CN113724784B - System and method for drawing asymmetric genetic structure of Alzheimer's disease semi-brain - Google Patents
System and method for drawing asymmetric genetic structure of Alzheimer's disease semi-brain Download PDFInfo
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Abstract
The invention provides a drawing system and a drawing method for a semi-brain asymmetric genetic structure of Alzheimer's disease. The system comprises an asymmetric brain connection extraction module, a data processing module and a data processing module, wherein the asymmetric brain connection extraction module is used for extracting abnormal asymmetric brain connection based on the function connection and white matter connection of the semi-brain in the multi-mode magnetic resonance image to be tested; the genetic data processing module is used for acquiring the whole genome sequencing data to be tested and carrying out quality control on the single nucleotide polymorphism; the abnormal genetic effect determining module is used for estimating the hemisphere difference of the inheritance degrees of the left and right hemisphere internal connections, the inheritance degrees of the asymmetric coefficients and the genetic correlation of the left and right hemisphere brain connections and determining the abnormal genetic effect of the AD patient; and the genetic structure drawing module is used for projecting the estimated inheritance degree and the genetic correlation to the connected brain areas based on the abnormal genetic effect and the whole genome sequencing data after the quality control, and averaging the inheritance degree of each brain area so as to draw the genetic structure of the abnormal asymmetry of the brain.
Description
Technical Field
The invention belongs to the field of drawing of brain image genetic structures, and particularly relates to a drawing system and method of an asymmetric genetic structure of Alzheimer's disease semi-brain.
Background
The statements in this section merely provide background information related to the present disclosure and may not necessarily constitute prior art.
The magnetic resonance image provides a technical means for discussing the asymmetry of the human brain and the genetic mechanism thereof. In recent years, researchers have been aware of the importance of characterization of brain junction patterns in understanding the asymmetry of the hemispheres of Alzheimer's Disease (AD) patients, and have been based on a macroscopic connection map of the structure and function of the human brain to deeply snoop the differences between the left and right hemispheres of brain junction patterns of AD patients from the viewpoint of macroscopic loops, thereby providing a new angle for understanding the lateralization of the brain.
At present, the genetic research of the hemibrain asymmetry of the AD patient based on the magnetic resonance image mainly focuses on the structural phenotype (cortex volume, cortex thickness, surface area and the like) of the brain gray matter region, neglects the influence of genes on the brain connection characteristics, has a single genetic research method for the hemibrain asymmetry of the AD patient, does not perform genetic analysis on the hemibrain connection asymmetry of the AD patient from multiple dimensions, and therefore lacks the complete drawing of the genetic structure of the hemibrain asymmetry of the Alzheimer disease from the perspective of the brain connection asymmetry, and therefore, the gene origin and the formation mechanism for exploring the abnormal asymmetry of the brain connection of the AD patient are hindered.
Disclosure of Invention
In order to solve the technical problems in the background art, the invention provides a drawing system and a drawing method for an asymmetric genetic structure of a Alzheimer's disease semi-brain, which draw a complete asymmetric genetic structure of the Alzheimer's disease semi-brain.
In order to achieve the purpose, the invention adopts the following technical scheme:
the first aspect of the present invention provides a genetic structure mapping system for Alzheimer's disease hemibrain asymmetry, comprising:
the asymmetric brain connection extraction module is used for extracting abnormal asymmetric brain connection based on the function connection and white matter connection of the semi-brain in the multi-modal magnetic resonance image to be tested;
the genetic data processing module is used for acquiring the whole genome sequencing data to be tested and carrying out quality control on the single nucleotide polymorphism;
the abnormal genetic effect determining module is used for estimating the hemispheric difference of the inheritance degrees of the left and right hemispheres internal connection, the inheritance degrees of the asymmetric coefficients and the genetic correlation of the left and right hemispheres internal connection based on the brain connection with the abnormal asymmetry and the whole genome sequencing data after the quality control, and determining the abnormal genetic effect of the AD patient;
and the genetic structure drawing module is used for projecting the estimated abnormal inheritance degree and the abnormal inheritance related mode to the connected brain regions based on the abnormal genetic effect of the AD patient and the whole genome sequencing data after quality control, and averaging the inheritance degree of each brain region so as to draw the abnormal asymmetric genetic structure of the brain.
Further, the multi-modality magnetic resonance image includes an srmri image, an fMRI image, and a dMRI image.
Further, in the asymmetric brain junction extraction module, an asymmetry coefficient is used to measure the degree of asymmetry of brain junction.
Further, in the asymmetric brain connection extraction module, abnormal asymmetric brain connections are extracted by using multiple comparison corrections.
Further, in the abnormal genetic effect determining module, the extracted abnormal lateralized brain connection of the AD patient is taken as a target parameter, the whole genome data of the selected group is combined, the genetic relationship matrix and the bivariate gene constraint maximum likelihood model are utilized, the genetic proportion of the abnormal brain connection asymmetry explained by the whole genome data and the influence degree of the genetic factors on the left and right half brain connections are estimated, and the abnormal genetic degree and the genetic correlation of the brain connection asymmetry of the AD patient are calculated.
Further, the system for mapping the genetic structure of the Alzheimer's disease with the hemibrain asymmetry further comprises:
and the polymorphic gene locus map drawing module is used for carrying out whole genome correlation analysis on the brain connection with abnormal genetic effect based on the drawn genetic structure of the abnormal asymmetry of the brain and drawing a polymorphic gene locus map related to the abnormal asymmetry of the brain of the AD patient.
The second aspect of the present invention provides a method for mapping an asymmetric genetic structure of a half brain of alzheimer's disease, comprising:
extracting abnormal asymmetric brain connections based on the function connections and white matter connections of the semi-brain in the tested multi-modal magnetic resonance image;
acquiring whole genome sequencing data of a tested object and performing quality control on single nucleotide polymorphism;
estimating the hemisphere difference of the inheritance degrees of left and right hemisphere internal connections, the inheritance degrees of asymmetric coefficients and the inheritance correlation of left and right hemisphere connections based on the brain connection with abnormal asymmetry and whole genome sequencing data after quality control, and determining the abnormal genetic effect of the AD patient;
based on the abnormal genetic effect of the AD patient and the whole genome sequencing data after quality control, the estimated abnormal inheritance degree and the abnormal inheritance related mode are projected to the connected brain regions, and the inheritance degree of each brain region is averaged, so that the abnormal asymmetric genetic structure of the brain is further drawn.
Further, the method for mapping the genetic structure of the Alzheimer's disease with the asymmetric hemibrain further comprises the following steps:
based on the drawn genetic structure of the abnormal asymmetry of the brain, the whole genome association analysis is carried out on the brain connection with abnormal genetic effect, and a polymorphic gene locus map related to the abnormal asymmetry of the brain of the AD patient is drawn.
A third aspect of the present invention provides a computer-readable storage medium, on which a computer program is stored, which when executed by a processor, implements the steps in the method for mapping genetic structures with half-brain asymmetry for alzheimer's disease as described above.
A fourth aspect of the present invention provides a computer device, comprising a memory, a processor and a computer program stored on the memory and executable on the processor, wherein the processor executes the program to implement the steps of the method for mapping the genetic structure of alzheimer's disease with a hemibrain asymmetry.
Compared with the prior art, the invention has the beneficial effects that:
the abnormal genetic effect of the hemibrain asymmetry of the AD patient is determined by estimating the hemisphere difference of the genetic degree of the left and right hemispheres internal connection, the genetic degree of an asymmetry coefficient and the genetic correlation of the left and right hemibrain connections based on the whole genome sequencing data after the brain connection and the quality control of the abnormal asymmetry, the estimated abnormal genetic degree and the genetic correlation mode are projected to the connected brain regions based on the abnormal genetic effect and the whole genome sequencing data after the quality control, and the genetic degree of each brain region is averaged, so that the genetic structure of the abnormal asymmetry of the brain is drawn; based on the brain connection information of the AD patient, the invention can more comprehensively reveal the genetic mechanism of AD semi-brain abnormal difference, thereby providing direct genetic basis for clinically taking abnormal asymmetry as a nerve image marker of diseases, and further snooping a human brain structure organization mode and a functional mechanism from the level of a macroscopic loop; on the other hand, the invention combines analysis methods such as inheritance degree, whole genome association analysis and genetic correlation and the like to comprehensively explore the gene origin of the abnormal brain connection asymmetry of the AD patient, thereby more effectively providing the image marker of the disease and having important clinical value.
Advantages of additional aspects of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a structural diagram of a system for mapping the genetic structure of Alzheimer's disease with hemibrain asymmetry according to an embodiment of the present invention;
FIG. 2 is a schematic diagram of the mapping of the genetic structure of Alzheimer's disease with a hemibrain asymmetry according to an embodiment of the present invention.
Detailed Description
The invention is further described with reference to the following figures and examples.
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
Example one
Referring to fig. 1, the present embodiment provides a system for mapping a genetic structure of alzheimer's disease with a hemibrain asymmetry, which includes:
(1) and the asymmetric brain connection extraction module is used for extracting abnormal asymmetric brain connection based on the function connection and white matter connection of the semi-brain in the multi-modal magnetic resonance image to be tested.
In specific embodiments, the test is derived from the International open database of the neuroimaging initiative for Alzheimer's Disease (ADNI). The multi-modality magnetic resonance imaging includes a subject sMRI image, an fMRI image, and a dMRI image.
In one or more embodiments, the system for mapping genetic structures of alzheimer's disease hemibrain asymmetry further comprises:
and the image preprocessing module is used for preprocessing the multi-mode magnetic resonance image to be tested.
The preprocessing flow of the sMRI image comprises the following steps:
and manually adjusting the original points of all sMRI to a front joint point, and performing image segmentation to obtain gray matter, white matter and cerebrospinal fluid.
The preprocessing flow of the dMRI image comprises the following steps:
and performing basic preprocessing such as dMRI eddy current correction, EPI distortion correction, head movement and gradient direction correction and dispersion statistical analysis on the fiber bundle skeleton to finally obtain dispersion parameter indexes such as anisotropic Fraction (FA), average dispersion coefficient (MD) and the like of the left and right semi-white matter fibers.
The preprocessing flow of the fMRI image comprises the following steps:
removing time points, head movement and time interval correction, space standardization and smooth filtering.
In the semi-brain junction building block, the brain regions are first defined:
the left and right gray matter hemispheres are segmented into 123 brain regions using a connectivity-based symmetric BNA246 template, the individual structure weighted images are normalized to MNI (coordinate system established from a series of magnetic resonance images of normal human brain) space, and the individual structure images are linearly aligned with the individual FA images, and finally the inverse of the two steps is applied to the template in MNI space. And then, semi-white matter connection is further extracted, and full-white matter fiber tracking is carried out by adopting a second-order integration algorithm (iFOD2) of fiber direction distribution based on anatomical prior information obtained by segmenting the structural image, so that full-white matter connection characteristics are constructed. Finally, the functional connections of the hemibrain are obtained based on the pilus correlation by calculating the BOLD signals of the brain regions.
It should be noted that, to ensure comparability of the two hemispheric brain junctions, extraction of the hemispheric brain junctions is limited to the presence of all subjects together and to the brain junctions common to both hemispheres.
And in the asymmetric brain junction extraction module, extracting abnormal asymmetric brain junctions by utilizing multiple comparative correction of Bonferroni. Wherein Bonferroni corrects: if n independent hypotheses are tested simultaneously on the same data set, then the statistical significance level for each hypothesis should be 1/n of the significance level when only one hypothesis is tested.
In a specific implementation, in the asymmetric brain junction extraction module, an asymmetry coefficient is used to measure a degree of asymmetry of a brain junction.
And measuring the brain connection asymmetry by adopting a general asymmetry coefficient AI (L-R)/(L + R), wherein L and R respectively represent left and right hemispheric brain connection parameters, so that the degree of the brain connection asymmetry is quantized. And further based on the asymmetry information, carrying out statistics on brain connections with significant asymmetry difference in AD and normal control population by utilizing multiple comparative corrections, and extracting abnormal lateralized brain connections of AD patients to serve as target connection parameters of subsequent genetic analysis.
(2) And the genetic data processing module is used for acquiring the whole genome sequencing data of the tested object and performing quality control on the single nucleotide polymorphism.
In the genetic data processing module, the SNP is targeted based on the genome-wide data provided by the advocacy of neuroimaging of Alzheimer's Disease (ADNI)(whole genome sequencing data) quality control, mainly comprising: knock out minimum allele frequency<0.01, genotyping Rate<90% and failed the Hudi-Winberg test (p)>1×10-7) And filtering the interpolated information score<0.8 SNP.
(3) And the abnormal genetic effect determining module is used for estimating the hemisphere difference of the inheritance degrees of the left and right hemisphere internal connections, the inheritance degrees of the asymmetric coefficients and the genetic correlation of the left and right hemisphere connections based on the brain connections with abnormal asymmetry and the whole genome sequencing data after quality control, and determining the abnormal genetic effect of the AD patient.
Taking the extracted abnormal lateralized brain connections of the AD patients as target parameters, combining with SNP screened into a group, estimating the genetic proportion of the asymmetry of the abnormal brain connections explained by the SNP by utilizing a genetic relationship matrix, namely calculating the genetic degree of target connection asymmetry coefficients of the AD patients and a normal control group, constructing a genetic weighting network of the brain connection asymmetry coefficients, namely taking the genetic degree of the asymmetry coefficients as the network of the brain connection weights, and performing comparison among groups;
in addition, based on the left and right hemisphere brain connections of the two groups of AD patients and normal control people, the genetic effect of a large amount of SNPs is further superposed to quantify the genetic degree of each brain connection of the left and right hemispheres, a genetic weighting network connected with each hemisphere brain is constructed, namely the genetic degree connected with the left and right hemispheres is taken as a network of brain connection weights, the hemisphere difference comparison of the genetic weighting networks in the groups is respectively carried out on the two groups of AD patients and normal control people, and the pattern comparison of the genetic asymmetry between the groups is further carried out on the differences.
The extracted abnormal lateralized left and right brain connections of the AD patient are taken as target parameters, SNP of the selected group is combined, a bivariate gene constraint maximum likelihood model is utilized, namely genetic covariance of connection of two hemispheres is divided by square roots of products of respective genetic variances of the genetic variances, further, genetic relevance of the left and right brain connections is estimated, namely, whether the left and right hemispheres have the same genetic factor influence and how much influence degree exists on the connection, and an abnormal inheritance degree mode of the AD patient is extracted.
(4) And the genetic structure drawing module is used for projecting the estimated abnormal inheritance degree and the abnormal genetic correlation to the connecting brain regions based on the abnormal genetic effect of the AD semi-brain asymmetry and the whole genome sequencing data after quality control, and averaging each brain region so as to draw the genetic structure of the abnormal brain asymmetry.
In a genetic structure drawing module, performing whole genome association analysis on the left and right hemisphere connection and lateralization coefficients of AD abnormal asymmetry aiming at the extracted connection and genetic information, wherein the obviously related SNPs are considered as those with the significance p<1×10-6To correct for multiple detection across the entire genome, thereby locating polymorphic sites that are significantly associated with AD abnormal asymmetry.
In other embodiments, the system for mapping genetic structures of alzheimer's disease hemibrain asymmetry further comprises:
and the polymorphic gene locus map drawing module is used for carrying out whole genome correlation analysis on the brain connection with abnormal genetic effect based on the drawn genetic structure of the abnormal asymmetry of the brain and drawing a polymorphic gene locus map related to the abnormal asymmetry of the brain of the AD patient.
Example two
Referring to fig. 2, the present embodiment provides a method for mapping a genetic structure of alzheimer's disease with hemibrain asymmetry, which includes:
step 1: extracting abnormal asymmetric brain connections based on the function connections and white matter connections of the semi-brain in the tested multi-modal magnetic resonance image;
step 2: acquiring the whole genome sequencing data of a tested object and performing quality control on single nucleotide polymorphism;
and step 3: estimating the hemisphere difference of the inheritance degrees of the left and right hemisphere internal connections, the inheritance degrees of the asymmetric coefficients and the inheritance correlation of the left and right hemisphere brain connections based on the brain connections with abnormal asymmetry and the whole genome sequencing data after quality control, and determining the abnormal inheritance effect of the AD patient;
and 4, step 4: based on the abnormal genetic effect of the AD patient and the whole genome sequencing data after quality control, the estimated abnormal inheritance degree and the abnormal inheritance related mode are projected to the connected brain regions, and the inheritance degree of each brain region is averaged, so that the genetic structure of the abnormal asymmetry of the brain is drawn.
Here, the order of step 1 and step 2 can be changed arbitrarily, and the genetic structure mapping method for alzheimer's disease hemibrain asymmetry after changing the order does not affect the final mapping result.
In one or more embodiments, the method for mapping genetic structure of alzheimer's disease hemibrain asymmetry further comprises:
and 5: based on the drawn genetic structure of the abnormal asymmetry of the brain, the whole genome association analysis is carried out on the brain connection with abnormal genetic effect, and a polymorphic gene locus map related to the abnormal asymmetry of the brain of the AD patient is drawn.
Here, the implementation process of each step in step 1 to step 5 in this embodiment is the same as the implementation process of each module in the first embodiment, and will not be described again here.
EXAMPLE III
The present embodiment provides a computer-readable storage medium, on which a computer program is stored, which when executed by a processor, implements the steps in the method for mapping genetic structures of alzheimer's disease hemibrain asymmetry as described in the second embodiment above.
Example four
The present embodiment provides a computer device, which includes a memory, a processor, and a computer program stored in the memory and executable on the processor, and the processor executes the computer program to implement the steps of the method for mapping the genetic structure of the alzheimer's disease hemibrain asymmetry according to the second embodiment.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A system for mapping an asymmetric genetic structure of a half brain of Alzheimer's disease, comprising:
the asymmetric brain connection extraction module is used for extracting abnormal asymmetric brain connection based on the function connection and white matter connection of the semi-brain in the multi-modal magnetic resonance image to be tested;
the genetic data processing module is used for acquiring the whole genome sequencing data of a tested object and performing quality control on the single nucleotide polymorphism, and specifically comprises the following steps: eliminating whole genome sequencing data with the minimum allele frequency of less than 0.01, the genotyping rate of less than 90% and failing to pass Hardy-Weinberg test, and filtering out whole genome sequencing data with the interpolation information score of less than 0.8;
the abnormal genetic effect determining module is used for estimating the hemisphere difference of the inheritance degree of the left and right hemisphere internal connections, the inheritance degree of the asymmetric coefficient and the genetic correlation of the left and right hemisphere brain connections based on the abnormal asymmetric brain connections and the whole genome sequencing data after quality control, and determining the abnormal genetic effect of the AD patient;
and the genetic structure drawing module is used for projecting the estimated abnormal inheritance degree and the abnormal genetic correlation mode to the connected brain regions based on the abnormal genetic effect of the AD patient and the whole genome sequencing data after quality control, and averaging the inheritance degree of each brain region so as to draw the abnormal asymmetric genetic structure of the brain.
2. The system for mapping genetic structures of Alzheimer's disease with hemibrain asymmetry as claimed in claim 1, wherein the multi-modality magnetic resonance image comprises sMRI images, fMRI images and dMRI images.
3. The system for mapping genetic structure of alzheimer's disease cerebellar asymmetry according to claim 1, wherein in said asymmetric brain junction extraction module an asymmetry factor is used to measure the degree of brain junction asymmetry.
4. The system for mapping genetic structure of alzheimer's disease hemispheres as defined in claim 1 wherein said asymmetric brain junction extraction module extracts abnormal asymmetric brain junctions using multiple comparative corrections.
5. The system for mapping an asymmetric genetic structure in the half brain of alzheimer's disease as claimed in claim 1, wherein in the abnormal genetic effect determining module, the extracted abnormal lateralized brain connections of AD patients are used as target parameters, the genetic relationship matrix and the bivariate gene constraint maximum likelihood model are combined to select the whole genome data of the group, the genetic proportion of the asymmetry of the abnormal brain connections explained by the whole genome data and the influence degree of the genetic factors on the left and right half brain connections are estimated, and the abnormal genetic degree and the genetic correlation of the asymmetry of the brain connections of AD patients are calculated.
6. The system for mapping genetic structure of Alzheimer's disease hemibrain asymmetry according to claim 1, further comprising:
and the polymorphic gene locus map drawing module is used for carrying out whole genome correlation analysis on the brain connection with abnormal genetic effect based on the drawn genetic structure of the abnormal asymmetry of the brain and drawing a polymorphic gene locus map related to the abnormal asymmetry of the brain of the AD patient.
7. A method for drawing an asymmetric genetic structure of a half brain of Alzheimer's disease is characterized by comprising the following steps:
extracting abnormal asymmetric brain connection based on the function connection and white matter connection of the semi-brain in the tested multi-modal magnetic resonance image;
acquiring whole genome sequencing data of a tested object and performing quality control on single nucleotide polymorphism, wherein the quality control specifically comprises the following steps: eliminating whole genome sequencing data with the minimum allele frequency of less than 0.01, the genotyping rate of less than 90% and failing to pass Hardy-Weinberg test, and filtering out whole genome sequencing data with the interpolation information score of less than 0.8;
estimating the hemisphere difference of the inheritance degrees of the left and right hemisphere internal connections, the inheritance degrees of the asymmetric coefficients and the inheritance correlation of the left and right hemisphere brain connections based on the brain connections with abnormal asymmetry and the whole genome sequencing data after quality control, and determining the abnormal genetic effect of the AD patient;
based on the abnormal genetic effect of the AD patient and the whole genome sequencing data after quality control, the estimated abnormal inheritance degree and the abnormal genetic correlation mode are projected to the connected brain regions, and the inheritance degree of each brain region is averaged, so that the abnormal asymmetric genetic structure of the brain is drawn.
8. The method for mapping genetic structure of Alzheimer's disease with asymmetry in the cerebellum according to claim 7, wherein the method for mapping genetic structure of Alzheimer's disease with asymmetry in the cerebellum further comprises:
based on the drawn genetic structure of the abnormal asymmetry of the brain, the brain connection of the abnormal inheritance degree is subjected to whole genome association analysis, and a polymorphic gene locus map related to the abnormal asymmetry of the brain of the AD patient is drawn.
9. A computer-readable storage medium, on which a computer program is stored, which program, when being executed by a processor, carries out the steps of the method for mapping genetic structures with half-brain asymmetry for alzheimer's disease as set forth in any of the claims 7-8.
10. A computer device comprising a memory, a processor and a computer program stored on the memory and executable on the processor, characterized in that the processor implements the steps in the method for mapping genetic structures with half-brain asymmetry for alzheimer's disease as claimed in any of claims 7-8 when executing said program.
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