TY - JOUR
T1 - Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations
AU - Demirkan, Ayse
AU - van Duijn, Cornelia M
AU - Ugocsai, Peter
AU - Isaacs, Aaron
AU - Pramstaller, Peter P
AU - Liebisch, Gerhard
AU - Wilson, James F
AU - Johansson, Åsa
AU - Rudan, Igor
AU - Aulchenko, Yurii S
AU - Kirichenko, Anatoly V
AU - Janssens, A Cecile J W
AU - Jansen, Ritsert C
AU - Gnewuch, Carsten
AU - Domingues, Francisco S
AU - Pattaro, Cristian
AU - Wild, Sarah H
AU - Jonasson, Inger
AU - Polasek, Ozren
AU - Zorkoltseva, Irina V
AU - Hofman, Albert
AU - Karssen, Lennart C
AU - Struchalin, Maksim
AU - Floyd, James
AU - Igl, Wilmar
AU - Biloglav, Zrinka
AU - Broer, Linda
AU - Pfeufer, Arne
AU - Pichler, Irene
AU - Campbell, Susan
AU - Zaboli, Ghazal
AU - Kolcic, Ivana
AU - Rivadeneira, Fernando
AU - Huffman, Jennifer
AU - Hastie, Nicholas D
AU - Uitterlinden, Andre
AU - Franke, Lude
AU - Franklin, Christopher S
AU - Vitart, Veronique
AU - Nelson, Christopher P
AU - Preuss, Michael
AU - Bis, Joshua C
AU - O'Donnell, Christopher J
AU - Franceschini, Nora
AU - Witteman, Jacqueline C M
AU - Axenovich, Tatiana
AU - Oostra, Ben A
AU - Meitinger, Thomas
AU - Hicks, Andrew A
AU - Hayward, Caroline
AU - DIAGRAM Consortium
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Carotid Intima-Media Thickness
KW - Databases, Genetic
KW - Diabetes Mellitus, Type 2/blood
KW - European Continental Ancestry Group/genetics
KW - Genetic Loci
KW - Genome, Human
KW - Genome-Wide Association Study
KW - Humans
KW - Phospholipids/blood
KW - Polymorphism, Single Nucleotide
KW - Sphingolipids/blood
U2 - 10.1371/journal.pgen.1002490
DO - 10.1371/journal.pgen.1002490
M3 - Article
C2 - 22359512
SN - 1553-7390
VL - 8
SP - e1002490
JO - Plos Genetics
JF - Plos Genetics
IS - 2
ER -