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. 2020 Jan 3;11:15. doi: 10.1038/s41467-019-13831-w

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© The Author(s) 2020

Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — This network comprises 72 CpG sites (green circles, same color and shape code as in Fig. 1) that associated with blood circulating levels of pappalysin-1 (PAPPA) (blue octagon), five of which were also associated with RNA expression in BIOS (gray squares) (Table 1). Ingenuity Pathway Analysis (IPA) was used to connect these CpG sites to PAPPA through protein-protein links (yellow diamonds) that were supported by experimental findings, reflecting the well documented role of PAPPA as an activator of the IGF and NFκB pathways. PAPPA levels also associated with relevant clinical phenotypes in KORA, reaching multiple testing corrected significance levels of p < 5.6 × 10⁻⁴ for CpG sites and p < 3.6 × 10⁻³ for proteins (purple rectangles). PAPPA has also been linked to various diseases in numerous previous studies (pink hexagons). Full literature support of these links is provided in Supplementary Note 3.