Perlis Roy H, Smoller Jordan W, Ferreira Manuel A R, McQuillin Andrew, Bass Nick, Lawrence Jacob, Sachs Gary S, Nimgaonkar Vishwajit, Scolnick Edward M, Gurling Hugh, Sklar Pamela, Purcell Shaun
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Am J Psychiatry. 2009 Jun;166(6):718-25. doi: 10.1176/appi.ajp.2009.08111633. Epub 2009 May 15.
Lithium remains a first-line treatment for bipolar disorder, but the mechanisms by which it prevents the recurrence of mood episodes are not known. The authors utilized data from a genomewide association study to examine associations between single nucleotide polymorphisms (SNPs) and the outcome of lithium treatment in two cohorts of patients with bipolar I disorder or bipolar II disorder.
The hazard for mood episode recurrence was examined among 1,177 patients with bipolar I disorder or bipolar II disorder, including 458 individuals treated with lithium carbonate or citrate, who were participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort. SNPs showing the greatest evidence of association in Cox regression models were then examined for association with positive lithium response among 359 bipolar I or II disorder patients treated with lithium carbonate or citrate in a second cohort from the University College London.
The strongest association in the STEP-BD cohort (minimum p=5.5 x 10(-7)) was identified for a region on chromosome 10p15 (rs10795189). Of the regions showing suggestive evidence (p<5 x 10(-4)) of association with lithium response, five were further associated with positive lithium response in the University College London cohort, including SNPs in a region on chromosome 4q32 spanning a gene coding for the glutamate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) receptor GRIA2.
Multiple novel loci merit further examination for association with lithium response in bipolar disorder patients, including one region that spans the GRIA2 gene, for which expression has been shown to be regulated by lithium treatment.
锂盐仍然是双相情感障碍的一线治疗药物，但其预防情绪发作复发的机制尚不清楚。作者利用全基因组关联研究的数据，在两组I型或II型双相情感障碍患者中检验单核苷酸多态性（SNP）与锂盐治疗结果之间的关联。
在1177例I型或II型双相情感障碍患者中检查情绪发作复发的风险，其中458例接受碳酸锂或枸橼酸锂治疗，这些患者是双相情感障碍系统治疗强化项目（STEP - BD）队列的参与者。然后，在伦敦大学学院的第二个队列中，对359例接受碳酸锂或枸橼酸锂治疗的I型或II型双相情感障碍患者，检查在Cox回归模型中显示出最强关联证据的SNP与锂盐阳性反应之间的关联。
在STEP - BD队列中，10号染色体10p15区域（rs10795189）的关联最为显著（最小p = 5.5×10⁻⁷）。在显示出与锂盐反应有提示性关联证据（p < 5×10⁻⁴）的区域中，有五个区域在伦敦大学学院队列中与锂盐阳性反应进一步相关，包括4号染色体4q32区域的SNP，该区域跨越一个编码谷氨酸/α - 氨基 - 3 - 羟基 - 5 - 甲基 - 4 - 异恶唑丙酸（AMPA）受体GRIA2的基因。
多个新位点值得进一步研究其与双相情感障碍患者锂盐反应的关联，包括一个跨越GRIA2基因的区域，其表达已被证明受锂盐治疗调控。
