Miller Christine L, Murakami Peter, Ruczinski Ingo, Ross Randal G, Sinkus Melissa, Sullivan Bernadette, Leonard Sherry
Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21227, USA.
Schizophr Res. 2009 Sep;113(2-3):259-67. doi: 10.1016/j.schres.2009.05.014. Epub 2009 Jun 6.
Prior studies of mRNA expression, protein expression, and pathway metabolite levels have implicated dysregulation of the kynurenine pathway in the etiology of schizophrenia and bipolar disorder. Here we investigate whether genes involved in kynurenine pathway regulation might interact with genes that respond to kynurenine metabolites, to enhance risk for these psychiatric phenotypes. Candidate genes were selected from prior studies of genetic association, gene expression profiling and animal models. A single nucleotide polymorphism (SNP) in each of six genes, TDO2, HM74, HM74A, MCHR1, MCHR2 and MC5R, was tested for association with phenotype (475 Caucasians, 88 African Americans with schizophrenia; 97 Caucasians, 3 African Americans with bipolar disorder; 191 Caucasian, 49 African American controls). An A allele in HM74 was significantly associated with schizophrenia and with schizophrenia plus bipolar disorder combined, odds ratios (OR) of 1.48, p=0.011 and 1.50, p=0.007, respectively. Augmentation of disease risk was found for the complex genotype HM74[A,any]+MCHR1[T,any]+MCHR2[C,any] which conferred an OR maximal for the combined diagnostic category of schizophrenia plus bipolar disorder (1.70, p=0.003), carried by 30% of the cases. TDO2[CC]+MC5R[G, any]+MCHR2[GC] conferred an OR maximal for schizophrenia alone (4.84, p=0.005), carried by 8% of schizophrenia cases. The combined risk posed by these related, complex genotypes is greater than any identified single locus and may derive from co-regulation of the kynurenine pathway by interacting genes, a lack of adequate melanotropin-controlled sequestration of the kynurenine-derived pigments, or the production of melanotropin receptor ligands through kynurenine metabolism.
先前关于mRNA表达、蛋白质表达及通路代谢物水平的研究表明，犬尿氨酸通路的失调与精神分裂症和双相情感障碍的病因有关。在此，我们研究参与犬尿氨酸通路调节的基因是否可能与对犬尿氨酸代谢物有反应的基因相互作用，从而增加这些精神疾病表型的风险。候选基因是从先前的遗传关联研究、基因表达谱分析和动物模型研究中挑选出来的。对六个基因（TDO2、HM74、HM74A、MCHR1、MCHR2和MC5R）中的每一个基因的单核苷酸多态性（SNP）进行了与表型的关联测试（475名高加索人、88名患有精神分裂症的非裔美国人；97名高加索人、3名患有双相情感障碍的非裔美国人；191名高加索人、49名非裔美国对照）。HM74基因中的A等位基因与精神分裂症以及精神分裂症合并双相情感障碍显著相关，优势比（OR）分别为1.48，p = 0.011和1.50，p = 0.007。发现复杂基因型HM74[A,any]+MCHR1[T,any]+MCHR2[C,any]会增加疾病风险，该基因型在精神分裂症合并双相情感障碍的联合诊断类别中具有最大的OR值（1.70，p = 0.003），30%的病例携带此基因型。TDO2[CC]+MC5R[G, any]+MCHR2[GC]在仅患有精神分裂症的患者中具有最大的OR值（4.84，p = 0.005），8%的精神分裂症病例携带此基因型。这些相关的复杂基因型所带来的综合风险大于任何已确定的单个基因座，可能源于相互作用的基因对犬尿氨酸通路的共同调节、犬尿氨酸衍生色素缺乏足够的促黑素控制的隔离，或通过犬尿氨酸代谢产生促黑素受体配体。
