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.
Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy.
Andrew A
AA
Hicks
Peter P
PP
Pramstaller
Asa
A
Johansson
Veronique
V
Vitart
Igor
I
Rudan
Peter
P
Ugocsai
Yurii
Y
Aulchenko
Christopher S
CS
Franklin
Gerhard
G
Liebisch
Jeanette
J
Erdmann
Inger
I
Jonasson
Irina V
IV
Zorkoltseva
Cristian
C
Pattaro
Caroline
C
Hayward
Aaron
A
Isaacs
Christian
C
Hengstenberg
Susan
S
Campbell
Carsten
C
Gnewuch
A Cecilej W
AC
Janssens
Anatoly V
AV
Kirichenko
Inke R
IR
König
Fabio
F
Marroni
Ozren
O
Polasek
Ayse
A
Demirkan
Ivana
I
Kolcic
Christine
C
Schwienbacher
Wilmar
W
Igl
Zrinka
Z
Biloglav
Jacqueline C M
JC
Witteman
Irene
I
Pichler
Ghazal
G
Zaboli
Tatiana I
TI
Axenovich
Annette
A
Peters
Stefan
S
Schreiber
H-Erich
HE
Wichmann
Heribert
H
Schunkert
Nick
N
Hastie
Ben A
BA
Oostra
Sarah H
SH
Wild
Thomas
T
Meitinger
Ulf
U
Gyllensten
Cornelia M
CM
van Duijn
James F
JF
Wilson
Alan
A
Wright
Gerd
G
Schmitz
Harry
H
Campbell
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