Abstract
To infer a causal relationship between two traits, several correlation-based causal direction (CD) methods have been proposed with the use of SNPs as instrumental variables (IVs) based on GWAS summary data for the two traits; however, none of the existing CD methods can deal with SNPs with correlated pleiotropy. Alternatively, reciprocal Mendelian randomization (MR) can be applied, which however may perform poorly in the presence of (unknown) invalid IVs, especially for bi-directional causal relationships. In this paper, first, we propose a CD method that performs better than existing CD methods regardless of the presence of correlated pleiotropy. Second, along with a simple but yet effective IV screening rule, we propose applying a closely related and state-of-the-art MR method in reciprocal MR, showing its almost identical performance to that of the new CD method when their model assumptions hold; however, if the modeling assumptions are violated, the new CD method is expected to better control type I errors. Notably bi-directional causal relationships impose some unique challenges beyond those for uni-directional ones, and thus requiring special treatments. For example, we point out for the first time several scenarios where a bidirectional relationship, but not a uni-directional one, can unexpectedly cause the violation of some weak modeling assumptions commonly required by many robust MR methods. We also offer some numerical support and a modeling justification for the application of our new methods (and more generally MR) to binary traits. Finally we applied the proposed methods to 12 risk factors and 4 common diseases, confirming mostly well-known uni-directional causal relationships, while identifying some novel and plausible bi-directional ones such as between body mass index and type 2 diabetes (T2D), and between diastolic blood pressure and stroke.
Original language | English (US) |
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Article number | e1010205 |
Journal | PLoS genetics |
Volume | 18 |
Issue number | 5 |
DOIs | |
State | Published - May 16 2022 |
Bibliographical note
Funding Information:HX was supported by NIH grant R01AG065636; WP was supported by NIH grants R01AG065636, R01 AG069895, RF1 AG067924, R01HL116720, R01GM113250 and R01GM126002. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The computing resources were provided by the Minnesota Supercomputing Institute at the University of Minnesota.
Publisher Copyright:
© 2022 Xue, Pan. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.