A1 Refereed original research article in a scientific journal
A genome-wide association meta-analysis of cholesterol synthesis intermediates identifies three associations for lanosterol
Authors: Förster, Franz; Horn, Katrin; Pott, Janne; Delgado, Graciela E.; Kleber, Marcus E.; März, Winfried; Moissl-Blanke, Angela Patricia; Silbernagel, Günther; Waldenberger, Melanie; Grallert, Harald; Peters, Annette; Gieger, Christian; Baber, Ronny; Kirsten, Holger; Loeffler, Markus; Isermann, Berend; Thiery, Joachim; Kovacs, Peter; Tönjes, Anke; Stumvoll, Michael; Gylling, Helena; Kähönen, Mika; Lehtimäki, Terho; Mishra, Pashupati Prasad; Raitakari, Olli; Ceglarek, Uta; Scholz, Markus
Publisher: Elsevier BV
Publication year: 2026
Journal: EBioMedicine
Article number: 106144
Volume: 124
eISSN: 2352-3964
DOI: https://doi.org/10.1016/j.ebiom.2026.106144
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Open Access publication channel
Web address : https://doi.org/10.1016/j.ebiom.2026.106144
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/508960855
Self-archived copy's licence: CC BY
Self-archived copy's version: Publisher`s PDF
Background
Cholesterol is a main contributor to coronary artery disease (CAD). Although the genetic basis of blood cholesterol concentration is well studied, there is currently a lack of studies investigating the genetics of its precursors from de novo biosynthesis.
Methods
We conducted a genome-wide association meta-analysis, combining data from KORA, LIFE-Heart, LIFE-Adult, LURIC, the Sorbs study, and YFS, resulting in up to 10,519 individuals. We investigated 14 traits related to serum concentrations of lanosterol, desmosterol, and cholesterol. Direct and indirect effects of lanosterol on CAD were investigated with a Mendelian randomisation mediation analysis.
Findings
Our analysis revealed four genome-wide significant (p < 5 × 10−8) associations not previously reported in the GWAS catalogue. These include two loci without prior connection to cholesterol, associated with lanosterol (7q21.2, CYP51A1) and free cholesterol (11q14.1), and two associations with lanosterol at loci previously reported for cholesterol (5q13.3, HMGCR; 11q23.3, APO cluster). We also replicated eight loci previously reported for associations with cholesterol-related traits. Lanosterol exhibited significant total and indirect effects on CAD, but its direct effect was not significant.
Interpretation
We demonstrate that the investigation of intermediate phenotypes can help to functionally fine map previously reported associations for cholesterol, improving our understanding of genetic regulation of cholesterol concentrations. Further, the effect of lanosterol on CAD is probably fully mediated by total cholesterol.
Funding
This investigation was primarily funded by the ministry for science and health of the Rhineland-Palatinate through the CoAGE graduate programme. A complete list of funding organisations is provided in the acknowledgements.
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Funding information in the publication:
We gratefully acknowledge the contributions of our colleague Joey Deutsch, who passed away before the completion of this work.
We thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. LURIC was supported by the 7th Framework Program (integrated project AtheroRemo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the European Union and by the H2020 Program TO_AITION (grant agreement number 848146).
We thank all participants for their long-term commitment to the KORA study, the staff for data collection and research data management and the members of the KORA Study Group (https://www.helmholtz-munich.de/en/epi/cohort/kora) who are responsible for the design and conduct of the study. The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Research, Technology and Space (BMFTR) and by the State of Bavaria. Data collection in the KORA study is done in cooperation with the University Hospital of Augsburg.
LIFE-Heart and LIFE-Adult are funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by means of the Free State of Saxony within the framework of the excellence initiative. The Sorbs study was supported by grants from the Collaborative Research Center funded by the German Research Foundation (CRC 1052; SPP 1629 TO 718/2), from the German Diabetes Association, from the DHFD (Diabetes Hilfs-und Forschungsfonds Deutschland), and from the German Center for Diabetes Research. We wish to thank all participants of LIFE-Heart, LIFE-Adult and the Sorbs study for their willingness to participate.
The Young Finns Study has been financially supported by the Academy of Finland: grants 356405, 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117797 (Gendi), and 141071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; the Sigrid Jusélius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To Aition); European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation; Finnish Society of Clinical Chemistry; the Cancer Foundation Finland; pBETTER4U_EU (Preventing obesity through Biologically and bEhaviorally Tailored inTERventions for you; project number: 101080117); CVDLink (EU grant nro. 101137278) and the Jane and Aatos Erkko Foundation.
Computations were performed using the IT infrastructure of the Centre for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI) Dresden/Leipzig, funded by the German Federal Ministry of Research, Technology and Space (BMFTR grant #01IS18026B).
Franz Förster is supported by the CoAGE graduate programme, funded by the ministry for science and health of the Rhineland-Palatinate. Katrin Horn is supported by the German Federal Ministry of Research, Technology and Space (BMFTR) (grant #01ZX1906B, project SYMPATH), the federal states of Germany and the Helmholtz society (grant # 01ER2301/14, NAKO). Janne Pott is supported by the United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and the Wellcome Trust (225790/Z/22/Z). Günther Silbernagel is supported by the Austrian Science Fund (FWF KLI-1117). Pashupati P. Mishra was supported by the Academy of Finland (Grant number: 349708) and Emma Raitoharju (grants: 330809, 338395).
Supported by the Open Access Publishing Fund of Leipzig University.
