Sellgren C M, Kegel M E, Bergen S E, Ekman C J, Olsson S, Larsson M, Vawter M P, Backlund L, Sullivan P F, Sklar P, Smoller J W, Magnusson P K E, Hultman C M, Walther-Jallow L, Svensson C I, Lichtenstein P, Schalling M, Engberg G, Erhardt S, Landén M
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Mol Psychiatry. 2016 Oct;21(10):1342-50. doi: 10.1038/mp.2015.186. Epub 2015 Dec 15.
Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.
源自胶质细胞的N-甲基-D-天冬氨酸受体拮抗剂犬尿喹啉酸（KYNA）的脑脊液（CSF）水平升高一直被认为与精神分裂症和双相情感障碍有关。在此，我们基于双相情感障碍患者的脑脊液KYNA进行了一项全基因组关联研究，发现1p21.3区域内的一个常见变异与之存在关联。在一个独立队列中进行重复验证后，我们将这个与分选衔接蛋白7（SNX7）表达降低相关的基因变异与双相情感障碍的阳性精神病性症状和执行功能缺陷联系起来。一系列尸检脑组织和体外实验表明，SNX7的下调会导致半胱天冬酶-8驱动的白细胞介素-1β激活，进而诱导脑犬尿氨酸途径。本研究证明了在精神疾病基因研究中使用生物标志物的潜力，并可能有助于确定双相情感障碍的新药物靶点。
