Dataset Information

MR-LDP: a two-sample Mendelian randomization for GWAS summary statistics accounting for linkage disequilibrium and horizontal pleiotropy.

ABSTRACT: The proliferation of genome-wide association studies (GWAS) has prompted the use of two-sample Mendelian randomization (MR) with genetic variants as instrumental variables (IVs) for drawing reliable causal relationships between health risk factors and disease outcomes. However, the unique features of GWAS demand that MR methods account for both linkage disequilibrium (LD) and ubiquitously existing horizontal pleiotropy among complex traits, which is the phenomenon wherein a variant affects the outcome through mechanisms other than exclusively through the exposure. Therefore, statistical methods that fail to consider LD and horizontal pleiotropy can lead to biased estimates and false-positive causal relationships. To overcome these limitations, we proposed a probabilistic model for MR analysis in identifying the causal effects between risk factors and disease outcomes using GWAS summary statistics in the presence of LD and to properly account for horizontal pleiotropy among genetic variants (MR-LDP) and develop a computationally efficient algorithm to make the causal inference. We then conducted comprehensive simulation studies to demonstrate the advantages of MR-LDP over the existing methods. Moreover, we used two real exposure-outcome pairs to validate the results from MR-LDP compared with alternative methods, showing that our method is more efficient in using all-instrumental variants in LD. By further applying MR-LDP to lipid traits and body mass index (BMI) as risk factors for complex diseases, we identified multiple pairs of significant causal relationships, including a protective effect of high-density lipoprotein cholesterol on peripheral vascular disease and a positive causal effect of BMI on hemorrhoids.

SUBMITTER: Cheng Q

PROVIDER: S-EPMC7671398 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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MR-LDP: a two-sample Mendelian randomization for GWAS summary statistics accounting for linkage disequilibrium and horizontal pleiotropy.

Cheng Qing Q Yang Yi Y Shi Xingjie X Yeung Kar-Fu KF Yang Can C Peng Heng H Liu Jin J

NAR genomics and bioinformatics 20200504 2

The proliferation of genome-wide association studies (GWAS) has prompted the use of two-sample Mendelian randomization (MR) with genetic variants as instrumental variables (IVs) for drawing reliable causal relationships between health risk factors and disease outcomes. However, the unique features of GWAS demand that MR methods account for both linkage disequilibrium (LD) and ubiquitously existing horizontal pleiotropy among complex traits, which is the phenomenon wherein a variant affects the o ...[more]

PMID: 33575584

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Project description:There is growing interest in testing genetic pleiotropy, which is when a single genetic variant influences multiple traits. Several methods have been proposed; however, these methods have some limitations. First, all the proposed methods are based on the use of individual-level genotype and phenotype data; in contrast, for logistical, and other, reasons, summary statistics of univariate SNP-trait associations are typically only available based on meta- or mega-analyzed large genome-wide association study (GWAS) data. Second, existing tests are based on marginal pleiotropy, which cannot distinguish between direct and indirect associations of a single genetic variant with multiple traits due to correlations among the traits. Hence, it is useful to consider conditional analysis, in which a subset of traits is adjusted for another subset of traits. For example, in spite of substantial lowering of low-density lipoprotein cholesterol (LDL) with statin therapy, some patients still maintain high residual cardiovascular risk, and, for these patients, it might be helpful to reduce their triglyceride (TG) level. For this purpose, in order to identify new therapeutic targets, it would be useful to identify genetic variants with pleiotropic effects on LDL and TG after adjusting the latter for LDL; otherwise, a pleiotropic effect of a genetic variant detected by a marginal model could simply be due to its association with LDL only, given the well-known correlation between the two types of lipids. Here, we develop a new pleiotropy testing procedure based only on GWAS summary statistics that can be applied for both marginal analysis and conditional analysis. Although the main technical development is based on published union-intersection testing methods, care is needed in specifying conditional models to avoid invalid statistical estimation and inference. In addition to the previously used likelihood ratio test, we also propose using generalized estimating equations under the working independence model for robust inference. We provide numerical examples based on both simulated and real data, including two large lipid GWAS summary association datasets based on ?100,000 and ?189,000 samples, respectively, to demonstrate the difference between marginal and conditional analyses, as well as the effectiveness of our new approach.

Project description:BACKGROUND:Associations between type 2 diabetes (T2D) and amyotrophic lateral sclerosis (ALS) were discovered in observational studies in both European and East Asian populations. However, whether such associations are causal remains largely unknown. METHODS:We employed a two-sample Mendelian randomization approach to evaluate the causal relationship of T2D with the risk of ALS in both European and East Asian populations. Our analysis was implemented using summary statistics obtained from large-scale genome-wide association studies with ~660,000 individuals for T2D and ~81,000 individuals for ALS in the European population, and ~191,000 individuals for T2D and ~4100 individuals for ALS in the East Asian population. The causal relationship between T2D and ALS in both populations was estimated using the inverse-variance-weighted methods and was further validated through extensive complementary and sensitivity analyses. RESULTS:Using multiple instruments that were strongly associated with T2D, a negative association between T2D and ALS was identified in the European population with the odds ratio (OR) estimated to be 0.93 (95% CI 0.88-0.99, p?=?0.023), while a positive association between T2D and ALS was observed in the East Asian population with OR?=?1.28 (95% CI 0.99-1.62, p?=?0.058). These results were robust against instrument selection, various modeling misspecifications, and estimation biases, with the Egger regression and MR-PRESSO ruling out the possibility of horizontal pleiotropic effects of instruments. However, no causal association was found between T2D-related exposures (including glycemic traits) and ALS in the European population. CONCLUSION:Our results provide new evidence supporting the causal neuroprotective role of T2D on ALS in the European population and provide empirically suggestive evidence of increasing risk of T2D on ALS in the East Asian population. Our results have an important implication on ALS pathology, paving ways for developing therapeutic strategies across multiple populations.

Project description:Orienting the causal relationship between pairs of traits is a fundamental task in scientific research with significant implications in practice, such as in prioritizing molecular targets and modifiable risk factors for developing therapeutic and interventional strategies for complex diseases. A recent method, called Steiger's method, using a single SNP as an instrument variable (IV) in the framework of Mendelian randomization (MR), has since been widely applied. We report the following new contributions. First, we propose a single SNP-based alternative, overcoming a severe limitation of Steiger's method in simply assuming, instead of inferring, the existence of a causal relationship. We also clarify a condition necessary for the validity of the methods in the presence of hidden confounding. Second, to improve statistical power, we propose combining the results from multiple, and possibly correlated, SNPs as multiple instruments. Third, we develop three goodness-of-fit tests to check modeling assumptions, including those required for valid IVs. Fourth, by relaxing one of the three IV assumptions in MR, we propose several methods, including an Egger regression-like approach and its multivariable version (analogous to multivariable MR), to account for horizontal pleiotropy of the SNPs/IVs, which is often unavoidable in practice. All our methods can simultaneously infer both the existence and (if so) the direction of a causal relationship, largely expanding their applicability over that of Steiger's method. Although we focus on uni-directional causal relationships, we also briefly discuss an extension to bi-directional relationships. Through extensive simulations and an application to infer the causal directions between low density lipoprotein (LDL) cholesterol, or high density lipoprotein (HDL) cholesterol, and coronary artery disease (CAD), we demonstrate the superior performance and advantage of our proposed methods over Steiger's method and bi-directional MR. In particular, after accounting for horizontal pleiotropy, our method confirmed the well known causal direction from LDL to CAD, while other methods, including bi-directional MR, might fail.

Dataset Information

MR-LDP: a two-sample Mendelian randomization for GWAS summary statistics accounting for linkage disequilibrium and horizontal pleiotropy.

Publications

MR-LDP: a two-sample Mendelian randomization for GWAS summary statistics accounting for linkage disequilibrium and horizontal pleiotropy.

Similar Datasets

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