90 Study limitations PhIP-Seq is currently limited to linear epitopes and lacks post-translational modification information, and thus new technologies or improvements of the current method (e.g. as in14) are still to be developed. Similarly, the nature of the assay will also miss tridimensional structure information from the antigens that might be recognized by the antibodies. In addition to these technological issues, our relatively small sample size for genetic studies hampers an accurate estimation of antibody-bound peptide heritability and genetic correlation. It is also important to acknowledge that the antibody-bound peptides we identified mainly correspond to circulating IgG and may overlook other types of immunoglobulins or immunoglobulins not in systemic circulation. Finally, due to the mostly cross-sectional nature of the experimental design, it is hard to draw causal links from the associations we present and further studies are needed to establish causality and dependence. Acknowledgments We thank K. McIntyre for English editing. The Lifelines Biobank initiative has been made possible by a subsidy from the Dutch Ministry of Health, Welfare and Sport; the Dutch Ministry of Economic Affairs; the University Medical Center Groningen; the University of Groningen and the Northern Provinces of the Netherlands. The authors wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centers delivering data to Lifelines and all the study participants. Funding The researchers participated in this project are supported by Netherlands Heart Foundation (INCONTROL CVON grants 2012-03 and 2018-27 to J.F. and A.Z.); the Netherlands Organization for Scientific Research (NWO) Gravitation Netherlands Organ-on-Chip Initiative to J.F. and C.W.; NWO Gravitation Exposome-NL (024.004.017) to J.F., A.K. and A.Z.; The Seerave foundation and the Netherlands Organization for Scientific Research to RKW; NWO-VIDI (864.13.013) and NWO-VICI (VI.C.202.022) to J.F.; NWO-VIDI (016.178.056) to A.Z.; NWO-VIDI (016.171.047) to I.J., NWO Spinoza Prize SPI 92-266 to C.W.; the European Research Council (ERC) (FP7/2007-2013/ERC Advanced Grant 2012-322698) to C.W.; ERC Starting Grant 715772 to A.Z.; ERC Consolidator Grant (grant agreement No. 101001678) to J.F.; and RuG Investment Agenda Grant Personalized Health to C.W.; A.R.B. [grant no. 17-57] and T.S. [grant no. 17-34] hold scholarships from the Junior Scientific Masterclass, University of Groningen. E.S. is supported by grants from the European Research Council, the Israel Science Foundation and by the Seerave foundation. T.V. gratefully acknowledges support from the Austrian Science Fund (FWF, Erwin Schrödinger fellowship J4256). I.J. and A.Z. were supported by a Rosalind Franklin Fellowship from the University of Groningen. Author contributions Conceptualization: SA-S, ARB, SZ, JF, RKW, IJ, TV, SL; Methodology: SA-S, AK, SH, AJR, AVV, ARB, TS, SL, TV, SK, INK; Investigation: SA-S, ARB, AK, SH, AR, AVV, TS, TV, AZ, JF, IJ; Funding acquisition: SZ, JF, RKW, CW; Supervision: SZ, JF, RKW; Writing – original draft: SA-S, ARB; Writing – review & editing: All co-authors. Chapter 3
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