<br>SLC1A2 的遗传变异与前扣带皮层谷氨酸升高和快速循环的终生病史有关。,Translational Psychiatry

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SLC1A2 的遗传变异与前扣带皮层谷氨酸升高和快速循环的终生病史有关。
Translational Psychiatry ( IF 5.8 ) Pub Date : 2019-05-23 , DOI: 10.1038/s41398-019-0483-9
Marin Veldic ₁ , Vincent Millischer _{2,

3} , John D Port ₄ , Ada Man-Choi Ho ₅ , Yun-Fang Jia ₅ , Jennifer R Geske ₆ , Joanna M Biernacka _{1,

6} , Lena Backlund _{2,

3} , Susan L McElroy ₇ , David J Bond ₈ , J Carlos Villaescusa _{2,

3} , Michelle Skime ₁ , Doo-Sup Choi _{1,

5} , Catharina Lavebratt _{2,

3} , Martin Schalling _{2,

3} , Mark A Frye ₁

Affiliation

谷氨酸能失调与情绪障碍的神经生物学有关。本研究调查了通过质子磁共振波谱（1H-MRS）测量的前扣带皮层（AC）谷氨酸与来自四个基因（GLUL、SLC1A3、SLC1A2 和 SLC1A7）的单核苷酸多态性（SNP）之间的关系，这些基因调节 26 名重度抑郁症（MDD;n = 15）和双相情感障碍（BD;n = 11）的抑郁症患者。两个 SNP （rs3812778 和 rs3829280），在 EAAT2 基因 SLC1A2 的 3' 非翻译区处于完美的连锁不平衡状态，与 AC 谷氨酸相关，与共同等位基因纯合子相比，次要等位基因携带者具有显着更高的谷氨酸水平（p < 0.001）。计算机分析显示 rs3812778/rs382920 的次要等位基因携带者与 11 号染色体上 SLC1A2 下游的星形胶质细胞标志物 CD44 的上调有关。最后，我们在一大群抑郁症患者中测试了这些 SNP 的疾病相关性 [MDD （n = 458）;BD （n = 1473）] 并发现次要等位基因携带者快速循环的风险显着升高（p = 0.006）。鼓励进一步的工作来描述兴奋性氨基酸转运蛋白遗传变异对 CD44 相关生理学和谷氨酸能神经传递的功能影响，特别是谷氨酸-谷氨酰胺循环，及其对情绪障碍亚表型的贡献。

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Genetic variant in SLC1A2 is associated with elevated anterior cingulate cortex glutamate and lifetime history of rapid cycling.

Glutamatergic dysregulation is implicated in the neurobiology of mood disorders. This study investigated the relationship between the anterior cingulate cortex (AC) glutamate, as measured by proton magnetic resonance spectroscopy (1H-MRS), and single-nucleotide polymorphisms (SNPs) from four genes (GLUL, SLC1A3, SLC1A2, and SLC1A7) that regulate the extracellular glutamate in 26 depressed patients with major depressive disorder (MDD; n = 15) and bipolar disorder (BD; n = 11). Two SNPs (rs3812778 and rs3829280), in perfect linkage disequilibrium, in the 3' untranslated region of the EAAT2 gene SLC1A2, were associated with AC glutamate, with minor allele carriers having significantly higher glutamate levels (p < 0.001) in comparison with common allele homozygotes. In silico analysis revealed an association of minor allele carriers of rs3812778/rs382920 with an upregulation of the astrocytic marker CD44 localized downstream of SLC1A2 on chromosome 11. Finally, we tested the disease relevance of these SNPs in a large group of depressed patients [MDD (n = 458); BD (n = 1473)] and found that minor allele carriers had a significantly higher risk for rapid cycling (p = 0.006). Further work is encouraged to delineate the functional impact of excitatory amino acid transporter genetic variation on CD44 associated physiology and glutamatergic neurotransmission, specifically glutamate-glutamine cycling, and its contribution to subphenotypes of mood disorders.

更新日期：2019-05-23

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