Causal mediation analysis for time-varying heritable risk factors with Mendelian Randomization


Understanding the causal pathogenic mechanisms of diseases is crucial in clinical research. When randomized controlled experiments are not available, Mendelian Randomization (MR) offers an alternative, leveraging genetic mutations as a natural experiment to mitigate environmental confoundings. However, most MR analyses treat the risk factors as static variables, potentially oversimplifying dynamic risk factor effects. The framework of life-course MR has been introduced to address this issue. However, current methods face challenges especially when the age-specific GWAS datasets have limited cohort sizes and there are substantial correlations between time points for a single trait. This study proposes a novel approach, estimating a unified system of structural equations for a sequence of temporally ordered heritable traits, requiring only GWAS summary statistics. The method facilitates statistical inference on direct, indirect, and path-wise causal effects and demonstrates superior efficiency and reliability, particularly with noisy GWAS data. By incorporating a spike-and-slab prior for genetic effects, the approach can address extreme polygenicity and weak instrument bias. Through this methodology, we uncovered a protective effect of BMI on breast cancer during a confined period of childhood development. We also analyzed how BMI, systolic blood pressure (SBP), and low-density cholesterol levels influence stroke risk across childhood and adulthood, and identified the intriguing relationships between these risk factors.

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