摘要： 目的·探讨
CREB1基因与抑郁症和双相Ⅱ型障碍的相关性。方法·共纳入抑郁症患者362例，双相Ⅱ型障碍患者381例以及健康志愿者416例。抑郁症组、双相Ⅱ型障碍组分别与健康对照组比较，其性别、年龄及受教育年限间的差异均无统计学意义。采用汉密尔顿抑郁量表评估抑郁症患者的严重程度，轻躁狂症状清单筛查抑郁症和双相Ⅱ型障碍患者的既往躁狂发作史；采集每位入组对象的静脉血2 mL，采用离心柱型基因组DNA试剂盒提取外周血白细胞全基因组DNA；使用单碱基延伸法（SNaPshot）单核苷酸多态性（single nucleotide polymorphism，SNP）分型技术对
CREB1基因标签SNP rs10932201和rs3770704位点进行分型；利用BRAINEAC数据库分析SNP对脑内
CREB1基因表达的影响。结果·抑郁症组、双相Ⅱ型障碍组与对照组
CREB1基因rs10932201和rs3770704位点基因型的观察值和期望值Hardy-Weinberg平衡吻合度均良好（
P>0.05）；连锁不平衡分析结果显示rs10932201和rs3770704位点之间具有较强的连锁不平衡，且位于同一区块内（
r2>0.4）。在
CREB1基因rs10932201位点，双相Ⅱ型障碍组与对照组等位基因分布频率相比，差异具有统计学意义（
χ2=4.27，
P=0.042）；抑郁症组与对照组等位基因分布频率相比，差异无统计学意义。抑郁症组、双相Ⅱ型障碍组分别与对照组基因型分布频率比较，差异均无统计学意义。在
CREB1基因rs3770704位点，无论是等位基因还是基因型分布频率，抑郁症组、双相Ⅱ型障碍组分别与对照组比较，差异均无统计学意义；
CREB1基因rs10932201和rs3770704位点之间构建的单倍型中，A-T单倍型在双相Ⅱ型障碍组中分布频率为57.5%，具有统计学意义（
χ2=4.07，
P=0.044）；表达数量性状分析结果显示rs10932201位点在颞叶皮层内与
CREB1基因表达显著相关（
P=0.048）。结论·
CREB1基因rs10932201位点与双相Ⅱ型障碍有关，可能是双相Ⅱ型障碍发生的风险因子，但与抑郁症无关。
关键词: CREB1基因, 抑郁症, 双相Ⅱ型障碍, 多态性, 表达数量性状分析 Abstract: Objective·To study the association of CREB1 gene with depression and bipolar disorder type Ⅱ.
Methods·Three hundred and sixty-two patients with depression, 381 patients with bipolar disorder type Ⅱ and 416 healthy subjects were included. There were no significant differences in gender, age and year of education between depression group, bipolar disorder type Ⅱ group and control group. Patients with severity of depression were evaluated by Hamilton Depression Rating Scale. Hypomania Check List-32 was used to screen the history of hypomanic episode of patients with depression and patients with bipolar disorder type Ⅱ. A total of 2 mL of venous blood was collected from each subject, and whole genome of peripheral blood leukocyte DNA was extracted using a centrifugal column genomic DNA kit. Single nucleotide polymorphism (SNP) genotyping of SNaPshot was used to identify the rs10932201 and rs3770704 loci of CREB1 gene, and the effects of SNP on CREB1 expression in brain were analyzed using BRAINEAC database.
Results·The genotypes of rs10932201 and rs3770704 of CREB1 gene in the depression group, bipolar disorder type Ⅱ group and control group were well matched with Hardy-Weinberg equilibrium (P>0.05). Linkage disequilibrium analysis showed that there was a strong linkage disequilibrium between rs10932201 and rs3770704 (r2>0.4). At the rs10932201 locus of CREB1 gene, there was a significant difference in allelic frequency between the bipolar disorder type Ⅱ group and the control group (χ2=4.27, P=0.042); there was no difference in allelic frequency between the depression group and the control group. There were no significant differences in either allelic or genotypic frequency of rs3770704 of CREB1 gene in the depression group and bipolar disorder type Ⅱ group compared with the control group. In the haplotype constructed between rs10932201 and rs3770704 of CREB1 gene, the frequency of haplotype A-T in the bipolar disorder type Ⅱ group was 57.5%, which was statistically significant (χ2=4.07,P=0.044). Expression quantitative trait loci analysis showed that rs10932201 was associated with CREB1 gene expression in temporal cortex (P=0.048).
Conclusion·The rs10932201 of CREB1 gene is associated with bipolar disorder type Ⅱ, and may be a risk factor for bipolar disorder type Ⅱ, not depression.
Key words: CREB1 gene, depression, bipolar disorder type Ⅱ, polymorphism, expression quantitative trait loci PDF全文下载地址:
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