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A multivariable cis-Mendelian randomization method robust to weak instrument bias and horizontal pleiotropy bias

Yihe Yang1, Noah Lorincz-Comi1, Mengxuan Li1

  • 1Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH 44106, United States.

Briefings in Bioinformatics
|June 5, 2025
PubMed

Insights

A new method, cis-Mendelian randomization bias correction estimating equation (cis-MRBEE), addresses biases in genetic studies. This robust approach identifies causal proteins for lipid traits and potential causes for Alzheimer's disease.

Area of Science:

  • Genetics and Bioinformatics
  • Statistical Genetics
  • Causal Inference

Background:

  • Multivariable cis-Mendelian randomization (cis-MVMR) is valuable for identifying therapeutic targets influencing disease susceptibility.
  • Existing cis-MVMR methods struggle with biases from weak instruments and horizontal pleiotropy, limiting their reliability.
  • Invalid instruments can lead to inaccurate conclusions in genetic association studies.

Purpose of the Study:

  • To develop a novel method, cis-Mendelian randomization bias correction estimating equation (cis-MRBEE), to overcome limitations in cis-MVMR.
  • To improve the accuracy and robustness of identifying causal relationships between genetic variants and disease traits.
  • To apply the new method to discover causal proteins for lipid traits and genetic factors for Alzheimer's disease.

Main Methods:

  • Proposed cis-Mendelian randomization bias correction estimating equation (cis-MRBEE) leveraging local sparse genetic architecture.
  • Employed fine-mapping to identify causal variants or exposure proxies.
  • Utilized double-penalized minimization for estimating causal exposures and accounting for horizontal pleiotropy.

Main Results:

  • Simulations demonstrated cis-MRBEE's robustness against weak instruments and horizontal pleiotropy, outperforming standard and existing cis-MVMR methods.
  • Applied to the ANGPTL3 locus, cis-MRBEE identified APOA1, APOC1, and PCSK9 as likely causal proteins for LDL-C, HDL-C, and TG, revealing a complex lipid regulation network.
  • Discovered CR1 expression in specific brain regions/cell types as potentially causal for Alzheimer's disease and its cerebrospinal fluid biomarkers (Aβ42, pTau).

Conclusions:

  • cis-MRBEE offers a robust and reliable method for causal inference in genetic studies, effectively mitigating common biases.
  • The study identified novel protein targets influencing lipid metabolism and potential genetic contributors to Alzheimer's disease pathogenesis.
  • This approach advances the identification of therapeutic targets and understanding of complex disease mechanisms through genetic data analysis.
Keywords:
cis-Mendelian randomizationhorizontal pleiotropymultivariable Mendelian randomizationweak instrument bias

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