期刊
PLOS GENETICS
卷 8, 期 2, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1002490
关键词
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资金
- European Commission [018947 (LSHG-CT-2006-01947), 2007-202272]
- Netherlands Organisation for Scientific Research [NWO-RFBR 047.017.043]
- Russian Foundation for Basic Research [NWO-RFBR 047.017.043]
- Netherlands Organisation for Scientific Research (Pionier) [047.016.009, 047.017.043]
- Centre for Medical Systems Biology (CMSB
- National Genomics Initiative)
- Erasmus MC
- Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano
- South Tyrolean Sparkasse Foundation
- Swedish Natural Sciences Research Council
- Swedish Medical Research Council
- European Commission through EUROSPAN
- Foundation for Strategic Research (SSF)
- Linneaus Centre for Bioinformatics (LCB)
- Scottish Executive Health Department
- Royal Society
- Wellcome Trust Clinical Research Facility in Edinburgh
- Medical Research Council UK
- Ministry of Science, Education, and Sport of the Republic of Croatia [108-1080315-0302]
- MRC [MC_PC_U127561128, MC_U127561128] Funding Source: UKRI
- Chief Scientist Office [CZB/4/710] Funding Source: researchfish
- Medical Research Council [MC_U127561128, MC_U106179471, MC_PC_U127561128] Funding Source: researchfish
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 x 10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10 x 10(-57)). After a correction for multiple comparisons (P-value, 2.2 x 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.
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