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Nat Genet DOI:10.1038/s41588-018-0099-7

Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases.

Publication TypeJournal Article
Year of Publication2018
AuthorsVerbanck, M, Chen, C-Y, Neale, B, Do, R
JournalNat Genet
Volume50
Issue5
Pages693-698
Date Published2018 05
ISSN1546-1718
KeywordsDisease, Genetic Pleiotropy, Genetic Predisposition to Disease, Genetic Variation, Humans
Abstract

Horizontal pleiotropy occurs when the variant has an effect on disease outside of its effect on the exposure in Mendelian randomization (MR). Violation of the 'no horizontal pleiotropy' assumption can cause severe bias in MR. We developed the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test to identify horizontal pleiotropic outliers in multi-instrument summary-level MR testing. We showed using simulations that the MR-PRESSO test is best suited when horizontal pleiotropy occurs in <50% of instruments. Next we applied the MR-PRESSO test, along with several other MR tests, to complex traits and diseases and found that horizontal pleiotropy (i) was detectable in over 48% of significant causal relationships in MR; (ii) introduced distortions in the causal estimates in MR that ranged on average from -131% to 201%; (iii) induced false-positive causal relationships in up to 10% of relationships; and (iv) could be corrected in some but not all instances.

DOI10.1038/s41588-018-0099-7
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/29686387?dopt=Abstract

Alternate JournalNat Genet
PubMed ID29686387
PubMed Central IDPMC6083837
Grant ListR01 MH107649 / MH / NIMH NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States
R01 MH094469 / MH / NIMH NIH HHS / United States
R35 GM124836 / GM / NIGMS NIH HHS / United States
15CVGPSD27130014 / AHA / American Heart Association-American Stroke Association / United States
R01 HL139865 / HL / NHLBI NIH HHS / United States