Genetic determinants of circulating sphingolipid concentrations in European populations.
Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08x10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases.
Hicks
Andrew A
AA
Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy.
Pramstaller
Peter P
PP
Johansson
Asa
A
Vitart
Veronique
V
Rudan
Igor
I
Ugocsai
Peter
P
Aulchenko
Yurii
Y
Franklin
Christopher S
CS
Liebisch
Gerhard
G
Erdmann
Jeanette
J
Jonasson
Inger
I
Zorkoltseva
Irina V
IV
Pattaro
Cristian
C
Hayward
Caroline
C
Isaacs
Aaron
A
Hengstenberg
Christian
C
Campbell
Susan
S
Gnewuch
Carsten
C
Janssens
A Cecilej W
AC
Kirichenko
Anatoly V
AV
König
Inke R
IR
Marroni
Fabio
F
Polasek
Ozren
O
Demirkan
Ayse
A
Kolcic
Ivana
I
Schwienbacher
Christine
C
Igl
Wilmar
W
Biloglav
Zrinka
Z
Witteman
Jacqueline C M
JC
Pichler
Irene
I
Zaboli
Ghazal
G
Axenovich
Tatiana I
TI
Peters
Annette
A
Schreiber
Stefan
S
Wichmann
H-Erich
HE
Schunkert
Heribert
H
Hastie
Nick
N
Oostra
Ben A
BA
Wild
Sarah H
SH
Meitinger
Thomas
T
Gyllensten
Ulf
U
van Duijn
Cornelia M
CM
Wilson
James F
JF
Wright
Alan
A
Schmitz
Gerd
G
Campbell
Harry
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000090943:Delta-5 Fatty Acid Desaturase; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013107:Sphingolipids / Q000097:blood*; D044465:White People / Q000235:genetics*; D055815:Young Adult
D000090943:Delta-5 Fatty Acid Desaturase; D013107:Sphingolipids; C000716847:FADS1 protein, human