谷氨酸通路基因多态性交互作用与快感缺失的关联研究

doi:10.3969/j.issn.1674-8115.2024.05.005

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (5): 576-583.doi: 10.3969/j.issn.1674-8115.2024.05.005

• 论著 · 基础研究 • 上一篇

谷氨酸通路基因多态性交互作用与快感缺失的关联研究

黄欣欣¹^,²(), 刘超³, 吕钦谕⁴, 胡国芹⁵, 鲍晨曦⁶, 张瑶², 易正辉²()

^1.南京医科大学附属脑科医院精神三科，南京 210029
^2.上海交通大学医学院附属精神卫生中心临床八科，上海 201108
^3.江苏省南通市第四人民医院精神二科，南通 226000
^4.上海交通大学医学院附属精神卫生中心临床六科，上海 201108
^5.上海市徐汇区精神卫生中心精神科，上海 200232
^6.南京医科大学附属脑科医院儿童心理卫生研究中心，南京 210029

收稿日期:2023-11-29 接受日期:2024-05-16 出版日期:2024-05-28 发布日期:2024-05-28
通讯作者: 易正辉 E-mail:xinxinhuang1994@163.com;yizhenghui1971@163.com
作者简介:黄欣欣（1994—），女，住院医师，博士；电子信箱：xinxinhuang1994@163.com。
基金资助:
科技部科技创新2030—“脑科学与类脑研究”重大项目(2022ZD0208500);2022年度南京市卫生科技发展专项资金资助项目(YKK22133);2023—2025年南京脑科医院青年人才项目(23-25-2R10);2022年江苏省“双创博士”计划(JSSCBS20221916);2022年南通市科学技术局社会民生面上项目(MS22022098);2023年南通市卫生健康委员会指令性青年课题(QN2023041)

Relationship between polymorphic interaction of glutamate pathway genes and anhedonia

HUANG Xinxin¹^,²(), LIU Chao³, LÜ Qinyu⁴, HU Guoqin⁵, BAO Chenxi⁶, ZHANG Yao², YI Zhenghui²()

^1.Department of Third Psychiatry Ward, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China
^2.Eighth Clinical Department, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, China
^3.Department of Second Psychiatry Ward, Nantong Fourth People′s Hospital, Jiangsu Province, Nantong 226000, China
^4.Sixth Clinical Department, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, China
^5.Department of Psychiatry, Shanghai Xuhui District Mental Health Center, Shanghai 200232, China
^6.Child Mental Health Research Center, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China

Received:2023-11-29 Accepted:2024-05-16 Online:2024-05-28 Published:2024-05-28
Contact: YI Zhenghui E-mail:xinxinhuang1994@163.com;yizhenghui1971@163.com
Supported by:
MOST 2030 Brain Project(2022ZD0208500);Medical Science and Technology Development Foundation, Nanjing Department of Health in 2022(YKK22133);Nanjing Brain Hospital Young Talent Program Project(23-25-2R10);Jiangsu Provincial Innovation Doctoral Program in 2022(JSSCBS20221916);Social and Livelihood General Project of Nantong Science and Technology Bureau in 2022(MS22022098);Mandatory Youth Project of Nantong Health Commission in 2023(QN2023041)

摘要/Abstract

摘要：

目的·探究谷氨酸通路基因-基因交互作用与快感缺失的关联。方法·纳入2017年1月—2020年8月在上海交通大学医学院附属精神卫生中心门诊及病房招募的279例精神分裂症（schizophrenia，SZ）患者、236例重型抑郁障碍（major depression disorder，MDD）患者，以及在社区招募的236例健康对照（healthy control，HC）为研究对象。收集并比较3组被试的一般人口学资料及临床特征。采用时间性愉快体验量表（Temporal Experience of Pleasure Scale，TEPS）中文版评估3组的愉快体验能力。采用广义多因子降维（generalized multifactor dimensionality reduction，GMDR）法建立谷氨酸通路基因（NOS1AP、GSK3β、DAOA、DISC1及GRIN2A）单核苷酸多态性（single nucleotide polymorphism，SNP）交互作用模型，依据该模型将SZ及MDD患者分为高风险组和低风险组，并对其愉快体验能力的差异进行组间比较，以分析基因-基因交互作用对快感缺失的影响。结果·年龄、受教育年限在3组间的差异具有统计学意义，首发年龄、病程在SZ、MDD组间的差异具有统计学意义（均P=0.000）。3组被试在总体愉快体验、期待性愉快体验及即时性愉快体验间差异均具有统计学意义（均P=0.000）；SZ、MDD组患者的总体愉快体验、期待性及即时性愉快体验均低于HC组（均P_校正=0.000），且SZ与MDD组在期待性愉快体验上具有边缘性统计学差异（P_校正=0.051）。通过GMDR建模发现，由DAOA-rs3916965与DISC1-rs821577组成的2位点交互作用模型对SZ患者总体愉快体验能力具有预测作用（P=0.003），由NOS1AP-rs1858232和GRIN2A-rs1014531组成的2位点交互作用模型对MDD患者期待性愉快体验能力具有预测作用（P=0.037）；且SZ高风险组患者的总体愉快体验能力、MDD高风险组患者的期待性愉快体验能力均分别低于其低风险组（t=3.443，P=0.000；t=3.471，P=0.001）。结论·谷氨酸通路基因多态性交互作用可能参与了快感缺失的发生。

关键词: 快感缺失, 谷氨酸通路, 广义多因子降维, 交互作用

Abstract:

Objective ·To explore the association between gene-gene interaction of glutamate pathway and anhedonia. Methods ·A total of 279 patients with schizophrenia (SZ) and 236 patients with major depression disorder (MDD) recruited in the outpatient department and ward of Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, and 236 healthy controls (HC) recruited in the community from January 2017 to August 2020 were included in the study. General demographic data and clinical characteristics of the three groups were collected and compared. The Chinese version of Temporal Experience of Pleasure Scale (TEPS) was used to evaluate the pleasure experience ability of the three groups. Generalized multifactor dimensionality reduction (GMDR) method was used to establish the interaction model of the single nucleotide polymorphism (SNP) in glutamate pathway genes (NOS1AP, GSK3β, DAOA, DISC1 and GRIN2A). According to the interaction model, SZ and MDD patients were divided into high-risk group and low-risk group, and the differences in pleasure experience ability were compared between the two groups, so as to analyze the effect of gene-gene interaction on anhedonia. Results ·There were significant differences in age and years of education among the three groups, and in age of onset and duration of illness between SZ and MDD groups (all P=0.000). There were significant differences among the three groups of participants in terms of overall pleasure experience, anticipatory pleasure experience and consummatory pleasure experience (all P=0.000); the overall pleasure experience, anticipatory pleasure experience and consummatory pleasure experience in the SZ and MDD group were lower than those in the HC group (all P_corr =0.000), and there was marginal statistical difference in anticipatory pleasure experience between the SZ and MDD groups (P_corr=0.051). Through GMDR modeling, it was found that the 2-loci interaction model composed of DAOA-rs3916965 and DISC1-rs821577 had a predictive effect on the overall pleasure experience ability of SZ patients (P=0.003), and the 2-loci interaction model composed of NOS1AP-rs1858232 and GRIN2A-rs1014531 had a predictive effect on the anticipatory pleasure experience ability of MDD patients (P=0.037); moreover, the overall pleasure experience ability of patients in the SZ high-risk group and anticipatory pleasure experience ability of patients in MDD high-risk groups were lower than those in their low-risk groups (t=3.443, P=0.000; t=3.471, P=0.001). Conclusion ·The interaction of glutamate pathway gene polymorphisms may be involved in the occurrence of anhedonia.

Key words: anhedonia, glutamate pathway, generalized multifactor dimensionality reduction (GMDR), interaction effect

中图分类号:

R749

黄欣欣, 刘超, 吕钦谕, 胡国芹, 鲍晨曦, 张瑶, 易正辉. 谷氨酸通路基因多态性交互作用与快感缺失的关联研究[J]. 上海交通大学学报（医学版）, 2024, 44(5): 576-583.

HUANG Xinxin, LIU Chao, LÜ Qinyu, HU Guoqin, BAO Chenxi, ZHANG Yao, YI Zhenghui. Relationship between polymorphic interaction of glutamate pathway genes and anhedonia[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(5): 576-583.

图/表 5

表1 3组被试的一般人口学资料、临床特征及快感缺失水平的比较

Tab 1 Comparison of general demographic data， clinical characteristics and anhedonia levels among the three groups of participants

Item	SZ group (n=279)	MDD group (n=236)	HC group (n=236)	χ²/Z/F value	P value
Gender/n(%)				4.757	0.093
Male	146 (52.3)	104 (44.1)	125 (53.0)
Female	133 (47.7)	132 (55.9)	111 (47.0)
Age/year	24.5 (19.0, 31.0)^①,④	27.0 (22.0, 33.0)^②	32.0 (24.0, 57.3)	76.941	0.000
Years of education/year	12.0 (9.4, 15.0)^①,④	15.0 (12.0, 15.0)^②	16.0 (12.6, 17.0)	78.504	0.000
Age of onset/year	19.0 (16.0, 24.0)	25.0 (20.0, 31.0)	‒	-7.125	0.000
Duration of illness/month	23.0 (7.5, 60.0)	6.0 (2.0, 24.0)	‒	-6.712	0.000
Number of episodes	1.0 (1.0, 1.0)	1.0 (1.0, 1.0)	‒	-0.309	0.757
TEPS total score/score	72.3±13.3^①	66.8±16.0^②,③	81.7±12.9	26.028	0.000
Anticipatory	34.0 (30.0, 38.0)^①	30.0 (24.0, 37.0)^②	37.0 (33.0, 43.0)	34.729	0.000
Abstract anticipatory	18.0 (14.0, 20.0)^①	15.0 (11.5, 19.0)^②,③	20.0 (18.0, 22.0)	51.744	0.000
Contextual anticipatory	16.0 (14.0, 19.0)	15.0 (13.0, 19.0)^②	18.0 (14.8, 21.0)	9.606	0.008
Consummatory	39.0 (34.0, 44.0)^①	38.0 (30.5, 42.5)^②	44.0 (38.8, 50.0)	34.277	0.000
Abstract consummatory	24.5±5.3^①	22.5±6.3^②,③	27.7±4.6	20.481	0.000
Contextual consummatory	14.0 (11.5, 17.0) ^①	15.0 (11.5, 16.5)^②	17.0 (14.0, 19.0)	22.299	0.000

表2 5个候选基因的17个SNPs的信息

Tab 2 Information on the 17 SNPs for the five candidate genes

Candidate gene	SNP	Chromosome	Position	Alleles	MAF	Feature
NOS1AP	rs12742393	1q23.3	162224586	C/A	0.32	Intron2
	rs1415259		162085309	C/T	0.42	Intron1
	rs1415263		162166043	C/T	0.48	Intron2
	rs1858232		162303838	G/A	0.33	Intron5
	rs348624		162335256	C/T	0.25	Synonymous_exon9
	rs6680461		162255286	G/T	0.39	Intron2
GSK3β	rs334558	3q13.33	119813282	G/A	0.40	5′-flanking
	rs6779828		119775147	C/T	0.28	Intron1
DAOA	rs3916965	13q33.2	106103360	C/T	0.36	Intergenic region
	rs778294		106142235	C/T	0.22	Synonymous_exon4
	rs947267		106139662	G/T	0.49	Intron3
DISC1	rs1538979	1q42.2	231896868	C/T	0.24	Intron4
	rs821577		232067057	G/T	0.38	Intron9
	rs821633		232148933	C/T	0.41	Intron11
	rs999710		232010943	G/A	0.40	Intron9
GRIN2A	rs1014531	16p13.2	9855794	G/A	0.27	3′-UTR
	rs1420040		9850397	G/A	0.42	3′-UTR

图1 GMDR分析预测SZ患者总体愉快体验能力的最优2位点交互作用模型Note： The best identified model. In each cell, the left bar represents a positive score, and the right bar represents a negative score. High-risk cells are indicated by dark shading, and low-risk cells are indicated by light shading. Cells (representing genotype combinations) are categorized into ‘high’ and ‘low’ risk when the sum of the score is above and below zero, respectively.

Fig 1 The best 2-loci interaction model for predicting the overall pleasure experience ability of SZ patients by GMDR analysis

图2 SZ和MDD患者高、低风险组总体、期待性愉快体验能力比较Note： A. Comparison of the overall pleasure experience ability of SZ patients between the high-risk group and low-risk group. B. Comparison of the anticipatory pleasure experience ability of MDD patients between the high-risk group and low-risk group.

Fig 2 Comparison of the overall and anticipatory pleasure experience ability between high-risk and low-risk group of the SZ and MDD patients

图3 GMDR分析预测MDD患者期待性愉快体验能力的最优2位点交互作用模型Note： The best identified model. In each cell, the left bar represents a positive score, and the right bar represents a negative score. High-risk cells are indicated by dark shading, and low-risk cells are indicated by light shading. Cells (representing genotype combinations) are categorized into ‘high’ and ‘low’ risk when the sum of the score is above and below zero, respectively.

Fig 3 The best 2-loci interaction model for predicting the anticipatory pleasure experience ability of MDD patients by GMDR analysis

参考文献 29

1	LAMBERT C, SILVA S D, CENITI A K, et al. Anhedonia in depression and schizophrenia: a transdiagnostic challenge[J]. CNS Neurosci Ther, 2018, 24(7): 615-623.
2	BERRIDGE K C, KRINGELBACH M L. Affective neuroscience of pleasure: reward in humans and animals[J]. Psychopharmacology, 2008, 199(3): 457-480.
3	LEE Y, SON H, KIM G, et al. Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice[J]. J Psychiatry Neurosci, 2013, 38(3): 183-191.
4	KÜÇÜKIBRAHIMOĞLU E, SAYGIN M Z, CALIŞKAN M, et al. The change in plasma GABA, glutamine and glutamate levels in fluoxetine- or S-citalopram-treated female patients with major depression[J]. Eur J Clin Pharmacol, 2009, 65(6): 571-577.
5	VEERMAN S R T, SCHULTE P F J, DE HAAN L. The glutamate hypothesis: a pathogenic pathway from which pharmacological interventions have emerged[J]. Pharmacopsychiatry, 2014, 47(4/5): 121-130.
6	BELFORTE J E, ZSIROS V, SKLAR E R, et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes[J]. Nat Neurosci, 2010, 13(1): 76-83.
7	ZHANG M M, KONG X R, CHEN J, et al. Dysfunction of GluN3A subunit is involved in depression-like behaviors through synaptic deficits[J]. J Affect Disord, 2023, 332: 72-82.
8	SERRETTI A. Anhedonia and depressive disorders[J]. Clin Psychopharmacol Neurosci, 2023, 21(3): 401-409.
9	CHUMAKOV I, BLUMENFELD M, GUERASSIMENKO O, et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia[J]. Proc Natl Acad Sci U S A, 2002, 99(21): 13675-13680.
10	AUTRY A E, ADACHI M, NOSYREVA E, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses[J]. Nature, 2011, 475(7354): 91-95.
11	WEI J, GRAZIANE N M, WANG H T, et al. Regulation of N-methyl-D-aspartate receptors by disrupted-in-schizophrenia-1[J]. Biol Psychiatry, 2014, 75(5): 414-424.
12	SEIRA O, DEL RÍO J A. Glycogen synthase kinase 3 beta (GSK3β) at the tip of neuronal development and regeneration[J]. Mol Neurobiol, 2014, 49(2): 931-944.
13	CHEN M H, KAO C F, TSAI S J, et al. Treatment response to low-dose ketamine infusion for treatment-resistant depression: a gene-based genome-wide association study[J]. Genomics, 2021, 113(2): 507-514.
14	HU G Q, YANG C Q, ZHAO L, et al. The interaction of NOS1AP, DISC1, DAOA, and GSK3B confers susceptibility of early-onset schizophrenia in Chinese Han population[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2018, 81: 187-193.
15	LI Z, SHI H S, ELIS O, et al. The structural invariance of the Temporal Experience of Pleasure Scale across time and culture[J]. Psych J, 2018, 7(2): 59-67.
16	CHAN R C, SHI Y F, LAI M K, et al. The Temporal Experience of Pleasure Scale (TEPS): exploration and confirmation of factor structure in a healthy Chinese sample[J]. PLoS One, 2012, 7(4): e35352.
17	CHAN R C, WANG Y, HUANG J, et al. Anticipatory and consummatory components of the experience of pleasure in schizophrenia: cross-cultural validation and extension[J]. Psychiatry Res, 2010, 175(1/2): 181-183.
18	JAGANNATH V, THEODORIDOU A, GERSTENBERG M, et al. Prediction analysis for transition to schizophrenia in individuals at clinical high risk for psychosis: the relationship of DAO, DAOA, and NRG1 variants with negative symptoms and cognitive deficits[J]. Front Psychiatry, 2017, 8: 292.
19	TOMPPO L, HENNAH W, MIETTUNEN J, et al. Association of variants in DISC1 with psychosis-related traits in a large population cohort[J]. Arch Gen Psychiatry, 2009, 66(2): 134-141.
20	CHEAH S Y, LAWFORD B R, YOUNG R M, et al. Association of NOS1AP variants and depression phenotypes in schizophrenia[J]. J Affect Disord, 2015, 188: 263-269.
21	LOU X Y, CHEN G B, YAN L, et al. A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence[J]. Am J Hum Genet, 2007, 80(6): 1125-1137.
22	HOU T T, LIN F, BAI S S, et al. Generalized multifactor dimensionality reduction approaches to identification of genetic interactions underlying ordinal traits[J]. Genet Epidemiol, 2019, 43(1): 24-36.
23	HUANG Y Q, WANG Y, WANG H, et al. Prevalence of mental disorders in China: a cross-sectional epidemiological study[J]. Lancet Psychiatry, 2019, 6(3): 211-224.
24	LI Y H, MOU X D, JIANG W H, et al. A comparative study of anhedonia components between major depression and schizophrenia in Chinese populations[J]. Ann Gen Psychiatry, 2015, 14: 24.
25	MEI H, CUCCARO M L, MARTIN E R. Multifactor dimensionality reduction-phenomics: a novel method to capture genetic heterogeneity with use of phenotypic variables[J]. Am J Hum Genet, 2007, 81(6): 1251-1261.
26	WANG X Y, HE G, GU N F, et al. Association of G72/G30 with schizophrenia in the Chinese population[J]. Biochem Biophys Res Commun, 2004, 319(4): 1281-1286.
27	TUOMINEN H J, TIIHONEN J, WAHLBECK K. Glutamatergic drugs for schizophrenia[J]. Cochrane Database Syst Rev, 2006(2): CD003730.
28	YAZIR Y, UTKAN T, ARICIOGLU F. Inhibition of neuronal nitric oxide synthase and soluble guanylate cyclase prevents depression-like behaviour in rats exposed to chronic unpredictable mild stress[J]. Basic Clin Pharmacol Toxicol, 2012, 111(3): 154-160.
29	DOUCET M V, LEVINE H, DEV K K, et al. Small-molecule inhibitors at the PSD-95/nNOS interface have antidepressant-like properties in mice[J]. Neuropsychopharmacology, 2013, 38(8): 1575-1584.

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谷氨酸通路基因多态性交互作用与快感缺失的关联研究

Relationship between polymorphic interaction of glutamate pathway genes and anhedonia

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