TY - JOUR
T1 - Genetic determinants of circulating sphingolipid concentrations in European populations
AU - Hicks, Andrew A.
AU - Pramstaller, Peter P.
AU - Johansson, Åsa
AU - Vitart, Veronique
AU - Rudan, Igor
AU - Ugocsai, Peter
AU - Aulchenko, Yurii
AU - Franklin, Christopher S.
AU - Liebisch, Gerhard
AU - Erdmann, Jeanette
AU - Jonasson, Inger
AU - Zorkoltseva, Irina V.
AU - Pattaro, Cristian
AU - Hayward, Caroline
AU - Isaacs, Aaron
AU - Hengstenberg, Christian
AU - Campbell, Susan
AU - Gnewuch, Carsten
AU - Janssens, A. Cecile J.W.
AU - Kirichenko, Anatoly V.
AU - König, Inke R.
AU - Marroni, Fabio
AU - Polasek, Ozren
AU - Demirkan, Ayse
AU - Kolcic, Ivana
AU - Schwienbacher, Christine
AU - Igl, Wilmar
AU - Biloglav, Zrinka
AU - Witteman, Jacqueline C.M.
AU - Pichler, Irene
AU - Zaboli, Ghazal
AU - Axenovich, Tatiana I.
AU - Peters, Annette
AU - Schreiber, Stefan
AU - Wichmann, H. Erich
AU - Schunkert, Heribert
AU - Hastie, Nick
AU - Oostra, Ben A.
AU - Wild, Sarah H.
AU - Meitinger, Thomas
AU - Gyllensten, Ulf
AU - Van Duijn, Cornelia M.
AU - Wilson, James F.
AU - Wright, Alan
AU - Schmitz, Gerd
AU - Campbell, Harry
PY - 2009/10
Y1 - 2009/10
N2 - 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 sphingolipidmetabolismare 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 b-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 matchedmetabolite ratiosmeasured 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 9.08610266. 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 in3 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=1024 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.
AB - 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 sphingolipidmetabolismare 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 b-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 matchedmetabolite ratiosmeasured 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 9.08610266. 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 in3 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=1024 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.
UR - http://www.scopus.com/inward/record.url?scp=73449117605&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1000672
DO - 10.1371/journal.pgen.1000672
M3 - Article
C2 - 19798445
AN - SCOPUS:73449117605
SN - 1553-7390
VL - 5
JO - PLoS Genetics
JF - PLoS Genetics
IS - 10
M1 - e1000672
ER -
