AbstractMediation analysis has been a useful tool for investigating the effect of mediators that lie in the path from the independent variable to the outcome. With the increasing dimensionality of mediators such as in (epi)genomics studies, high-dimensional mediation model is needed. In this work, we focus on epigenetic studies with the goal to identify important DNA methylations that act as mediators between an exposure disease outcome. Specifically, we focus on gene-based high-dimensional mediation analysis implemented with kernel principal component analysis to capture potential nonlinear mediation effect. We first review the current high-dimensional mediation models and then propose two gene-based analytical approaches: gene-based high-dimensional mediation analysis based on linearity assumption between mediators and outcome (gHMA-L) and gene-based high-dimensional mediation analysis based on nonlinearity assumption (gHMA-NL). Since the underlying true mediation relationship is unknown in practice, we further propose an omnibus test of gene-based high-dimensional mediation analysis (gHMA-O) by combing gHMA-L and gHMA-NL. Extensive simulation studies show that gHMA-L performs better under the model linear assumption and gHMA-NL does better under the model nonlinear assumption, while gHMA-O is a more powerful and robust method by combining the two. We apply the proposed methods to two datasets to investigate genes whose methylation levels act as important mediators in the relationship: (1) between alcohol consumption and epithelial ovarian cancer risk using data from the Mayo Clinic Ovarian Cancer Case-Control Study and (2) between childhood maltreatment and comorbid post-traumatic stress disorder and depression in adulthood using data from the Gray Trauma Project.