Multivariate permutation analysis associates multiple polymorphisms with subphenotypes of major depression
Multivariate permutation analysis associates multiple polymorphisms with subphenotypes of major depression
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DOI：
10.1111/j.1601-183x.2007.00384.x
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发表时间：
2008-06-01
影响因子：
2.5
通讯作者：
Shelton, R.
中科院分区：
文献类型：
--
作者：
Hahn, M. K.;Blackford, J. U.;Shelton, R.
单极重性抑郁症（MDD）是一种普遍的致残疾病，多种遗传和环境因素影响疾病风险。MDD的诊断依赖于来自多个特征维度的累积测量，单独在阐明MDD遗传决定因素方面是有限的。我们和其他人提出，使用评估特定基因如何与MDD的组成特征相关联的范式，可以更好地剖析MDD。这种疾病内设计既需要一个表型良好的队列，也需要一个强大的统计方法，该方法在多种遗传关联测试中保持效力。在本研究中，研究人员对110例单极型重度抑郁症患者进行了基因分型，分析了与体外功能改变或体内抑郁相关的中枢单胺能和胆碱能通路相关的常见基因多态性变异。亚表型特征采用精神障碍诊断与统计手册（DSM IV）结构化临床访谈、17项汉密尔顿抑郁评定量表（HAM-D）和NEO五因素量表对个别项目进行评估。多变量排列测试（MPT）被用来推断基因型-表型之间的关系，这些关系是临床类别中维度发现的基础。MPT分析显示，去甲肾上腺素转运蛋白(NET, SLC6A2) -182 T/C （rs2242446）与复发性抑郁有显著相关性[比值比，OR = 4.15 (1.91 - 9.02)], NET -3081 A/T （rs28386840）与食欲增加有显著相关性[比值比= 3.58(1.53 - 8.39)]，突触前胆碱转运蛋白（CHT, SLC5A7） Ile89Val （rs1013940）与HAM-D-17总分{即。总体抑郁严重程度[OR = 2.74(1.05 - 7.18)]}。这些关系说明了一种阐明基因对重度抑郁症特征成分的影响及其复制的方法，可能有助于确定可以从更有针对性的药物治疗中受益的重度抑郁症亚群。
Unipolar major depressive disorder (MDD) is a prevalent, disabling condition with multiple genetic and environmental factors impacting disease risk. The diagnosis of MDD relies on a cumulative measure derived from multiple trait dimensions and alone is limited in elucidating MDD genetic determinants. We and others have proposed that MDD may be better dissected using paradigms that assess how specific genes associate with component features of MDD. This within-disease design requires both a well-phenotyped cohort and a robust statistical approach that retains power with multiple tests of genetic association. In the present study, common polymorphic variants of genes related to central monoaminergic and cholinergic pathways that previous studies align with functional change in vitro or depression associations in vivo were genotyped in 110 individuals with unipolar MDD. Subphenotypic characteristics were examined using responses to individual items assessed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM IV), the 17-item Hamilton Rating Scale for Depression (HAM-D) and the NEO Five Factor Inventory. Multivariate Permutation Testing (MPT) was used to infer genotype-phenotype relationships underlying dimensional findings within clinical categories. MPT analyses show significant associations of the norepinephrine transporter (NET, SLC6A2) -182 T/C (rs2242446) with recurrent depression [odds ratio, OR = 4.15 (1.91 - 9.02)], NET -3081 A/T (rs28386840) with increase in appetite [OR = 3.58 (1.53 - 8.39)] and the presynaptic choline transporter (CHT, SLC5A7) Ile89Val (rs1013940) with HAM-D-17 total score {i.e. overall depression severity [OR = 2.74 (1.05 - 7.18)]}. These relationships illustrate an approach to the elucidation of gene influences on trait components of MDD and with replication, may help identify MDD subpopulations that can benefit from more targeted pharmacotherapy.