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Mendelian randomization accounting for complex correlated horizontal pleiotropy while elucidating shared genetic etiology

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  • Qing Cheng

    (Southwestern University of Finance and Economics
    Duke-NUS Medical School)

  • Xiao Zhang

    (Duke-NUS Medical School)

  • Lin S. Chen

    (The University of Chicago)

  • Jin Liu

    (Duke-NUS Medical School)

Abstract

Mendelian randomization (MR) harnesses genetic variants as instrumental variables (IVs) to study the causal effect of exposure on outcome using summary statistics from genome-wide association studies. Classic MR assumptions are violated when IVs are associated with unmeasured confounders, i.e., when correlated horizontal pleiotropy (CHP) arises. Such confounders could be a shared gene or inter-connected pathways underlying exposure and outcome. We propose MR-CUE (MR with Correlated horizontal pleiotropy Unraveling shared Etiology and confounding), for estimating causal effect while identifying IVs with CHP and accounting for estimation uncertainty. For those IVs, we map their cis-associated genes and enriched pathways to inform shared genetic etiology underlying exposure and outcome. We apply MR-CUE to study the effects of interleukin 6 on multiple traits/diseases and identify several S100 genes involved in shared genetic etiology. We assess the effects of multiple exposures on type 2 diabetes across European and East Asian populations.

Suggested Citation

  • Qing Cheng & Xiao Zhang & Lin S. Chen & Jin Liu, 2022. "Mendelian randomization accounting for complex correlated horizontal pleiotropy while elucidating shared genetic etiology," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34164-1
    DOI: 10.1038/s41467-022-34164-1
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    1. Yihe Yang & Noah Lorincz-Comi & Xiaofeng Zhu, 2023. "Unbiased estimation and asymptotically valid inference in multivariable Mendelian randomization with many weak instrumental variables," Papers 2301.05130, arXiv.org, revised Feb 2024.
    2. Zhaotong Lin & Wei Pan, 2024. "A robust cis-Mendelian randomization method with application to drug target discovery," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Han Zhang & Rahul Kalla & Jie Chen & Jianhui Zhao & Xuan Zhou & Alex Adams & Alexandra Noble & Nicholas T. Ventham & Judith Wellens & Gwo-Tzer Ho & Malcolm G. Dunlop & Jan Krzysztof Nowak & Yuan Ding , 2024. "Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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