CN109750095A - Relevant mononucleotide polymorphism site of schizophrenia and application thereof - Google Patents
Relevant mononucleotide polymorphism site of schizophrenia and application thereof Download PDFInfo
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- CN109750095A CN109750095A CN201711089463.XA CN201711089463A CN109750095A CN 109750095 A CN109750095 A CN 109750095A CN 201711089463 A CN201711089463 A CN 201711089463A CN 109750095 A CN109750095 A CN 109750095A
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Abstract
The present invention provides relevant mononucleotide polymorphism sites of schizophrenia and application thereof.Specifically, the present invention relates to SNP site in preparation for predicting the purposes in subject in the detection reagent of schizoid risk, wherein the SNP site is selected from: one of chr2_200825237_I, rs12129573, rs211829, rs4523957, rs7267348, chr22_39987017_D, rs12325245, rs215411 or combinations thereof.These SNP sites are suitable for carrying out schizophrenia early stage Risk Screening in subspecies crowd, especially Chinese population.
Description
Technical field
The present invention relates to biomedicine technical fields, in particular it relates to the relevant mononucleotide of schizophrenia
Polymorphic site and application thereof.
Background technique
Schizoid heredity grade is up to 80%, is a kind of typical polygenes complex disease.In the past 30 years both at home and abroad
It is exactly to find its Disease-causing gene for one of schizoid Study on Molecular Mechanism Main way, and it is desirable that in this, as the disease
The biomarker of disease.So far, for reported schizophrenia susceptibility gene up to 1008, chromosome susceptibility regions are super
Cross 30.But since schizoid height heterogeneity, different research institutes are using selective problems of sample etc., make
Reproducibility of the susceptibility loci in different crowd is poor, still cannot function as the foundation of diagnosis.
The appearance of genome-wide association study (GWAS) provides a kind of possibility to break this predicament.GWAS passes through inspection
All variation gene frequencies are found out in all sites SNPs for surveying human genome, so as to avoid as candidate gene strategy
It equally needs to pre-suppose that Disease-causing gene.But this strategy brings a problem again: due to needing to carry out to the site magnanimity SNPs
Detection, therefore required sample cluster will become very huge, this limits this technology in schizophrenia to a certain extent
The application of disease research field.
2014, (PGC) schizophrenia working group, international mental disease genome association delivered on " Nature "
Its research project led report, the project whole high quality GWAS data before almost are summarized after assemble
Analysis is related to more ethnic groups and amounts to 36,989 schizophreniacs and 113,075 normal healthy controls.The research has obtained 108
Schizophrenia susceptibility site is distributed on every chromosome of the mankind, and wherein the strongest site of signal is nearly all located at six
Region where number chromosome, that is, MHC.Important pass between this result strong indication immune system and schizophrenia
Connection.After researcher eliminates the signal of MHC, remaining site is subjected to clustering again, still discovery spirit point
It is significantly related to bone-marrow-derived lymphocyte relevant molecule signal to split disease.The research of PGC also found that the highest SNPs combination of risk can
The patients' OR value for carrying these combinations is set to reach 22.Researcher thinks, this 108 sites can be used as patient " static state refers to
Mark ", has a potential quality for clinical diagnosis, and the combination of different susceptibility loci can be used for carrying out patient that " polygenes risk is commented
Estimate analysis " (RSP).But RSP analysis also faces choice problem between susceptibility and specificity, when 108 sites are used for RSP
When analysis, if that number of patients's highest that can be detected just reaches 7% using highest level.Although this result meaning
It is great, but its crowd's queue being included in contain only few asian population (3% schizophreniac, 5% health it is right
According to), the Sites Combination mode put forward in the paper may be not particularly suited for asian population.
Therefore, it needs to develop SNP site and Sites Combination mode use that one kind is suitable for subspecies crowd, especially Chinese population
In schizoid early stage Risk Screening.
Summary of the invention
Based on above-mentioned purpose, the present invention expands the parting research for 108 SNP sites in Chinese population, it is intended to
The special schizophrenia risk Sites Combination mode suitable for subspecies crowd, especially Chinese population is found out, to be used for the disease
The early stage Risk Screening of disease.
One aspect of the invention provides SNP site in preparation for predicting schizoid risk in subject
Detection reagent in purposes, wherein the SNP site is selected from: chr2_200825237_I, rs12129573, rs211829,
One of rs4523957, rs7267348, chr22_39987017_D, rs12325245, rs215411 or combinations thereof.
In a specific embodiment, the subject is people.
In a preferred embodiment, the subject is the people from Asia.
In a further preferred embodiment, the subject is the people from China.
In one specifically embodiment, the detection reagent is detection kit.
Second aspect of the present invention provides SNP site and diagnoses in subject in schizoid detection reagent in preparation
Purposes, wherein the SNP site is selected from: chr2_200825237_I, rs12129573, rs211829, rs4523957,
One of rs7267348, chr22_39987017_D, rs12325245, rs215411 or combinations thereof.
In a specific embodiment, the subject is people.
In a preferred embodiment, the subject is the people from Asia.
In a further preferred embodiment, the subject is the people from China.
In one specifically embodiment, the detection reagent is detection kit.
Third aspect present invention provide it is a kind of for predicting the kit or chip of schizoid risk,
Including at least detection be selected from following SNP site detection reagent: chr2_200825237_I, rs12129573, rs211829,
One of rs4523957, rs7267348, chr22_39987017_D, rs12325245, rs215411 or combinations thereof.
In specifically embodiment, the detection reagent is primer or probe.
Fourth aspect present invention provides one kind for diagnosing schizoid kit or chip, includes at least inspection
Survey be selected from following SNP site detection reagent: chr2_200825237_I, rs12129573, rs211829, rs4523957,
One of rs7267348, chr22_39987017_D, rs12325245, rs215411 or combinations thereof.
In specifically embodiment, the detection reagent is primer or probe.
Specific embodiment
Below the present invention will be further illustrated by following non-limiting embodiments.It is well known to those skilled in the art, not
In the case where spirit of that invention, many modifications can be made to the present invention, such modification also falls into the scope of the present invention.
Unless otherwise instructed, used experimental material can be obtained from commercial company.
Embodiment 1: the collection and preservation of sample
All subjects take 10ml morning fasting blood, and EDTA anticoagulant tube is collected, and 800g is centrifuged 10min.By upper plasma point
It is attached in 1.5ml EP pipe, is centrifuged 5 minutes removal cell fragments using Thermo SORVALL 21R refrigerated centrifuge 12000g,
Upper plasma is dispensed into 0.6ml EP pipe, -20 DEG C of preservations in Thermo-UGL2320V refrigerator.Remaining haemocyte uses
Leucocyte separating liquid separates monocyte with remaining cellular blood components, Liquid nitrogen storage.
Embodiment 2: the detection of schizophrenia science of heredity biomarker
1) extraction of peripheral blood genomic DNA
I) blood sample is put into 50 milliliters of centrifuge tube, the ddH of 5~10 times of volumes is added2O, mixes, and ice bath 10min makes
Solution is in clear and transparent.
Ii) 4 DEG C, 3500rpm, it is centrifuged 15min, inhales and abandons supernatant, retains bottom precipitation.
Iii it) is added in the every pipe precipitating of digesting protein:
15mM TES 5ml；
250 μ l of 10%SDS；
25 μ l of 10mg/ml Proteinase K；
Mixing system, 50 DEG C of water-baths digest 2h, and 37 DEG C of water-bath digestion are overnight.
Iv) the protein in removal system
A. centrifuge tube is taken out from water-bath, isometric Tris saturated phenol is added in every pipe in ice bath 5min, and room temperature mixes
5min。
B.4 DEG C, 3500rpm is centrifuged 15min, draws upper strata aqueous phase into a new centrifuge tube.
C. it is each primary that step a and b are repeated.
D. isometric chloroform: isoamyl alcohol (24:1) is added in every centrifuge tube, room temperature mixes 5min.
E.4 DEG C, 3500rpm is centrifuged 5min, draws upper strata aqueous phase into a new centrifuge tube.
F. it is each primary that step d and e are repeated.
V) DNA is precipitated
A. supernatant is moved into the beaker sterilized, 95% cold ethyl alcohol of 2.5 times of volumes is added, ice bath 20min makes big
Part DNA condenses into cotton-shaped.
B. liquid is blown and beaten with suction pipe, stands 10~15min, condenses into surplus DNA also cotton-shaped.
C. beaker is gently shaken, keeps the DNA of condensation agglomerating.
Vi DNA) is collected
A. DNA precipitating is sucked out, with 75% cold ethanol washing.
B. DNA is precipitated in sucking 1.5ml Eppendorf pipe, absorbs ethyl alcohol extra in pipe.
C. it is sealed with sealed membrane, pricks several apertures, drying at room temperature 30min or aspirate 5min with vaccum centrifugal pump.
D. 0.5ml TE, dissolving DNA is added in every pipe.
E. all DNA samples -20 DEG C of long-term preservations in Thermo-UGL2320V refrigerator.
2) DNA is quantified
The NanoDrop ND1000 produced using Thermo Scientific company, the U.S. is quantitative to DNA and purity is surveyed
It is fixed.
Embodiment 3: the detection of schizophrenia science of heredity susceptibility loci
1) 108 schizophrenia susceptibility site information such as the following table 1: table 1:
2) detection in schizophrenia inheritance susceptible site
The genomic DNA of quality inspection qualification is digested, and DNA carries out fragmentation, the fragmentation of product after amplification label, amplification
DNA and Axiom Genome-Wide CHB1&2 array board hybridization reaction clean chip after reaction, dyeing scanning, by light
Signal value is converted into digital signal, and the genotyping result (A, T, G, C) of each SNP site is judged according to digital signal value height.
Embodiment 4: statistical analysis
1) Kolmogorov-Smirnov examines the normal distribution situation for being used to analyze each group of data.
2) using polygenes risk score (Polygenic Risk Score) assessment risk Sites Combination to schizophrenia
The prediction effect of disease patient.
Experimental result: the schizophrenia risk site in Chinese population
It studies and 108 candidates is directed to a queue comprising 1000 schizophreniacs and 1000 normal healthy controls
Risk site has carried out Genotyping, and chip successfully reads 79 sites, and 29 sites fail to read.It is controlled by quality, 79
There are 19 site data not meet quality inspection requirement in a reading site, is considered as detection failure.60 sites can actually be detected.
In detection site, only 8 sites show enough statistics effect (p < 0.05), illustrate Chinese population
In schizophrenia risk site carrying mode and American-European crowd there are larger differences, but have simultaneously with uniformity.?
This simultaneous 8 risk sites in two kinds of crowds, it is likely that reacted the genetic mechanism of disease profound level, can be used to
The risk profile of early stage is carried out to the disease (referring to the following table 2).Table 2
Claims (7)
- The site 1.SNP is being prepared for predicting the purposes in subject in the detection reagent of schizoid risk, Described in SNP site be selected from: chr2_200825237_I, rs12129573, rs211829, rs4523957, rs7267348, One of chr22_39987017_D, rs12325245, rs215411 or combinations thereof.
- Purposes of the site 2.SNP in preparation diagnosis subject in schizoid detection reagent, wherein the SNP site is selected From: chr2_200825237_I, rs12129573, rs211829, rs4523957, rs7267348, chr22_39987017_D, One of rs12325245, rs215411 or combinations thereof.
- 3. purposes according to claim 1 or 2, in which:The subject is people；Preferably, the subject is the people from Asia；It is highly preferred that the subject is to come from The people of China.
- 4. purposes according to claim 1 or 2, wherein the detection reagent is detection kit.
- 5. it is a kind of for predicting the kit or chip of schizoid risk, detection is included at least selected from following The detection reagent of SNP site: chr2_200825237_I, rs12129573, rs211829, rs4523957, rs7267348, One of chr22_39987017_D, rs12325245, rs215411 or combinations thereof.
- 6. one kind includes at least the inspection that detection is selected from following SNP site for diagnosing schizoid kit or chip Test agent: chr2_200825237_I, rs12129573, rs211829, rs4523957, rs7267348, chr22_ One of 39987017_D, rs12325245, rs215411 or combinations thereof.
- 7. it is according to claim 5 or 6 for diagnosing schizoid kit or chip, wherein the detection examination Agent is primer or probe.
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| CN201711089463.XA CN109750095A (en) | 2017-11-08 | 2017-11-08 | Relevant mononucleotide polymorphism site of schizophrenia and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114277123A (en) * | 2021-12-29 | 2022-04-05 | 上海交通大学 | Polynucleotides containing SNP sites related to schizophrenia and application |
| RU2819816C1 (en) * | 2022-12-29 | 2024-05-24 | Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" | Multiplex set of markers as tool for developing genetic testing of susceptibility to schizophrenia, alcoholism and connection with personality traits in young people and mental abilities in old age |
-
2017
- 2017-11-08 CN CN201711089463.XA patent/CN109750095A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| S. H. GAGE ET AL: "Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study", 《PSYCHOLOGICAL MEDICINE》 * |
| 张洪丽: "基于精神分裂症SNP点的初步研究与实现", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 王庆中: "SNAP25、CMYA5、ZNF804A、CDH7基因与精神分裂症和重度抑郁症的关联分析研究", 《中国优秀博士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114277123A (en) * | 2021-12-29 | 2022-04-05 | 上海交通大学 | Polynucleotides containing SNP sites related to schizophrenia and application |
| RU2819816C1 (en) * | 2022-12-29 | 2024-05-24 | Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" | Multiplex set of markers as tool for developing genetic testing of susceptibility to schizophrenia, alcoholism and connection with personality traits in young people and mental abilities in old age |
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Application publication date: 20190514 |