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Author (up) 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.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.; Nelson, C.P.; Preuss, M.; Bis, J.C.; O'Donnell, C.J.; Franceschini, N.; 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. url  doi
  Title Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations Type Journal Article
  Year 2012 Publication PLoS Genetics Abbreviated Journal PLoS Genet  
  Volume 8 Issue 2 Pages e1002490  
  Keywords Carotid Intima-Media Thickness; Databases, Genetic; Diabetes Mellitus, Type 2/blood/genetics; European Continental Ancestry Group/*genetics; Genetic Loci; *Genome, Human; *Genome-Wide Association Study; Humans; *Phospholipids/blood/genetics; Polymorphism, Single Nucleotide; *Sphingolipids/blood/genetics  
  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 = 9.88x10(-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.  
  Address Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands  
  Corporate Author EUROSPAN consortium Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1553-7390 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:22359512; PMC3280968 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1520  
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