Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations
Open accessAbstract
Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57)). After a correction for multiple comparisons (P-value<2.2×10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits.
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Human genome-wide association studies link variants in PLEKHH1 with sphingolipid concentrations that, when altered, lead to neurological and psychiatric disease.
“Human genome-wide association studies link variants in PLEKHH1 with sphingolipid concentrations that, when altered, lead to neurological and psychiatric disease (49).”
From Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication (2014) · cites this paper as [49]
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- Authors
- Demirkan, A., van Duijn, C. M., Ugocsai, P., Isaacs, A., Pramstaller, P. P., Liebisch, G., Wilson, J. F., Johansson, Å., Rudan, I., Aulchenko, Y. S., Kirichenko, A. V., Janssens, A. C. J. W., Jansen, R. C., Gnewuch, C., Domingues, F. S., Pattaro, C., Wild, S. H., Jonasson, I., Polasek, O., Zorkoltseva, I. V., Hofman, A., Karssen, L. C., Struchalin, M., Floyd, J., Igl, W., Biloglav, Z., Broer, L., Pfeufer, A., Pichler, I., Campbell, S., Zaboli, G., Kolcic, I., Rivadeneira, F., Huffman, J., Hastie, N. D., Uitterlinden, A., Franke, L., Franklin, C. S., Vitart, V., DIAGRAM Consortium, Nelson, C. P., Preuss, M., CARDIoGRAM Consortium, Bis, J. C., O'Donnell, C. J., Franceschini, N., CHARGE Consortium, Witteman, J. C. M., Axenovich, T., Oostra, B. A., Meitinger, T., Hicks, A. A., Hayward, C., Wright, A. F., Gyllensten, U., Campbell, H., Schmitz, G., & on behalf of the EUROSPAN consortium
- Affiliations
- Erasmus MC (NL)
- Eurac Research (IT)
- University Hospital Regensburg (DE)
- University of Edinburgh (GB)
- Uppsala University (SE)
- University of Split (HR)
- Russian Academy of Sciences (RU)
- University of Groningen (NL)
- Wellcome Sanger Institute (GB)
- University of Zagreb (HR)
- Institute of Genetics and Cancer (GB)
- University Medical Center Groningen (NL)
- University of Leicester (GB)
- University of Lübeck (DE)
- University of Washington (US)
- University of North Carolina at Chapel Hill (US)
- Helmholtz Munich (DE)
- Corresponding author
- Isaacs, Aaron
- ORCID
- Demirkan, Ayşe
- Isaacs, Aaron
- Pramstaller, Peter P.
- Liebisch, Gerhard
- Wilson, James F.
- Johansson, Åsa
- Rudan, Igor
- Aulchenko, Yurii S.
- Janssens, A. Cecile J. W.
- Domingues, Francisco S.
- Pattaro, Cristian
- Wild, Sarah H.
- Zorkoltseva, Irina V.
- Karssen, Lennart C.
- Struchalin, Maksim
- Igl, Wilmar
- Biloglav, Zrinka
- Broer, Linda
- Pichler, Irene
- Rivadeneira, Fernando
- Huffman, Jennifer
- Hastie, Nicholas D.
- Franke, Lude
- Franklin, Christopher S.
- Nelson, Christopher P.
- Preuss, Michael
- Bis, Joshua C.
- Franceschini, Nora
- Axenovich, Tatiana
- Meitinger, Thomas
- Hicks, Andrew A.
- Hayward, Caroline
- Gyllensten, Ulf
- Schmitz, Gerd
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-02-16
- Volume
- 8
- Issue
- 2
- Pages
- e1002490
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3280968
- OpenAlex
- W2132495615
- Cited by
- 205
- References
- 39
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 11 · 2023: 14 · 2022: 14 · 2021: 12 · 2020: 13 · 2019: 20 · 2018: 16 · 2017: 17 · 2016: 16 · 2015: 14 · 2014: 22 · 2013: 13 · 2012: 10
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (acceptedVersion, other-oa)
- Leicester Research Archive (University of Leicester) (acceptedVersion, other-oa)
- Research Explorer (The University of Manchester) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion)
- Figshare (submittedVersion, cc-by)
- IRIS (submittedVersion)
- Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- SERVAL (Université de Lausanne) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- OPUS (Augsburg University) (submittedVersion, cc-by)
- Open Research (University of Surrey) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Apollo (cc-by)
- Funders
- Wellcome Trust (202272, 090532)
- Royal Society
- European Commission (018947, LSHG-CT-2006-01947, 202272)
- Russian Foundation for Basic Research (047.017.043, NWORFBR 047.017.043)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (047.016.009, NWO-RFBR 047.017.043, RFBR 047.017.043, 047.017.043)
- Centre for Medical Systems Biology
- Provincia autonoma di Bolzano - Alto Adige
- National Institutes of Health (UL1TR000124)
- Medical Research Council
- National Heart, Lung, and Blood Institute (R01HL105756)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491)
- National Center for Advancing Translational Sciences
- H2020 European Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- phospholipids, sphingolipids, plasma lipid levels, genetic loci, sphingomyelin, ceramide, phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, plasmalogens, PKD2L1, phospholipase D2, apolipoprotein E, fatty acid elongation, fatty acid saturation, glycerophospholipids
- MeSH terms
- Delta-5 Fatty Acid Desaturase, Diabetes Mellitus, Type 2, Humans, Phospholipids, Sphingolipids, Genome, Human, Polymorphism, Single Nucleotide, Databases, Genetic, White People, Genome-Wide Association Study, Genetic Loci, Carotid Intima-Media Thickness
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