These authors contributed equally to this work.
Schizophrenia is one of the most devastating neuropsychiatric disorders. Genetic epidemiological studies have confirmed that schizophrenia is a genetic disease. Genes promoting neurodevelopment may be potential candidates for schizophrenia. As an adaptor linking a number of tyrosine kinase receptors in multiple intracellular signaling cascades, Src homology 2 domain containing transforming protein 3 (
An independent case-control association study was performed in a sample including 710 schizophrenia patients and 1314 healthy controls from a Northeast Chinese Han population.
The allelic and genotypic association analyses showed that four SNPs in
Our present results suggest
Schizophrenia is one of the most devastating neuropsychiatric disorders with a lifetime prevalence of about 1% worldwide. It is characterized by a breakdown in cognition and emotion along with characteristic positive (i.e., hallucinations, delusions, or disorganized speech and thoughts) and negative (i.e., apathy, alogia, or avolition) symptoms [
Genetic epidemiological studies have confirmed that schizophrenia is a genetic disease with heritability estimates of approximately 80% [
With the advancement of molecular biology techniques and methods for obtaining genetic data, the screening and research of candidate genes for schizophrenia have entered a period of rapid development. Candidate genes for schizophrenia are genes that have obtained some evidence that they may be associated with schizophrenia. Src homology 2 domain-containing transforming protein 3 (SHC3), also known as
Previous study have shown that SHC3 as a critical hub for neurotrophic pathways control of neuronal metabolism and functions in the adulthood, such as Alzheimer disease and other metabolic and degeneratibe CNS diseases, like Parkinson’s disease and glaucoma [
Subjects were all recruited in the Northeast China from Department of Psychiatry, Dalian Seventh People’s Hospital, P.R. China, and unrelated Chinese Han nationality born. The sample set included 710 schizophrenia patients (334 males and 376 females; mean age: 29.92±9.95 years) and 1,314 healthy controls (658 males and 656 females; mean age: 27.90±9.39 years). The consensus diagnoses were made by at least two experienced psychiatrists according to the diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria [
The SNPs were selected by downloading the information of all the SNPs within and neighboring the human
Nine single nucleotide polymorphisms (SNPs) in the human
Deviation of the genotypes from the Hardy-Weinberg equilibrium was examined by a χ2 goodness-of-fit test (
According to the GTEx database, the
To further investigate genotypic association of the nine SNPs with schizophrenia, we examined these SNPs under different genetic models. After analyzing the association of the SNPs by five genetic models (codominant, dominant, recessive, overdominant, and log-additive models) with schizophrenia, the consequences demonstrated that three of them showed significant differences between cases and control under at least three different genetic models, and one of them showed difference between cases and control under codominant genetic model: 1) rs2316280, codominant (p=0.021), dominant (p=0.017) and overdominant (p=0.022); 2) rs4877041, codominant (p=0.012), dominant (p=0.047), recessive (p=0.0131), and log-additive (p=0.0143); 3) rs944485, codominant (p=0.014), dominant (p=0.011), overdominant (p=0.015), and log-additive (p=0.037); and 4) rs7021743, codominant (p=0.0003) (
To investigate whether the haplotype constructed by the four schizophrenia-associated
Schizophrenia is a psychiatric syndrome characterized by positive symptoms such as hallucinations, delusions and speech disorders, negative symptoms such as decreased motivation and expression. It also presents some cognitive symptoms such as impaired executive function, memory and mental processing speed [
In the present study we examined the association between the
Our study first reported that the human
In conclusion, our study indicated
We extend our gratitude to all the patients participating in this study. This work was supported by grants from the National Natural Science Foundation of China (81601174 and 81671298), and Natural Science Foundation of Liaoning Province, China (2019-ZD-0938). Teaching Reform Project Foundation for Undergraduate Innovative Talent Cultivation of Dalian Medical University (111806010301).
The authors have no potential conflicts of interest to disclose.
Conceptualization: Zhi-Lin Luan. Data curation: Ye Lv, Yang Sun, ZhiLin Luan. Formal analysis: Ye Lv. Funding acquisition: Zhi-Lin Luan. Investigation: Yang Sun. Methodology: Zhi-Lin Luan, Ye Lv. Project administration: Yang Sun. Resources: Zhi-Lin Luan, Yang Sun. Software: Ye Lv. Supervision: Jian Yin. Validation: Guan-Yu Wang. Visualization: Cheng-Jie Li, Yi-Yang Luo. Writing—original draft: Ye Lv. Writing—review & editing: Zhi-Lin, Luan.
List of SNPs included in the present study
rs code | Position |
Distance from SNP1 (kb) | Allele change | HCB |
Sample-set HWE p | Case HWE p | Control HWE p |
---|---|---|---|---|---|---|---|
rs3812501 | 90814217 | 0 | G>A | 0.244 | 0.407 | 0.899 | 0.382 |
rs2316280 | 90825605 | 1.139 | G>A | 0.049 | 0.932 | 0.991 | 0.953 |
rs4877041 | 90843569 | 2.935 | A>G | 0.024 | 0.113 | 0.006 | 0.723 |
rs7021743 | 90856632 | 4.242 | A>C | 0.012 | 0.669 | 0.675 | 0.868 |
rs944485 | 90869638 | 5.542 | G>T | 0.024 | 0.661 | 0.794 | 0.654 |
rs1547696 | 90883940 | 6.972 | C>T | 0.037 | 0.998 | 0.828 | 0.944 |
rs4876968 | 90916697 | 10.248 | G>A | 0.012 | 0.547 | 0.718 | 0.645 |
rs1556384 | 90953947 | 13.973 | G>A | 0.024 | 0.426 | 0.579 | 0.575 |
rs4534195 | 90958468 | 14.425 | T>C | 0.037 | 0.931 | 0.927 | 0.923 |
from International HapMap database release#27,
Chinese Han population MAF from the International HapMap Project Database.
HCB: Han Chinese in Beijing, MAF: minor allele frequency, HWE: Hardy-Weinberg Equilibrium
Allele frequencies of 9 SNPs in the human
rs code | Subjects | Allele and | frequency |
χ2 p (p |
OR (95% CI) |
---|---|---|---|---|---|
A | G | ||||
rs3812501 | Case | 269 (0.189) | 1,151 (0.811) | χ2=0.386 | 1.054 (0.893–1.244) |
Control | 477 (0.182) | 2,151 (0.818) | p=0.535 | ||
A | G | ||||
rs2316280 | Case | 53 (0.037) | 1,367 (0.963) | χ2=5.844 | 0.674 (0.488–0.930) |
Control | 143 (0.054) | 2,485 (0.946) | p=0.016 |
||
A | G | ||||
rs4877041 | Case | 1,352 (0.952) | 68 (0.048) | χ2=5.792 | 0.673 (0.486–0.931) |
Control | 2,542 (0.967) | 86 (0.033) | p=0.016 |
||
A | C | ||||
rs7021743 | Case | 1,398 (0.985) | 22 (0.015) | χ2=13.215 | 0.291 (0.144–0.591) |
Control | 2,616 (0.995) | 12 (0.005) | p=0.0003 (0.0027) |
||
G | T | ||||
rs944485 | Case | 1,334 (0.939) | 86 (0.061) | χ2=6.687 | 0.684 (0.512–0.914) |
Control | 2,517 (0.958) | 111 (0.042) | p=0.010 |
||
C | T | ||||
rs1547696 | Case | 1,372 (0.966) | 48 (0.034) | χ2=0.867 | 0.840 (0.581–1.213) |
Control | 2,553 (0.971) | 75 (0.029) | p=0.352 | ||
A | G | ||||
rs4876968 | Case | 19 (0.013) | 1,401 (0.987) | χ2=0.049 | 1.066 (0.604–1.882) |
Control | 33 (0.013) | 2,595 (0.987) | p=0.824 | ||
A | G | ||||
rs1556384 | Case | 29 (0.020) | 1,391 (0.980) | χ2=1.489 | 1.349 (0.833–2.185) |
Control | 40 (0.015) | 2,588 (0.985) | p=0.222 | ||
C | T | ||||
rs4534195 | Case | 51 (0.036) | 1,369 (0.964) | χ2=1.485 | 1.251 (0.872–1.794) |
Control | 76 (0.029) | 2,552 (0.971) | p=0.223 |
frequencies are shown in parenthesis,
p value after the strict Bonferroni correction,
significant p values (p<0.05)
Genotype association of 9 SNPs in the human
rs code | Subjets | Genotype |
Codominant |
Dominant |
Recessive |
Overdominant |
Log-additive |
||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
OR (95%CI) | p | OR (95%CI) | p | OR (95%CI) | p | OR (95%CI) | p | p | |||||
AA | AG | GG | |||||||||||
rs3812501 | Case | 26 (0.037) | 217 (0.306) | 467 (0.658) | 1.079 (0.882–1.322) | 0.456 | 1.073 (0.887–1.302) | 0.472 | 0.998 (0.623–1.598) | 0.992 | 1.001 (0.857–1.171) | 0.986 | 0.758 |
Control | 48 (0.037) | 381 (0.290) | 885 (0.674) | 1.026 (0.638–1.652) | 0.917 | ||||||||
AA | AG | GG | |||||||||||
rs2316280 | Case | 1 (0.001) | 51 (0.072) | 658 (0.927) | 0.675 (0.484–0.940) | 0.021 |
0.668 (0.481–0.925) | 0.017 |
2.165 (0.361–26.53) | 0.479 | 1.48 (1.062–2.062) | 0.022 |
0.054 |
Control | 4 (0.003) | 135 (0.103) | 1,175 (0.894) | 2.24 (0.373–27.45) | 0.459 | ||||||||
AA | AG | GG | |||||||||||
rs4877041 | Case | 647 (0.911) | 58 (0.082) | 5 (0.007) | 0.762 (0.543–1.075) | 0.126 | 1.408 (1.001–1.978) | 0.047 |
0.107 (0.013–0.773) | 0.0131 |
0.768 (0.548–1.082) | 0.135 | 0.0143 |
Control | 1,229 (0.935) | 84 (0.064) | 1 (0.001) | 0.105 (0.012–0.758) | 0.012 |
||||||||
AA | AC | CC | |||||||||||
rs7021743 | Case | 688 (0.969) | 22 (0.031) | 0 (0.000) | 0.024 (0.003–0.144) | 0.0003 |
- | - | - | - | - | - | - |
Control | 1,302 (0.991) | 12 (0.009) | 0 (0.000) | - | - | ||||||||
GG | GT | TT | |||||||||||
rs944485 | Case | 627 (0.883) | 80 (0.113) | 3 (0.004) | 0.682 (0.505–0.922) | 0.014 |
1.478 (1.091–2.006) | 0.011 |
0.539 (0.126–2.316) | 0.443 | 0.684 (0.506–0.924) | 0.015 |
0.037 |
Control | 1,206 (0.918) | 105 (0.080) | 3 (0.002) | 1.923 (0.448–8.255) | 0.8139 | ||||||||
CC | CT | TT | |||||||||||
rs1547696 | Case | 663 (0.934) | 46 (0.065) | 1 (0.001) | 0.849 (0.578–1.237) | 0.397 | 1.188 (0.821–1.735) | 0.371 | 0.540 (0.034–10.27) | 0.658 | 1.178 (0.808–1.730) | 0.399 | 0.064 |
Control | 1,240 (0.944) | 73 (0.056) | 1 (0.001) | 0.5347 (0.033–10.17) | 0.653 | ||||||||
AA | AG | GG | |||||||||||
rs4876968 | Case | 0 (0.000) | 19 (0.027) | 691 (0.973) | 1.067 (0.606–1.882) | 0.823 | - | - | - | - | - | - | - |
Control | 0 (0.000) | 33 (0.025) | 1,281 (0.975) | - | - | ||||||||
AA | AG | GG | |||||||||||
rs1556384 | Case | 0 (0.000) | 29 (0.041) | 681 (0.959) | 1.356 (0.830–2.203) | 0.218 | - | - | - | - | - | - | 0.218 |
Control | 0 (0.000) | 40 (0.030) | 1,274 (0.970) | - | - | ||||||||
CC | CT | TT | |||||||||||
rs4534195 | Case | 1 (0.001) | 49 (0.069) | 660 (0.930) | 1.243 (0.850–1.802) | 0.2523 | 0.799 (0.554–.161) | 0.234 | 0.540 (0.034–10.27) | 0.658 | 1.242 (0.849–1.800) | 0.254 | 0.471 |
Control | 1 (0.001) | 74 (0.056) | 1,239 (0.943) | 1.877 (0.099–35.69) | 0.6509 |
frequencies are shown in parenthesis,
significant p values (p<0.05)
Estimated haplotype frequencies and case-control haplotype results of the four schizophrenia-associated SNPs of human
Haplotype | Haplotype frequency |
χ2 | p | OR (95% CI) | Global |
||
---|---|---|---|---|---|---|---|
Case | Control | χ2 | p | ||||
A-A-A-G | 48.00 (0.034) | 136.74 (0.052) | 6.575 | 0.010 |
0.647 (0.462–0.904) | 11.233 | 0.004 |
G-A-A-G | 1,257.08 (0.885) | 2,344.47 (0.892) | 0.522 | 0.470 | 1.099 (0.850–1.421) | ||
G-A-A-T | 45.52 (0.032) | 54.96 (0.021) | 5.063 | 0.024 |
1.574 (1.057–2.345) |
All those frequency <0.03 are ignored in analysis.
frequencies are shown in parenthesis,
significant p values (p<0.05)