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. 2021 Dec 2;52(2):92–107. doi: 10.1007/s10519-021-10094-4

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — Flow-chart of the different analysis phases, with each phase in a different colour. In the Genomic SEM model, path (a) denotes the EA GWAS (direct SNP-EA associations), path (b) the smoking GWAS (direct SNP-smoking associations), and path (c’) the SNP-smoking association remaining after controlling for mediation through EA, capturing SNP effects on smoking-without-EA. In the NEMESIS-2 sample we used multiple imputation, such that N was constant (N = 3090) for all analyses. PGS PolyGenic Score, EA educational attainment, PGS_EA PGS for EA, PGS_smok-noEA PGS for smoking-without-EA, PGS_allsmk PGS for lifetime smoking (Color figure online)