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

doi:10.3969/j.issn.1674-8115.2021.01.005

Abstract

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

CLC Number:

R749.302

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

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

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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