上海交通大学学报（医学版）

上海交通大学学报（医学版） >

2021 , Vol. 41 >Issue 10: 1303 - 1307

DOI: https://doi.org/10.3969/j.issn.1674-8115.2021.10.005

论著 · 临床研究

CREB1基因与抑郁症和双相Ⅱ型障碍的关联研究

  • 施波 ,
  • 陈建民 ,
  • 赵俊雄 ,
  • 唐伟 ,
  • 范卫星 ,
  • 张程赪 ,
  • 张晨
展开
  • 1.浙江省金华市第二医院精神科，金华 321016
    2.温州医科大学附属康宁医院精神科，温州 325000
    3.广东省韶关市粤北第三人民医院精神科，韶关 512200
    4.上海交通大学医学院附属精神卫生中心心境障碍科，上海 200030
施 波（1980—），男，副主任医师，学士；电子信箱：shibojinhua@163.com。
张 晨，电子信箱：zhangchen645@gmail.com。

网络出版日期: 2021-09-22

基金资助

国家重点研发计划(2018YFC1314300);国家自然科学基金(81771450);金华市科学技术局项目(2015-3-063)

收起

Association study of CREB1 gene with depression and bipolar disorder typeⅡ

  • Bo SHI ,
  • Jian-min CHEN ,
  • Jun-xiong ZHAO ,
  • Wei TANG ,
  • Wei-xing FAN ,
  • Cheng-cheng ZHANG ,
  • Chen ZHANG
Expand
  • 1.Department of Psychiatry, Jinhua Second Hospital, Jinhua, Zhejiang 321016, China
    2.Department of Psychiatry, The Affiliated Kangning Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 32500, China
    3.Department of Psychiatry, Yuebei Third People's Hospital, Shaoguan, Guangdong 512200, China
    4.Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
ZHANG Chen, Email: zhangchen645@gmail.com.

Online published: 2021-09-22

Supported by

National Key Research and Development Plan(2018YFC1314300);National Natural Science Foundation of China(81771450);Project of Science and Technology Bureau of Jinhua(2015-3-063)

Fold

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

本文引用格式

施波 , 陈建民 , 赵俊雄 , 唐伟 , 范卫星 , 张程赪 , 张晨 . CREB1基因与抑郁症和双相Ⅱ型障碍的关联研究[J]. 上海交通大学学报（医学版）, 2021 , 41(10) : 1303 -1307 . DOI: 10.3969/j.issn.1674-8115.2021.10.005

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

参考文献

1 史一凡, 黄佳, 方贻儒. 吡格列酮抗抑郁作用研究进展[J]. 上海交通大学学报(医学版), 2019, 39(12): 1456-1459.
2 Patoz MC, Hidalgo-Mazzei D, Pereira B, et al. Patients' adherence to smartphone apps in the management of bipolar disorder: a systematic review[J]. Int J Bipolar Disord, 2021, 9(1): 19.
3 Perich T, Hadzi-Pavlovic D, Frankland A, et al. Are there subtypes of bipolar depression?[J]. Acta Psychiatr Scand, 2016, 134(3): 260-267.
4 Xiao X, Zhang C, Grigoroiu-Serbanescu M, et al. The cAMP responsive element-binding CREB1 gene increases risk of major psychiatric disorders[J]. Mol Psychiatry, 2018, 23(9): 1957-1967.
5 Tang W, Yang F, Lu WH, et al. Association study of CREB1 and CBP genes with Alzheimer's disease in Han Chinese[J]. Asia Pac Psychiatry, 2017, 9(3). Doi: 10.1111/appy.12274.
6 Li M, Liu S, D'Arcy C, et al. Interactions of childhood maltreatment and genetic variations in adult depression: a systematic review[J]. J Affect Disord, 2020, 276: 119-136.
7 Amidfar M, de Oliveira J, Kucharska E, et al. The role of CREB and BDNF in neurobiology and treatment of Alzheimer's disease[J]. Life Sci, 2020, 257: 118020.
8 Aguilar E, Monreal JA, Palao DJ. Pharmacogenetics in psychiatry: clinical case of resistant depression and a previous history of multiple adverse effects[J]. Actas Esp Psiquiatr, 2017, 45(6): 303-306.
9 Wang JQ, Mao L. The ERK pathway: molecular mechanisms and treatment of depression[J]. Mol Neurobiol, 2019, 56(9): 6197-6205.
10 刘晓华, 徐一峰, 崔东红, 等. 抑郁症与cAMP反应元件结合蛋白基因的关联研究[J]. 中华医学遗传学杂志, 2010, 27(3): 263-266.
11 Angelescu I, Brugger SP, Borgan F, et al. The magnitude and variability of brain structural alterations in bipolar disorder: a double meta-analysis of 5534 patients and 6651 healthy controls[J]. J Affect Disord, 2021, 291: 171-176.
12 Agah E, Asgari-Rad N, Ahmadi M, et al. Evaluating executive function in patients with temporal lobe epilepsy using the frontal assessment battery[J]. Epilepsy Res, 2017, 133: 22-27.
13 Wolf C, An Y, Tanaka T, et al. Cross-sectional and longitudinal effects of CREB1 genotypes on individual differences in memory and executive function: findings from the BLSA[J]. Front Aging Neurosci, 2017, 9: 142.
14 Zhao GQ, Zhang C, Chen J, et al. Ratio of mBDNF to proBDNF for differential diagnosis of major depressive disorder and bipolar depression[J]. Mol Neurobiol, 2017, 54(7): 5573-5582.
Options
文章导航

/

〈 〉