CREB1基因与抑郁症和双相Ⅱ型障碍的关联研究

doi:10.3969/j.issn.1674-8115.2021.10.005

上海交通大学学报(医学版) ›› 2021, Vol. 41 ›› Issue (10): 1303-1307.doi: 10.3969/j.issn.1674-8115.2021.10.005

CREB1基因与抑郁症和双相Ⅱ型障碍的关联研究

施波¹(), 陈建民¹, 赵俊雄¹, 唐伟², 范卫星¹, 张程赪³, 张晨⁴()

^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

出版日期:2021-10-28 发布日期:2021-09-22
通讯作者: 张晨 E-mail:shibojinhua@163.com;zhangchen645@gmail.com
作者简介:施波（1980—），男，副主任医师，学士；电子信箱：shibojinhua@163.com。
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)

Association study of CREB1 gene with depression and bipolar disorder typeⅡ

Bo SHI¹(), Jian-min CHEN¹, Jun-xiong ZHAO¹, Wei TANG², Wei-xing FAN¹, Cheng-cheng ZHANG³, Chen ZHANG⁴()

^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

Online:2021-10-28 Published:2021-09-22
Contact: Chen ZHANG E-mail:shibojinhua@163.com;zhangchen645@gmail.com
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)

摘要/Abstract

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

中图分类号:

R749.4

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.

Bo SHI, Jian-min CHEN, Jun-xiong ZHAO, Wei TANG, Wei-xing FAN, Cheng-cheng ZHANG, Chen ZHANG. Association study of CREB1 gene with depression and bipolar disorder typeⅡ[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(10): 1303-1307.

图/表 5

图1 抑郁症组和双相Ⅱ型障碍组CREB1基因标签SNP位点之间的连锁不平衡

Fig 1 Linkage disequilibrium between the tagSNPs of CREB1 gene in the depression group and bipolar disorder type Ⅱ group

表1 抑郁症和双相Ⅱ型障碍组分别与对照组CREB1基因rs10932201基因型和等位基因频率分布比较（n，%）

Tab 1 Comparison of genotypic and allelic frequencies in rs10932201 loci of CREB1 gene between the depression， bipolar Ⅱ disorder and control groups， respectively （n， %）

SNP	Depression group/n （%）	Bipolar Ⅱ disorder group/n （%）	Control group/n （%）	χ²/P value （depression group vs control group）	χ²/P value （bipolar Ⅱ disorder group vs control group）
Genotype				1.03/0.603	5.36/0.069
G/G	50 （13.9）	64 （17.0）	48 （11.5）
G/A	176 （48.8）	182 （48.3）	204 （49.0）
A/A	135 （37.4）	131 （34.7）	164 （39.4）
Allele				0.78/0.378	4.27/0.042
G	276 （38.2）	310 （41.1）	300 （36.1）
A	446 （61.8）	444 （58.9）	532 （63.9）

表2 抑郁症和双相Ⅱ型障碍组分别与对照组CREB1基因rs3770704位点基因型和等位基因频率分布比较（n，%）

Tab 2 Comparison of genotypic and allelic frequencies in rs3770704 loci of CREB1 gene between the depression， bipolar Ⅱ disorder and control groups， respectively （n， %）

SNP	Depression group/n （%）	Bipolar Ⅱ disorder group/n （%）	Control group/n （%）	χ²/P value （depression group vs control group）	χ²/P value （bipolar II disorder group vs control group）
Genotype				3.30/0.193	4.33/0.113
C/C	23 （6.4）	31 （8.2）	19 （4.6）
C/T	149 （41.6）	135 （35.6）	155 （37.4）
T/T	186 （52.0）	213 （56.2）	240 （58.0）
Allele				3.14/0.081	1.16/0.218
C	195 （27.2）	197 （26.0）	193 （23.3）
T	521 （72.8）	561 （74.0）	635 （76.7）

表3 CREB1基因rs10932201和rs3770704位点单倍型与抑郁症和双相Ⅱ型障碍的相关性

Tab 3 Association of CREB1 gene rs10932201 and rs3770704 haplotypes with depression and bipolar Ⅱ disorder groups

Haplotype rs10932201 and rs3770704	Depression group/%	Control group/%	χ² value	P value	Bipolar Ⅱ disorder group/%	Control group/%	χ² value	P value
A-T	61.5	62.3	0.70	0.430	57.5	62.3	4.07	0.044
G-C	23.6	21.7	3.54	0.059	21.7	21.7	1.84	0.176
G-T	13.4	14.4	1.27	0.215	14.4	14.4	1.36	0.258
A-C	1.5	1.6	0.01	0.942	1.4	1.6	0.06	0.797

图2 rs10932201位点对各脑区CREB1基因表达的影响Note：SNIG—substantia nigra, PUTM—putamen, MEDU—medulla,THAL—thalamus, OCTX—occipital cortex, HIPP—hippocampus, FCTX—frontal cortex, WHMT—intralobular white matter, CRBL—cerebellar cortex.

Fig 2 Effect of rs10932201 on expression of CREB1 gene in different brain regions

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CREB1基因与抑郁症和双相Ⅱ型障碍的关联研究

Association study of CREB1 gene with depression and bipolar disorder typeⅡ

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