Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations


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Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations
PLoS Genet
Demirkan A., van Duijn  C. M., Ugocsai P., Isaacs A., Pramstaller  P. P., Liebisch G., Wilson  J. F., Johansson A., Rudan I., Aulchenko  Y. S., Kirichenko  A. V., Janssens  A. C., 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., Nelson  C. P., Preuss M., Bis  J. C., O'Donnell  C. J., Franceschini N., Witteman  J. C., Axenovich T., Oostra  B. A., Meitinger T., Hicks  A. A., Hayward C., Wright  A. F., Gyllensten U., Campbell H., Schmitz G.
Working group(s)
Consortium Diagram, Consortium C. ARDIoGRAM, Consortium Charge, consortium Eurospan
Publication state
Issued date
Demirkan, Ayse
van Duijn, Cornelia M
Ugocsai, Peter
Isaacs, Aaron
Pramstaller, Peter P
Liebisch, Gerhard
Wilson, James F
Johansson, Asa
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
Nelson, Christopher P
Preuss, Michael
Bis, Joshua C
O'Donnell, Christopher J
Franceschini, Nora
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
Medical Research Council/United Kingdom
Wellcome Trust/United Kingdom
PLoS Genet. 2012;8(2):e1002490. doi: 10.1371/journal.pgen.1002490. Epub 2012 Feb 16.
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 = 9.88x10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10x10(-57)). After a correction for multiple comparisons (P-value<2.2x10(-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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10/01/2013 12:44
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