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

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.

SUBMITTER: Demirkan A

PROVIDER: S-EPMC3280968 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Demirkan Ayşe A van Duijn Cornelia M CM Ugocsai Peter P Isaacs Aaron A Pramstaller Peter P PP Liebisch Gerhard G Wilson James F JF Johansson Åsa Å Rudan Igor I Aulchenko Yurii S YS Kirichenko Anatoly V AV Janssens A Cecile J W AC Jansen Ritsert C RC Gnewuch Carsten C Domingues Francisco S FS Pattaro Cristian C Wild Sarah H SH Jonasson Inger I Polasek Ozren O Zorkoltseva Irina V IV Hofman Albert A Karssen Lennart C LC Struchalin Maksim M Floyd James J Igl Wilmar W Biloglav Zrinka Z Broer Linda L Pfeufer Arne A Pichler Irene I Campbell Susan S Zaboli Ghazal G Kolcic Ivana I Rivadeneira Fernando F Huffman Jennifer J Hastie Nicholas D ND Uitterlinden Andre A Franke Lude L Franklin Christopher S CS Vitart Veronique V Nelson Christopher P CP Preuss Michael M Bis Joshua C JC O'Donnell Christopher J CJ Franceschini Nora N Witteman Jacqueline C M JC Axenovich Tatiana T Oostra Ben A BA Meitinger Thomas T Hicks Andrew A AA Hayward Caroline C Wright Alan F AF Gyllensten Ulf U Campbell Harry H Schmitz Gerd G

PLoS genetics 20120216 2

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 as ...[more]

PMID: 22359512

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Dataset Information

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

Publications

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

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