Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations
journal contributionposted on 17.06.2013, 14:01 by Ayse Demirkan, Cornelia M. van Duijn, Peter Ugocsai, Aaron Isaacs, Peter P. Pramstaller, Gerhard Liebisch, James F. Wilson, Asa Johansson, Igor Rudan, Yurii S. Aulchenko, Anatoly V. Kirichenko, A. Cecile J.W. Janssens, Ritsert C. Jansen, Carsten Gnewuch, Francisco S. Domingues, Cristian Pattaro, Sarah H. Wild, Inger Jonasson, Ozren Polasek, Irina V. Zorkoltseva, Albert Hofman, Lennart C. Karssen, Maksim Struchalin, James Floyd, Wilmar Igl, Zrinka Biloglav, Linda Broer, Arne Pfeufer, Irene Pichler, Susan Campbell, Ghazal Zaboli, Ivana Kolcic, Fernando Rivadeneira, Jennifer Huffman, Nicholas D. Hastie, Andre Uitterlinden, Lude Franke, Christopher S. Franklin, Veronique Vitart, DIAGRAM Consortium, Christopher P. Nelson, Michael Preuss, CARDIoGRAM Consortium, Joshua C. Bis, Christopher J. O'Donnell, Nora Franceschini, CHARGE Consortium, Jacqueline C.M. Witteman, Tatiana Axenovich, Ben A. Oostra, Thomas Meitinger, Andrew A. Hicks, Caroline Hayward, Alan F. Wright, Ulf Gyllensten, Harry Campbell, Gerd Schmitz
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.