Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations.
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...
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2012-01-01
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doaj-1056cf3c6b034729babb9ff6cf53a0342020-11-25T02:49:23ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-01-0182e100249010.1371/journal.pgen.1002490Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations.Ayşe DemirkanCornelia M van DuijnPeter UgocsaiAaron IsaacsPeter P PramstallerGerhard LiebischJames F WilsonÅsa JohanssonIgor RudanYurii S AulchenkoAnatoly V KirichenkoA Cecile J W JanssensRitsert C JansenCarsten GnewuchFrancisco S DominguesCristian PattaroSarah H WildInger JonassonOzren PolasekIrina V ZorkoltsevaAlbert HofmanLennart C KarssenMaksim StruchalinJames FloydWilmar IglZrinka BiloglavLinda BroerArne PfeuferIrene PichlerSusan CampbellGhazal ZaboliIvana KolcicFernando RivadeneiraJennifer HuffmanNicholas D HastieAndre UitterlindenLude FrankeChristopher S FranklinVeronique VitartDIAGRAM ConsortiumChristopher P NelsonMichael PreussCARDIoGRAM ConsortiumJoshua C BisChristopher J O'DonnellNora FranceschiniCHARGE ConsortiumJacqueline C M WittemanTatiana AxenovichBen A OostraThomas MeitingerAndrew A HicksCaroline HaywardAlan F WrightUlf GyllenstenHarry CampbellGerd SchmitzEUROSPAN consortiumPhospho- 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.http://europepmc.org/articles/PMC3280968?pdf=render |
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language |
English |
format |
Article |
sources |
DOAJ |
author |
Ayşe Demirkan Cornelia M van Duijn Peter Ugocsai Aaron Isaacs Peter P Pramstaller Gerhard Liebisch James F Wilson Åsa Johansson Igor Rudan Yurii S Aulchenko Anatoly V Kirichenko A Cecile J W Janssens Ritsert C Jansen Carsten Gnewuch Francisco S Domingues Cristian Pattaro Sarah H Wild Inger Jonasson Ozren Polasek Irina V Zorkoltseva Albert Hofman Lennart C Karssen Maksim Struchalin James Floyd Wilmar Igl Zrinka Biloglav Linda Broer Arne Pfeufer Irene Pichler Susan Campbell Ghazal Zaboli Ivana Kolcic Fernando Rivadeneira Jennifer Huffman Nicholas D Hastie Andre Uitterlinden Lude Franke Christopher S Franklin Veronique Vitart DIAGRAM Consortium Christopher P Nelson Michael Preuss CARDIoGRAM Consortium Joshua C Bis Christopher J O'Donnell Nora Franceschini CHARGE Consortium Jacqueline C M Witteman Tatiana Axenovich Ben A Oostra Thomas Meitinger Andrew A Hicks Caroline Hayward Alan F Wright Ulf Gyllensten Harry Campbell Gerd Schmitz EUROSPAN consortium |
spellingShingle |
Ayşe Demirkan Cornelia M van Duijn Peter Ugocsai Aaron Isaacs Peter P Pramstaller Gerhard Liebisch James F Wilson Åsa Johansson Igor Rudan Yurii S Aulchenko Anatoly V Kirichenko A Cecile J W Janssens Ritsert C Jansen Carsten Gnewuch Francisco S Domingues Cristian Pattaro Sarah H Wild Inger Jonasson Ozren Polasek Irina V Zorkoltseva Albert Hofman Lennart C Karssen Maksim Struchalin James Floyd Wilmar Igl Zrinka Biloglav Linda Broer Arne Pfeufer Irene Pichler Susan Campbell Ghazal Zaboli Ivana Kolcic Fernando Rivadeneira Jennifer Huffman Nicholas D Hastie Andre Uitterlinden Lude Franke Christopher S Franklin Veronique Vitart DIAGRAM Consortium Christopher P Nelson Michael Preuss CARDIoGRAM Consortium Joshua C Bis Christopher J O'Donnell Nora Franceschini CHARGE Consortium Jacqueline C M Witteman Tatiana Axenovich Ben A Oostra Thomas Meitinger Andrew A Hicks Caroline Hayward Alan F Wright Ulf Gyllensten Harry Campbell Gerd Schmitz EUROSPAN consortium Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations. PLoS Genetics |
author_facet |
Ayşe Demirkan Cornelia M van Duijn Peter Ugocsai Aaron Isaacs Peter P Pramstaller Gerhard Liebisch James F Wilson Åsa Johansson Igor Rudan Yurii S Aulchenko Anatoly V Kirichenko A Cecile J W Janssens Ritsert C Jansen Carsten Gnewuch Francisco S Domingues Cristian Pattaro Sarah H Wild Inger Jonasson Ozren Polasek Irina V Zorkoltseva Albert Hofman Lennart C Karssen Maksim Struchalin James Floyd Wilmar Igl Zrinka Biloglav Linda Broer Arne Pfeufer Irene Pichler Susan Campbell Ghazal Zaboli Ivana Kolcic Fernando Rivadeneira Jennifer Huffman Nicholas D Hastie Andre Uitterlinden Lude Franke Christopher S Franklin Veronique Vitart DIAGRAM Consortium Christopher P Nelson Michael Preuss CARDIoGRAM Consortium Joshua C Bis Christopher J O'Donnell Nora Franceschini CHARGE Consortium Jacqueline C M Witteman Tatiana Axenovich Ben A Oostra Thomas Meitinger Andrew A Hicks Caroline Hayward Alan F Wright Ulf Gyllensten Harry Campbell Gerd Schmitz EUROSPAN consortium |
author_sort |
Ayşe Demirkan |
title |
Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations. |
title_short |
Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations. |
title_full |
Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations. |
title_fullStr |
Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations. |
title_full_unstemmed |
Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations. |
title_sort |
genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2012-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3280968?pdf=render |
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