Signalling lipids of the N-acyl ethanolamine (NAE) and ceramide (CER) classes have emerged as potential biomarkers of cardiovascular disease (CVD). We sought to establish the heritability of plasma NAEs (including the endocannabinoid anandamide) and CERs, to identify common DNA variants influencing the circulating concentrations of the heritable lipids, and assess causality of these lipids in CVD using 2-sample Mendelian randomization (2SMR). Nine NAEs and 16 CERs were analyzed in plasma samples from 999 members of 196 British Caucasian families, using targeted ultra-performance liquid chromatography with tandem mass spectrometry. All lipids were significantly heritable (h2 = 36–62%). A missense variant (rs324420) in the gene encoding the enzyme fatty acid amide hydrolase (FAAH), which degrades NAEs, associated at genome-wide association study (GWAS) significance (P < 5 × 10−8) with four NAEs (DHEA, PEA, LEA and VEA). For CERs, rs680379 in the SPTLC3 gene, which encodes a subunit of the rate-limiting enzyme in CER biosynthesis, associated with a range of species (e.g. CER[N(24)S(19)]; P = 4.82 × 10−27). We observed three novel associations between SNPs at the CD83, SGPP1 and DEGS1 loci, and plasma CER traits (P < 5 × 10−8). 2SMR in the CARDIoGRAMplusC4D cohorts (60 801 cases; 123 504 controls) and in the DIAGRAM cohort (26 488 cases; 83 964 controls), using the genetic instruments from our family-based GWAS, did not reveal association between genetically determined differences in CER levels and CVD or diabetes. Two of the novel GWAS loci, SGPP1 and DEGS1, suggested a casual association between CERs and a range of haematological phenotypes, through 2SMR in the UK Biobank, INTERVAL and UKBiLEVE cohorts (n = 110 000–350 000).

中文翻译：

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N-酰基乙醇胺和神经酰胺血浆脂质组的遗传力和基于家族的 GWAS 分析

N-酰基乙醇胺 (NAE) 和神经酰胺 (CER) 类信号脂质已成为心血管疾病 (CVD) 的潜在生物标志物。我们试图确定血浆 NAE（包括内源性大麻素 anandamide）和 CER 的遗传力，以确定影响可遗传脂质循环浓度的常见 DNA 变异，并使用 2 样本孟德尔随机化 (2SMR) 评估这些脂质在 CVD 中的因果关系。使用靶向超高效液相色谱和串联质谱分析了来自 196 个英国白人家族 999 名成员的血浆样本中的 9 种 NAE 和 16 种 CER。所有脂质均具有显着遗传性（h2 = 36–62%）。编码脂肪酸酰胺水解酶 (FAAH) 的基因中的错义变体 (rs324420) 可降解 NAE，在全基因组关联研究 (GWAS) 显着性 (P < 5 × 10−8) 中与四种 NAE (DHEA) 相关、PEA、LEA 和 VEA）。对于 CER，SPTLC3 基因中的 rs680379 编码 CER 生物合成中限速酶的亚基，与一系列物种相关（例如 CER[N(24)S(19)]；P = 4.82 × 10−27 ）。我们观察到 CD83、SGPP1 和 DEGS1 位点的 SNP 与血浆 CER 特征之间的三种新关联（P < 5 × 10−8）。使用来自我们基于家庭的 GWAS 的遗传仪器，在 CARDIoGRAMplusC4D 队列（60 801 例；123 504 例对照）和 DIAGRAM 队列（26 488 例；83 964 例对照）中进行的 2SMR 并未揭示 CER 中遗传决定的差异之间的关联水平和 CVD 或糖尿病。通过英国生物库、INTERVAL 和 UKBiLEVE 队列（n = 110 000-350 000）中的 2SMR，两个新的 GWAS 基因座 SGPP1 和 DEGS1 表明 CER 与一系列血液学表型之间存在偶然关联。