Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations..pdf (592.15 kB)
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Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations.

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posted on 21.01.2016, 09:38 by A. Demirkan, C. M. van Duijn, P. Ugocsai, A. Isaacs, P. P. Pramstaller, G. Liebisch, J. F. Wilson, Å. Johansson, I. Rudan, Y. S. Aulchenko, A. V. Kirichenko, A. C. Janssens, R. C. Jansen, C. Gnewuch, F. S. Domingues, C. Pattaro, S. H. Wild, I. Jonasson, O. Polasek, I. V. Zorkoltseva, A. Hofman, L. C. Karssen, M. Struchalin, J. Floyd, W. Igl, Z. Biloglav, L. Broer, A. Pfeufer, I. Pichler, S. Campbell, G. Zaboli, I. Kolcic, F. Rivadeneira, J. Huffman, N. D. Hastie, A. Uitterlinden, L. Franke, C. S. Franklin, V. Vitart, DIAGRAM Consortium, Christopher P. Nelson, M. Preuss, CARDIoGRAM Consortium, J. C. Bis, C. J. O'Donnell, N. Franceschini, CHARGE Consortium, J. C. Witteman, T. Axenovich, B. A. Oostra, T. Meitinger, A. A. Hicks, C. Hayward, A. F. Wright, U. Gyllensten, H. Campbell, G. Schmitz, EUROSPAN consortium
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.

History

Citation

PLoS Genet, 2012, 8 (2), e1002490

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

Version

VoR (Version of Record)

Published in

PLoS Genet

Publisher

Public Library of Science

issn

1553-7390

eissn

1553-7404

Acceptance date

05/12/2011

Copyright date

2012

Available date

21/01/2016

Publisher version

http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002490

Language

en