A variant near DHCR24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents.,Molecular Psychiatry

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A variant near DHCR24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents.
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2020-01-03 , DOI: 10.1038/s41380-019-0640-9
Eeva Sliz _{1,

2,

3} , Jean Shin _{1,

2} , Catriona Syme _{1,

2} , Yash Patel ₄ , Nadine Parker ₄ , Louis Richer ₅ , Daniel Gaudet ₆ , Steffany Bennett ₇ , Tomas Paus _{4,

8} , Zdenka Pausova _{1,

2}

Affiliation

Visceral adiposity has been associated with altered microstructural properties of white matter in adolescents. Previous evidence suggests that circulating phospholipid PC(16:0/2:0) may mediate this association. To investigate the underlying biology, we performed a genome-wide association study (GWAS) of the shared variance of visceral fat, PC(16:0/2:0), and white matter microstructure in 872 adolescents from the Saguenay Youth Study. We further studied the metabolomic profile of the GWAS-lead variant in 931 adolescents. Visceral fat and white matter microstructure were assessed with magnetic resonance imaging. Circulating metabolites were quantified with serum lipidomics and metabolomics. We identified a genome-wide significant association near DHCR24 (Seladin-1) encoding a cholesterol-synthesizing enzyme (rs588709, p = 3.6 × 10-8); rs588709 was also associated nominally with each of the three traits (white matter microstructure: p = 2.1 × 10-6, PC(16:0/2:0): p = 0.005, visceral fat: p = 0.010). We found that the metabolic profile associated with rs588709 resembled that of a TM6SF2 variant impacting very low-density lipoprotein (VLDL) secretion and was only partially similar to that of a HMGCR variant. This suggests that the effect of rs588709 on VLDL lipids may arise due to altered phospholipid rather than cholesterol metabolism. The rs588709 was also nominally associated with circulating concentrations of omega-3 fatty acids in interaction with visceral fat and PC(16:0/2:0), and these fatty acid measures showed robust associations with white matter microstructure. Overall, the present study provides evidence that the DHCR24 locus may link peripheral metabolism to brain microstructure, an association with implications for cognitive impairment.

中文翻译：

DHCR24 附近的一个变异与青少年白质和外周脂质代谢的微观结构特性相关。

内脏肥胖与青少年白质微观结构特性的改变有关。先前的证据表明循环磷脂 PC(16:0/2:0) 可能介导这种关联。为了研究潜在的生物学原理，我们对 Saguenay Youth Study 的 872 名青少年的内脏脂肪、PC(16:0/2:0) 和白质微结构的共同方差进行了全基因组关联研究 (GWAS)。我们进一步研究了 931 名青少年的 GWAS-先导变异的代谢组学特征。通过磁共振成像评估内脏脂肪和白质微观结构。通过血清脂质组学和代谢组学对循环代谢物进行定量。我们在编码胆固醇合成酶的 DHCR24 (Seladin-1) 附近发现了全基因组显着关联 (rs588709，p = 3.6 × 10-8)；rs588709 名义上也与这三个特征中的每一个相关（白质微观结构：p = 2.1 × 10-6，PC（16:0/2:0）：p = 0.005，内脏脂肪：p = 0.010）。我们发现与 rs588709 相关的代谢谱与影响极低密度脂蛋白 (VLDL) 分泌的 TM6SF2 变体的代谢谱相似，并且与 HMGCR 变体的代谢谱仅部分相似。这表明 rs588709 对 VLDL 脂质的影响可能是由于磷脂而不是胆固醇代谢的改变而产生的。rs588709 名义上还与与内脏脂肪和 PC(16:0/2:0) 相互作用的 omega-3 脂肪酸循环浓度相关，并且这些脂肪酸测量结果显示与白质微观结构有很强的相关性。总体而言，本研究提供的证据表明 DHCR24 位点可能将外周代谢与大脑微观结构联系起来，这种关联与认知障碍有关。

更新日期：2020-01-04

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