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Cited by 205Genetic Associations and EpidemiologySphingolipid Metabolism and SignalingLipid metabolism and biosynthesis

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Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations

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Demirkan, Ayşe, van Duijn, Cornelia M., Ugocsai, Peter, Isaacs, Aaron, Pramstaller, Peter P., Liebisch, Gerhard, Wilson, James F., Johansson, Åsa, Rudan, Igor, Aulchenko, Yurii S., Kirichenko, Anatoly V., Janssens, A. Cecile J. W., Jansen, Ritsert C., Gnewuch, Carsten, Domingues, Francisco S., Pattaro, Cristian, Wild, Sarah H., Jonasson, Inger, Polasek, Ozren, Zorkoltseva, Irina V., Hofman, Albert, Karssen, Lennart C., Struchalin, Maksim, Floyd, James, Igl, Wilmar, Biloglav, Zrinka, Broer, Linda, Pfeufer, Arne, Pichler, Irene, Campbell, Susan, Zaboli, Ghazal, Kolcic, Ivana, Rivadeneira, Fernando, Huffman, Jennifer, Hastie, Nicholas D., Uitterlinden, Andre, Franke, Lude, Franklin, Christopher S., Vitart, Veronique, DIAGRAM Consortium, Nelson, Christopher P., Preuss, Michael, CARDIoGRAM Consortium, Bis, Joshua C., O'Donnell, Christopher J., Franceschini, Nora, CHARGE Consortium, Witteman, Jacqueline C. M., Axenovich, Tatiana, Oostra, Ben A., Meitinger, Thomas, Hicks, Andrew A., Hayward, Caroline, Wright, Alan F., Gyllensten, Ulf, Campbell, Harry, Schmitz, Gerd, on behalf of the EUROSPAN consortium·2012·PLoS Genetics
DOI 10.1371/journal.pgen.1002490PMC PMC3280968
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Abstract

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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Figure 1 Genome-wide association results for 115 phospholipid species. (A) Genome-wide association results for plasma levels of 115 phospholipid species. (B) Genome-wide association results for within-class proportions of 115 plasma phospholipid species. Manhattan plots show the combined association signals (−log10(P-value)) on the y-axis versus SNPs according to their position in the genome on the x-axis (NCBI build 36). Novel genes are represented in red, while previously known loci are represented in black.
Figure 1 Genome-wide association results for 115 phospholipid species. (A) Genome-wide association results for plasma levels of 115 phospholipid species. (B) Genome-wide association results for within-class proportions of 115 plasma phospholipid species. Manhattan plots show the combined association signals (−log10(P-value)) on the y-axis versus SNPs according to their position in the genome on the x-axis (NCBI build 36). Novel genes are represented in red, while previously known loci are represented in black.CC BY · PubMed Central
Figure 2 Genome-wide association results for 33 sphingolipid species. (A) Genome-wide association results for plasma levels of 33 sphingolipid species. (B) Genome-wide association results for within-class proportions of 33 sphingolipid species. Manhattan plots show the combined association signals (−log10(P-value)) on the y-axis versus SNPs according to their position in the genome on the x-axis (NCBI build 36). Novel genes are represented in red, while previously known loci are represented in black.
Figure 2 Genome-wide association results for 33 sphingolipid species. (A) Genome-wide association results for plasma levels of 33 sphingolipid species. (B) Genome-wide association results for within-class proportions of 33 sphingolipid species. Manhattan plots show the combined association signals (−log10(P-value)) on the y-axis versus SNPs according to their position in the genome on the x-axis (NCBI build 36). Novel genes are represented in red, while previously known loci are represented in black.CC BY · PubMed Central

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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
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
DOI
10.1371/journal.pgen.1002490
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
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
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  • PubMed (publishedVersion)
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  • Research Explorer (The University of Manchester) (submittedVersion)
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  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
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  • 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)
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  • 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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