Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations

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

Study populations.

<p>Values for age and lipid concentrations are presented as mean (standard deviation).</p

Genome-wide association results for 115 phospholipid species.

<p>(A) Genome-wide association results for plasma levels of 115 phospholipid species. (B) Genome-wide association results for within-class proportions of 115 plasma phospholipid species. Manhattan plots show the combined association signals (−log₁₀(<i>P</i>-value)) on the y-axis versus SNPs according to their position in the genome on the x-axis (NCBI build 36). Novel genes are represented in red, while previously known loci are represented in black.</p

Variants significantly associated with circulating sphingolipid levels and proportions.

<p><i>P</i>-value_Corrected: Genome-wide association p-value after adjustment for number of independent vectors; MAF: Minor Allele Frequency.</p><p>*Loci significantly associated to lipid levels after Bonferroni correction.</p>⋈<p>Loci associated to sphingolipids for the first time.</p><p><>\vskip -3\raster="rg1"<>Loci significantly (<i>P</i>-value<2.2×10⁻⁹) associated to within class sphingolipid ratios.</p

Genome-wide association results for 33 sphingolipid species.

<p>(A) Genome-wide association results for plasma levels of 33 sphingolipid species. (B) Genome-wide association results for within-class proportions of 33 sphingolipid species. Manhattan plots show the combined association signals (−log₁₀(<i>P</i>-value)) on the y-axis versus SNPs according to their position in the genome on the x-axis (NCBI build 36). Novel genes are represented in red, while previously known loci are represented in black.</p

Variants significantly associated with circulating phospholipid levels and proportions.

<p><i>P</i>-value_Corrected: Genome-wide association p-value after adjustment for number of independent vectors; MAF: Minor Allele Frequency.</p><p>*Loci significantly associated with lipid levels.</p>⋈<p>Loci associated with phospholipids for the first time.</p><p><>\vskip -3\raster="rg1"<>Loci significantly (<i>P</i>-value<2.2×10⁻⁹) associated with within-class phospholipid ratios.</p