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Nat Genet. 2018 May;50(5):693-698. doi: 10.1038/s41588-018-0099-7. Epub 2018 Apr 23.

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

Verbanck M1,2,3, Chen CY4,5,6, Neale B7,8,9, Do R10,11,12.

Author information

1
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
5
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
6
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
7
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. bneale@broadinstitute.org.
8
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. bneale@broadinstitute.org.
9
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA. bneale@broadinstitute.org.
10
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ron.do@mssm.edu.
11
The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ron.do@mssm.edu.
12
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ron.do@mssm.edu.

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.

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