COMT基因多态性对脑结构及功能调控的多模态MRI研究

发布时间：2018-04-18 04:26

本文选题：COMT + DRD2　；参考：《天津医科大学》2014年硕士论文

【摘要】：目的： COMT基因rs4680位点多态性作用于人脑结构或功能的研究多是独立进行的,而且多数是基于感兴趣区的分析,缺乏结合结构及功能研究的全脑分析。此外,性别对COMT活性的影响以及其它多巴胺系统基因多态性与COMT的交互作用是现有研究中的薄弱之处。本研究采用大样本青年被试及多模态磁共振成像(magnetic resonance imaging, MRI)分析技术,联合运用基于体素的形态学分析(voxel-based morphometry analysis, VBM)、静息态功能连接(resting-state functional connectivity, rsFC)、功能连接密度(functional connectivity density,FCD)方法,研究COMT基因多态性对正常人脑结构及功能的影响。材料与方法：选择右利手的健康青年志愿者323例。利用GE3.0T Signa HDX磁共振扫描仪对所有受试者进行静息态以及结构像数据的采集。 1.基因型测定,应用聚合酶链反应(polymerase chain reaction, PCR)-连接酶检测反应(ligation detection reaction, LDR)的方法,检测受试者COMT基因rs4680位点G/A等位基因多态性以及DRD2基因rs1076560位点G/T等位基因多态性。 2.采用基于Matlab平台的SPM8软件及其插件包VBM8对高分辨率结构像进行预处理,预处理过程包括：灰、白质分割、空间标准化及空间平滑。采用基于Matlab平台的DPARSF软件对静息态功能数据进行预处理,预处理过程包括：时间校正、头动校正、空间标准化、重采样到3mm×3mm×3mm的立方体素及空间平滑。对于时间校正、头动校正、空间标准化后得到的静息态功能图像,我们用Tomasi等人提出的FCD方法计算全脑灰质mask内每个体素的短程(local FCD)和长程功能连接密度(long-range FCD)值,再用每个体素local FCD和long-range FCD值除以全脑的平均local FCD和long-range FCD值,得到每个受试者标准化的local FCD和long-range FCD图,最后进行空间平滑。 3.采用预处理后的高分辨率结构像数据,研究COMT基因对大脑灰质体积影响的主效应及基因-性别交互效应。然后,我们将有显著差异的脑区作为感兴趣区进行基于种子区的全脑功能连接计算。同样地,我们研究COMT基因对感兴趣区与全脑功能连接影响的主效应以及基因-性别交互效应。 4.在控制受试年龄、性别、教育年限后,FCD数据在SPM8软件中进行统计分析,研究COMT及DRD2基因对全脑功能连接密度调控的主效应及基因-基因交互效应。 5.统计分析采用双因素方差分析(COMT基因型-性别或COMT基因型-DRD2基因型),采用AlphaSim或FWE方法对结果进行多重比较校正。结果： 1.通过COMT、DRD2基因分型检测,基因型分布频率符合Hardy-Weinberg分布。 2.双因素方差分析发现右侧后扣带区的灰质体积存在显著COMT基因主效应,即Val纯合子右侧后扣带的灰质体积比Met等位基因携带者要小。左内侧额上回区灰质体积存在显著的COMT基因型-性别交互效应,即男性Val纯合子的左内侧额上回的灰质体积比男性Met等位基因携带者要小,在女性中则不存在这一现象。 3.以右侧后扣带区及左内侧额上回区为种子区进行全脑功能连接计算。单样本t检验(校正后P0.05)显示右后扣带与左内侧额上回表现出类似的功能连接模式,它们均与默认网络内的主要脑区呈正功能连接。这表明右侧后扣带区和左内侧额上回均属于默认网络的一部分。 4.当以右侧后扣带区作为种子区进行全脑功能连接,右后扣带与左内侧额极的功能连接存在显著的COMT基因主效应。当以左内侧额上回作为种子区进行全脑功能连接,左内侧额上回与左内侧额极的功能连接同样存在显著的COMT基因主效应。它们均表现为Val纯合子的功能连接强度比Met等位基因携带者小。 5.在控制种子区的灰质体积后我们重复了功能连接分析。我们发现新得到的结果与控制灰质体积之前的结果没有显著差异,表明功能连接的变化与结构变化不存在显著关联。 6.双因素方差分析发现右侧颞极上部、左侧舌回的local FCD以及右侧壳核、左内侧前额叶皮层的long-range FCD存在显著的COMT-DRD2基因交互效应。FCD与各基因型之间的关系呈系统依赖型非线性变化。结论： 1. COMT Val158Met基因多态性调控默认网络脑区的结构及相关的功能连接强度；这可能是由于不同人群中COMT活性差异导致部分脑区多巴胺浓度不同而引起的。 2. COMT Vall58Met基因多态性对默认网络脑区结构及功能的调控是相对独立的过程,不存在直接关联性。 3. COMT Vai158Met基因多态性对前额叶形态的调控具有性别依赖性。 4. COMT与DRD2基因多态性对大脑功能连接密度的调控具有系统依赖性。
[Abstract]:Objective:
COMT gene rs4680 polymorphism study in human brain structure or function is independent, and most are analyzed based on region of interest, lack of research combined with the analysis of whole brain structure and function. In addition, due to the interaction of polymorphism and COMT effect of gender on the activity of COMT and other dopamine system is a weak base from the prior research. This study uses a large sample of young subjects and multi modality magnetic resonance imaging (magnetic resonance, imaging, MRI) analysis technique, combined with voxel based morphometry (voxel-based morphometry, analysis, VBM), resting state functional connectivity (resting-state functional connectivity, rsFC), functional connectivity (density functional connectivity density, FCD) method, the effects of COMT gene polymorphism on the structure and function of normal human brain.
Materials and methods:
323 healthy young volunteers with right-handed hands were selected. The resting state and structural data of all subjects were collected by GE3.0T Signa HDX magnetic resonance scanner.
1. genotypes were determined by polymerase chain reaction (polymerase chain reaction, PCR) - ligase detection reaction (ligation detection reaction, LDR) method to detect subjects COMT gene rs4680 G/A allele gene polymorphism and DRD2 gene rs1076560 G/T allele polymorphism.
2. platform using Matlab SPM8 software and VBM8 plug-in package based on high resolution structure image pretreatment, pretreatment process including: grey, white matter segmentation, spatial normalization and smoothing. Matlab platform using DPARSF software based on resting state functional data pretreatment, the pretreatment process includes: time correction, head dynamic correction, spatial normalization, re sampling to 3mm * 3mm * 3mm cubes and spatial smoothing. For time correction, head correction, resting state functional image space after standardization, we use the FCD method proposed by Tomasi et al is calculated for each voxel in whole brain gray matter mask (short local FCD) and long range (long-range FCD) functional connectivity density values, then each voxel local FCD and long-range FCD value divided by the whole brain average local FCD and long-range FCD, are each subject to standard local FCD and long-range FCD map, and finally the space is smooth.
3. using the high resolution structure after pretreatment of the image data, the main effect and effect of COMT gene gene on the volume of gray matter in the brain sex interaction. Then, we will have significant differences in brain regions as region of interest connection calculation seed zones of whole brain functions based on. Similarly, we study the COMT gene in the main the effect of region of interest and the influence of whole brain functional connectivity and gene sex interaction.
4., after controlling age, sex and education years, FCD data were analyzed statistically in SPM8 software to study the main effect of COMT and DRD2 gene on the regulation of whole brain functional connectivity and gene gene interaction.
5. statistical analysis was based on two factor analysis of variance (COMT genotype -DRD2 genotype), and AlphaSim or FWE method was used to make multiple comparisons of the results of COMT.
Result:
1. by COMT and DRD2 genotyping, the frequency of genotype distribution accords with the distribution of Hardy-Weinberg.
Two factor analysis of variance 2. found right after deduction of gray matter volume zone have significant main effect of COMT gene, namely Val homozygote right posterior cingulate gray matter volume than the Met allele carriers to small. The left medial frontal gyrus gray matter volume in significant COMT genotype sex interaction, namely gray matter volume Val homozygous male the left medial frontal gyrus than male Met allele carriers should be small, it does not exist this phenomenon in women.
3. in the right posterior cingulate and left medial frontal gyrus area as the seed region of whole brain functional connectivity calculation. One sample t test (adjusted P0.05) display right after the buckle connection mode with similar and left medial frontal gyrus showed the function of their main brain areas with the default network in positive function connection this shows that the right. After deduction of a part of the belt and left medial frontal gyrus belong to the default network.
4. when the right posterior cingulate region as the seed region of whole brain functional connectivity, right posterior cingulate and left medial frontal pole function connections have a significant main effect of COMT gene. When in the left medial frontal gyrus as seed area of whole brain functional connectivity, left medial frontal gyrus and left medial frontal pole connection function there is also a significant main effect of the COMT gene. They were homozygous for Val functional connectivity than Met allele carriers.
5., after controlling the volume of gray matter in the seed area, we repeated functional connectivity analysis. We found that the new results were not significantly different from those before controlling gray matter volume, indicating that there is no significant correlation between functional connectivity and structural changes.
6., two factor analysis of variance showed that there was a significant COMT-DRD2 gene interaction in the right temporal pole upper part, local FCD in the left lingual gyrus, and long-range FCD in the left medial prefrontal cortex, and the relationship between.FCD and genotype was a system dependent nonlinear change.
Conclusion:
1. COMT Val158Met gene polymorphism regulates the structure and functional connectivity of the brain in the default network. This may be due to the difference of COMT activity in different brain regions caused by the difference of dopamine concentration in some brain regions.
The regulation of 2. COMT Vall58Met gene polymorphism on the structure and function of the brain region of the default network is a relatively independent process, and there is no direct correlation.
The regulation of 3. COMT Vai158Met gene polymorphism on prefrontal lobe morphology is sex dependent.
4. COMT and DRD2 gene polymorphisms are systematically dependent on the regulation of brain function connection density.

【学位授予单位】：天津医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R445.2

【参考文献】