NOS1AP基因非编码区位点多态性与精神分裂症的关联研究

doi:10.3969/j.issn.1674-8115.2021.01.005

上海交通大学学报(医学版) ›› 2021, Vol. 41 ›› Issue (1): 29-34.doi: 10.3969/j.issn.1674-8115.2021.01.005

NOS1AP基因非编码区位点多态性与精神分裂症的关联研究

胡国芹¹(), 吕钦谕², 赵静², 朱明环³, 禹顺英², 易正辉²(), 陈健¹()

^1.上海市黄浦区精神卫生中心精神科，上海 200011
^2.上海交通大学医学院附属精神卫生中心精神科，上海 200030
^3.上海市浦东新区精神卫生中心精神科，上海 200122

出版日期:2021-01-28 发布日期:2021-02-22
通讯作者: 易正辉,陈健 E-mail:huguoqin1990@126.com;yizhenghui1971@163.com;chenjian20001967@163.com
作者简介:胡国芹（1990—），女，主治医师，硕士；电子信箱：huguoqin1990@126.com。
基金资助:
上海市黄浦区科学技术委员会科研计划项目(HKQ201813);上海市黄浦区卫生计生系统专业人才梯队培养计划(2019GG11);上海市卫生健康委员会科研课题(20194Y0406)

Association study of non-coding variant of NOS1AP gene with schizophrenia

Guo-qin HU¹(), Qin-yu LÜ², Jing ZHAO², Ming-huan ZHU³, Shun-ying YU², Zheng-hui YI²(), Jian CHEN¹()

^1.Psychiatry Department, Shanghai Mental Health Center of Huangpu District, Shanghai 200011, China
^2.Psychiatry Department, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
^3.Psychiatry Department, Shanghai Pudong New Area Mental Health Center, Shanghai 200122, China

Online:2021-01-28 Published:2021-02-22
Contact: Zheng-hui YI,Jian CHEN E-mail:huguoqin1990@126.com;yizhenghui1971@163.com;chenjian20001967@163.com
Supported by:
Funding Information] Scientific Research Project of Shanghai Huangpu District Science and Technology Commission(HKQ201813);Shanghai Huangpu District Health and Family Planning Professional Talent Echelon Training Plan(2019GG11);Scientific Research Project of Shanghai Municipal Health Committee(20194Y0406)

摘要/Abstract

摘要：

目的·明确一氧化氮合成酶1接头蛋白（nitric oxide synthase 1 adaptor protein，NOS1AP）基因与中国汉族人群精神分裂症患者的相关性，并对NOS1AP基因阳性多态性位点变异引起的RNA和蛋白质的二级结构改变进行预测。方法·选择2012年10月至2015年12月期间上海交通大学医学院附属精神卫生中心收治的333例早发性精神分裂症（early onset schizophrenia，EOS）患者和491例非早发性精神分裂症（non-early onset schizophrenia，non-EOS）患者，通过招募方式在上海交通大学医学院附属精神卫生中心的职工和复旦大学附属中山医院青浦分院体检中心的受检人群中筛选901名健康对照（health control，HC），用TaqMan探针检测3组人群NOS1AP基因rs12742393、rs4145621和rs1415263位点多态性。使用SHEsis在线软件进行各位点Hardy-Weinberg（H-W）平衡检验，分析等位基因和基因型频率的分布。通过SNPstats在线网站进行最优遗传模型的分析。利用RNAfold软件和DNAstar软件对阳性多态性位点变异引起的RNA和蛋白质的二级结构改变进行预测。结果·3个多态性位点基因型频率在各组中均符合H-W遗传平衡（P>0.05）。经Bonferroni校正后，EOS组与HC组相比，NOS1AP基因rs12742393位点等位基因和基因型频率分布差异均具有统计学意义（P=0.012，P=0.039）。遗传模型分析发现rs12742393位点最优基因型分布符合显性遗传模式（P=0.004）。软件预测发现，rs12742393位点A等位基因变异成C等位基因后，NOS1AP基因编码RNA和蛋白质的二级结构发生重要改变，导致空间稳定性下降。结论·NOS1AP基因非编码区rs12742393位点对EOS易感性存在重要影响。

关键词: 精神分裂症, 一氧化氮合成酶1接头蛋白基因, 多态性, 二级结构, 生物信息学

Abstract:

Objective·To clarify the correlation between nitric oxide synthase 1 adaptor protein (NOS1AP)gene and Han Chinese schizophrenia patients, and predict the changes in the secondary structure of RNA and protein caused by variation of NOS1AP gene positive polymorphism.

Methods·From October 2012 to December 2015, 333 patients with early onset schizophrenia (EOS) and 491 patients with non-early onset schizophrenia (non-EOS) were included from Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, and 901 healthy controls (HC) were selected from the staff of Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine and the people receiving physical examination in the Physical Examination Center of Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University through recruitment. The rs12742393, rs4145621 and rs1415263 polymorphisms of NOS1AP gene were detected by TaqMan probe. The Hardy-Weinberg (H-W) equilibrium of the three polymorphism loci and the allele and genotype frequencies were analyzed by the SHEsis online software. The optimal genetic model analysis was carried out by the SNPstats online website. RNAfold and DNAstar softwares were used to predict the secondary structures of RNA and protein encoded by the significantly different polymorphism locus.

Results·The distribution of genotypes fit H-W equilibrium(P>0.05). There were significant difference in allele and genotype frequencies between EOS patients and HC subjects for rs12742393 after Bonferroni correction (P=0.012, P=0.039). Genetic model analysis found that the distribution of genotypes best fit the dominant genetic pattern (P=0.004). After the mutation of the A allele into the C allele for rs12742393, the secondary structures of RNA and protein encoded by the NOS1AP gene underwent important changes, resulting in the decrease in spatial stability.

Conclusion·The NOS1AP rs12742393 polymorphism has a major influence on susceptibility to EOS.

Key words: schizophrenia, nitric oxide synthase 1 adaptor protein(NOS1AP) gene, polymorphism, secondary structure, bioinformatics

中图分类号:

R749.302

胡国芹, 吕钦谕, 赵静, 朱明环, 禹顺英, 易正辉, 陈健. NOS1AP基因非编码区位点多态性与精神分裂症的关联研究[J]. 上海交通大学学报(医学版), 2021, 41(1): 29-34.

Guo-qin HU, Qin-yu LÜ, Jing ZHAO, Ming-huan ZHU, Shun-ying YU, Zheng-hui YI, Jian CHEN. Association study of non-coding variant of NOS1AP gene with schizophrenia[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(1): 29-34.

Item	non-EOS (n=491)	EOS group (n=333)	HC group (n=901)	χ²/t value	df	P value
Male/female/n	251/240	180/153	462/439	0.83	2	0.663
Age/year	47.74±0.74	47.64±0.65	48.85±0.35	5.31	2	0.071

Item	non-EOS (n=491)	EOS group (n=333)	HC group (n=901)	χ²/t value	df	P value
Male/female/n	251/240	180/153	462/439	0.83	2	0.663
Age/year	47.74±0.74	47.64±0.65	48.85±0.35	5.31	2	0.071

Group	N	Genotype/n (%)				Allele/n (%)
Group	N	A/A	A/C	C/C	P value	A	C	OR (95%CI)	P value
EOS group	286	160 (55.94)	108 (37.76)	18 (6.29)	0.013^①	428 (74.83)	144 (25.17)	0.72 (0.58?0.90)	0.004^①
non-EOS group	491	300 (61.10)	172 (35.03)	19 (3.87)	0.181^②	772 (78.62)	210 (21.38)	0.81 (0.63?1.03)	0.086^②
HC group	872	572 (65.60)	259 (29.70)	41 (4.70)	0.116^③	1 403 (80.45)	341 (19.55)	0.89 (0.74?1.08)	0.253^③

Group	N	Genotype/n (%)				Allele/n (%)
Group	N	A/A	A/C	C/C	P value	A	C	OR (95%CI)	P value
EOS group	286	160 (55.94)	108 (37.76)	18 (6.29)	0.013^①	428 (74.83)	144 (25.17)	0.72 (0.58?0.90)	0.004^①
non-EOS group	491	300 (61.10)	172 (35.03)	19 (3.87)	0.181^②	772 (78.62)	210 (21.38)	0.81 (0.63?1.03)	0.086^②
HC group	872	572 (65.60)	259 (29.70)	41 (4.70)	0.116^③	1 403 (80.45)	341 (19.55)	0.89 (0.74?1.08)	0.253^③

Group	N	Genotype/n(%)				Allele/n(%)
Group	N	C/C	C/T	T/T	P value	C	T	OR(95%CI)	P value
EOS group	333	202 (60.66)	112 (33.63)	19 (5.71)	0.454^①	516 (77.48)	150 (22.52)	0.93 (0.75?1.14)	0.476^①
non-EOS group	332	190 (57.23)	128 (38.55)	14 (4.22)	0.335^②	508 (76.51)	156 (23.49)	1.05 (0.82?1.36)	0.674^②
HC group	901	545 (60.49)	313 (34.74)	43 (4.77)	0.775^③	1 403 (77.86)	399 (22.14)	0.98 (0.79?1.21)	0.840^③

NOS1AP基因非编码区位点多态性与精神分裂症的关联研究

Association study of non-coding variant of NOS1AP gene with schizophrenia

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Metrics

Model	EOS group /n (%)	HC group /n (%)	OR (95%CI)	P value	AIC
Codominant				0.014	1 290.10
C/C	18 (6.29)	41 (4.70)	1.00
A/C	108 (37.76)	259 (29.70)	0.67 (0.50?0.89)
A/A	160 (55.94)	572 (65.60)	0.64 (0.36?1.14)
Dominant				0.004	1 290.10
A/C+C/C	126 (44.06)	300 (34.40)	1.00
A/A	160 (55.94)	572 (65.60)	0.67 (0.51?0.87)
Recessive				0.300	1 297.50
C/C	18 (6.29)	41 (4.70)	1.00
A/A+A/C	268 (93.71)	831 (95.30)	0.73 (0.42?1.30)
Overdominant				0.012	1 292.30
A/A+C/C	178 (62.24)	613 (70.30)	1.00
A/C	108 (37.76)	259 (29.70)	0.70 (0.53?0.92)

rs12742393 allele	MHC class-Ⅰbinding ligand		MHC class-Ⅱbinding ligand
rs12742393 allele	Start position	Amino acid sequence	Start position	Amino acid sequence
A	50	SCTPYPPQE	50	SCTPYPPQE
C	50	ACTPYPPQE	50	ACTPYPPQE

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Group	N	Genotype/n(%)				Allele/n(%)
Group	N	C/C	C/T	T/T	P value	C	T	OR(95%CI)	P value
EOS group	258	71 (27.52)	123 (47.67)	64 (24.81)	0.967^①	265 (51.36)	251 (48.64)	1.00 (0.82?1.22)	0.964^①
non-EOS group	354	100 (28.25)	163 (46.05)	91 (25.70)	0.923^②	363 (51.27)	345 (48.73)	1.00 (0.80?1.26)	0.976^②
HC group	804	224 (27.86)	376 (46.77)	204 (25.37)	0.975^③	824 (51.24)	784 (48.76)	1.00 (0.84?1.19)	0.990^③

Group	N	Genotype/n(%)				Allele/n(%)
Group	N	C/C	C/T	T/T	P value	C	T	OR(95%CI)	P value
EOS group	258	71 (27.52)	123 (47.67)	64 (24.81)	0.967^①	265 (51.36)	251 (48.64)	1.00 (0.82?1.22)	0.964^①
non-EOS group	354	100 (28.25)	163 (46.05)	91 (25.70)	0.923^②	363 (51.27)	345 (48.73)	1.00 (0.80?1.26)	0.976^②
HC group	804	224 (27.86)	376 (46.77)	204 (25.37)	0.975^③	824 (51.24)	784 (48.76)	1.00 (0.84?1.19)	0.990^③