent loss of light-sensitive retinal neurons known as photoreceptors, or their support cells, the retinal pigmented epithelium (RPE). Metabolic dysfunction has been implicated as a common mechanism of degeneration. In this study, we used the drug metformin in a gain-of-function approach to activate adenosine monophosphate-activated protein kinase (AMPK). We found that treatment protected photoreceptors and the RPE from acute injury and delayed inherited retinal degeneration. Protection was associated with decreased oxidative stress, decreased DNA damage, and increased mitochondrial energy production. To determine whether protection was a local or a systemic effect of metformin, we used AMPK retinal knockout mice and found that local expression of AMPK catalytic subunit α2 was required for metformin-induced protection. Our data demonstrate that increasing the activity of AMPK in retinal neurons or glia can delay or prevent degeneration of photoreceptors and the RPE from multiple types of cell-death triggers.

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“…Studies have shown that many traits are genetically correlated with each other 8 . Furthermore, studies have shown that hundreds of individual variants identified from GWA studies are associated with multiple traits [9][10][11][12][13][14] . Many of these variants for the most part have been used as IVs for causal inference in MR studies with the assumption that these variants do not have pleiotropic effects.…”

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Widespread pleiotropy confounds causal relationships between complex traits and diseases inferred from Mendelian randomization

Verbanck

Chen

Neale

et al. 2017

Preprint

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A fundamental assumption in inferring causality of an exposure on complex disease using Mendelian randomization (MR) is that the genetic variant used as the instrumental variable cannot have pleiotropic effects. Violation of this 'no pleiotropy' assumption can cause severe bias. Emerging evidence have supported a role for pleiotropy amongst disease-associated loci identified from GWA studies. However, the impact and extent of pleiotropy on MR is poorly understood. Here, we introduce a method called the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test to detect and correct for pleiotropy in multi-instrument summary-level MR testing. We show using simulations that existing approaches are less sensitive to the detection of pleiotropy when it occurs in a subset of instrumental variables, as compared to MR-PRESSO. Next, we show that pleiotropy is widespread in MR, occurring in 41% amongst significant causal relationships (out of 4,250 MR tests total) from pairwise comparisons of 82 complex traits and diseases from summary level genome-wide association data. We demonstrate that pleiotropy causes distortion between -168% and 189% of the causal estimate in MR. Furthermore, pleiotropy induces false positive causal relationships -defined as those causal estimates that were no longer statistically significant in the pleiotropy corrected MR test but were previously significant in the naive MR test -in up to 10% of the MR tests using a P < 0.05 cutoff that is commonly used in MR studies. Finally, we show that MR-PRESSO can correct for distortion in the causal estimate in most cases. Our results demonstrate that pleiotropy is widespread and pervasive, and must be properly corrected for in order to maintain the validity of MR.. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/157552 doi: bioRxiv preprint first posted online Epidemiological studies have established correlations among numerous exposures and complex diseases 1 . It can be challenging to draw causal inference from these studies due to reverse causation, confounding and/or other biases 2 .Mendelian randomization (MR) is a commonly-used human genetics approach that can infer causality of an exposure with complex disease 3,4 . MR presents a number of advantages over observational epidemiology, including controlling for non-heritable environmental confounders in such analyses and the ability to use genetic instruments to evaluate the impact of an exposure without necessitating the collection of that exposure in the outcome group. MR utilizes genetic variants as genetic instrumental variables (IVs) that are robustly associated with the exposure of interest and tests whether these variants results in a proportional effect on the outcome.With the discovery of thousands of trait-associated loci identified from genome-wide association (GWA) studies, multi-instrument MR methods have been developed to ...

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Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits

Cited by 56 publications

References 119 publications

Repository of proposed pathways and protein–protein interaction networks in age-related macular degeneration

Repository of proposed pathways and protein–protein interaction networks in age-related macular degeneration

Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium

Widespread pleiotropy confounds causal relationships between complex traits and diseases inferred from Mendelian randomization

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