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It is of significant scientific interest to unravel the role of potentially high-dimensional intermediate phenotypes in the relationship between environmental exposure and traits. Mediation analysis is an important tool for investigating such relationships. However, it has mainly focused on low-dimensional settings, and there is a lack of a good measure of the total mediation effect. Here, we extend an R-squared (R<jats:inline-formula><jats:alternatives><jats:tex-math>$$^2$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\"><mml:msup><mml:mrow\/><mml:mn>2<\/mml:mn><\/mml:msup><\/mml:math><\/jats:alternatives><\/jats:inline-formula>) effect size measure, originally proposed in the single-mediator setting, to the moderate- and high-dimensional mediator settings in the mixed model framework.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Based on extensive simulations, we compare our measure and estimation procedure with several frequently used mediation measures, including product, proportion, and ratio measures. Our R<jats:inline-formula><jats:alternatives><jats:tex-math>$$^2$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\"><mml:msup><mml:mrow\/><mml:mn>2<\/mml:mn><\/mml:msup><\/mml:math><\/jats:alternatives><\/jats:inline-formula>-based second-moment measure has small bias and variance under the correctly specified model. To mitigate potential bias induced by non-mediators, we examine two variable selection procedures, i.e., iterative sure independence screening and false discovery rate control, to exclude the non-mediators. We establish the consistency of the proposed estimation procedures and introduce a resampling-based confidence interval. By applying the proposed estimation procedure, we found that 38% of the age-related variations in systolic blood pressure can be explained by gene expression profiles in the Framingham Heart Study of 1711 individuals. An R package \u201cRsqMed\u201d is available on CRAN.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>R-squared (R<jats:inline-formula><jats:alternatives><jats:tex-math>$$^2$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\"><mml:msup><mml:mrow\/><mml:mn>2<\/mml:mn><\/mml:msup><\/mml:math><\/jats:alternatives><\/jats:inline-formula>) is an effective and efficient measure for total mediation effect especially under high-dimensional setting.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12859-021-04322-1","type":"journal-article","created":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T08:03:32Z","timestamp":1629705812000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Estimation of total mediation effect for high-dimensional omics mediators"],"prefix":"10.1186","volume":"22","author":[{"given":"Tianzhong","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingbo","family":"Niu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7758-6116","authenticated-orcid":false,"given":"Peng","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,8,23]]},"reference":[{"issue":"2","key":"4322_CR1","doi-asserted-by":"publisher","first-page":"271","DOI":"10.2217\/epi.15.102","volume":"8","author":"C Ladd-Acosta","year":"2016","unstructured":"Ladd-Acosta C, Fallin MD. 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