Abstract
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 β-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 9.08×10−66. 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.
Highlights
Sphingolipids are essential components of plasma membranes and endosomes and are believed to play critical roles in cell surface protection, protein and lipid transport and sorting, and cellular signalling cascades
The 4p12 locus showed the strongest association with serum glucosylceramides and the 20p12.1 locus showed the strongest association with serum ceramide concentrations
Direct experimental evidence indicates a role for sphingolipids 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 (T2D) [15]
Summary
Sphingolipids are essential components of plasma membranes and endosomes and are believed to play critical roles in cell surface protection, protein and lipid transport and sorting, and cellular signalling cascades. They are known to have roles in both health and disease [1,2]. Identifying common genetic variants that influence the balance between individual sphingolipid concentrations represents an important step towards understanding the contribution of sphingolipids to common human disease To achieve this goal, we conducted a genome-wide association study (GWAS) on plasma levels of 33 major sphingolipid species (24 sphingomyelins and 9 ceramides) in five European populations, both within and across populations. All traits displayed substantial heritabilities in that much of the observed variation in sphingolipid levels could be attributed to genetic variation among individuals in each population
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