Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations
Open Access
- 16 February 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 8 (2), e1002490
- https://doi.org/10.1371/journal.pgen.1002490
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−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. Phospho- and sphingolipids are integral to membrane formation and are involved in crucial cellular functions such as signalling, membrane fluidity, membrane protein trafficking, neurotransmission, and receptor trafficking. In addition to severe monogenic diseases resulting from defective phospho- and sphingolipid function and metabolism, the evidence suggests that variations in these lipid levels at the population level are involved in the determination of cardiovascular and neurologic traits and subsequent disease. We took advantage of modern laboratory methods, including microarray-based genotyping and electrospray ionization tandem mass spectrometry, to hunt for genetic variation influencing the levels of more than 350 phospho- and sphingolipid phenotypes. We identified nine novel loci, in addition to confirming a number of previously described loci. Several other genetic regions provided substantial evidence of their involvement in these traits. All of these loci are strong candidates for further research in the field of lipid biology and are likely to yield considerable insights into the complex metabolic pathways underlying circulating phospho- and sphingolipid levels. Understanding these mechanisms might help to illuminate factors leading to the development of common cardiovascular and neurological diseases and might provide molecular targets for the development of new therapies.Keywords
This publication has 41 references indexed in Scilit:
- Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaqueNature Genetics, 2011
- Large-scale association analysis identifies 13 new susceptibility loci for coronary artery diseaseNature Genetics, 2011
- MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypesGenetic Epidemiology, 2010
- Biological, clinical and population relevance of 95 loci for blood lipidsNature, 2010
- METAL: fast and efficient meta-analysis of genomewide association scansBioinformatics, 2010
- Twelve type 2 diabetes susceptibility loci identified through large-scale association analysisNature Genetics, 2010
- Biological pathway analysis by ArrayUnlock and Ingenuity Pathway AnalysisBMC Proceedings, 2009
- Lattices, rafts, and scaffolds: domain regulation of receptor signaling at the plasma membraneThe Journal of cell biology, 2009
- ConsensusPathDB—a database for integrating human functional interaction networksNucleic Acids Research, 2008
- Membrane lipids: where they are and how they behaveNature Reviews Molecular Cell Biology, 2008