title: 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.
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ayşe
authors.initials: A
authors.lastname: Demirkan
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Peter
authors.initials: P
authors.lastname: Ugocsai
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: Gerhard
authors.initials: G
authors.lastname: Liebisch
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.forename: Åsa
authors.initials: Å
authors.lastname: Johansson
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.forename: Anatoly V
authors.initials: AV
authors.lastname: Kirichenko
authors.forename: A Cecile J W
authors.initials: AC
authors.lastname: Janssens
authors.forename: Ritsert C
authors.initials: RC
authors.lastname: Jansen
authors.forename: Carsten
authors.initials: C
authors.lastname: Gnewuch
authors.forename: Francisco S
authors.initials: FS
authors.lastname: Domingues
authors.forename: Cristian
authors.initials: C
authors.lastname: Pattaro
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Wild
authors.forename: Inger
authors.initials: I
authors.lastname: Jonasson
authors.forename: Ozren
authors.initials: O
authors.lastname: Polasek
authors.forename: Irina V
authors.initials: IV
authors.lastname: Zorkoltseva
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Lennart C
authors.initials: LC
authors.lastname: Karssen
authors.forename: Maksim
authors.initials: M
authors.lastname: Struchalin
authors.forename: James
authors.initials: J
authors.lastname: Floyd
authors.forename: Wilmar
authors.initials: W
authors.lastname: Igl
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Biloglav
authors.forename: Linda
authors.initials: L
authors.lastname: Broer
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.forename: Irene
authors.initials: I
authors.lastname: Pichler
authors.forename: Susan
authors.initials: S
authors.lastname: Campbell
authors.forename: Ghazal
authors.initials: G
authors.lastname: Zaboli
authors.forename: Ivana
authors.initials: I
authors.lastname: Kolcic
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Jennifer
authors.initials: J
authors.lastname: Huffman
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.forename: Andre
authors.initials: A
authors.lastname: Uitterlinden
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Franklin
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.forename: Michael
authors.initials: M
authors.lastname: Preuss
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Jacqueline C M
authors.initials: JC
authors.lastname: Witteman
authors.forename: Tatiana
authors.initials: T
authors.lastname: Axenovich
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hicks
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
mesh_terms: D059168:Carotid Intima-Media Thickness; D030541:Databases, Genetic; D000090943:Delta-5 Fatty Acid Desaturase; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics; D056426:Genetic Loci; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D010743:Phospholipids / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013107:Sphingolipids / Q000097:blood / Q000235:genetics; D044465:White People / Q000235:genetics*
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D010743:Phospholipids; D013107:Sphingolipids; C000716847:FADS1 protein, human