本文選題：COMT + DRD2��； 參考：《天津醫(yī)科大學(xué)》2014年碩士論文

【摘要】：目的： COMT基因rs4680位點多態(tài)性作用于人腦結(jié)構(gòu)或功能的研究多是獨立進行的,而且多數(shù)是基于感興趣區(qū)的分析,缺乏結(jié)合結(jié)構(gòu)及功能研究的全腦分析。此外,性別對COMT活性的影響以及其它多巴胺系統(tǒng)基因多態(tài)性與COMT的交互作用是現(xiàn)有研究中的薄弱之處。本研究采用大樣本青年被試及多模態(tài)磁共振成像(magnetic resonance imaging, MRI)分析技術(shù),聯(lián)合運用基于體素的形態(tài)學(xué)分析(voxel-based morphometry analysis, VBM)、靜息態(tài)功能連接(resting-state functional connectivity, rsFC)、功能連接密度(functional connectivity density,FCD)方法,研究COMT基因多態(tài)性對正常人腦結(jié)構(gòu)及功能的影響。 材料與方法： 選擇右利手的健康青年志愿者323例。利用GE3.0T Signa HDX磁共振掃描儀對所有受試者進行靜息態(tài)以及結(jié)構(gòu)像數(shù)據(jù)的采集。 1.基因型測定,應(yīng)用聚合酶鏈反應(yīng)(polymerase chain reaction, PCR)-連接酶檢測反應(yīng)(ligation detection reaction, LDR)的方法,檢測受試者COMT基因rs4680位點G/A等位基因多態(tài)性以及DRD2基因rs1076560位點G/T等位基因多態(tài)性。 2.采用基于Matlab平臺的SPM8軟件及其插件包VBM8對高分辨率結(jié)構(gòu)像進行預(yù)處理,預(yù)處理過程包括：灰、白質(zhì)分割、空間標準化及空間平滑。采用基于Matlab平臺的DPARSF軟件對靜息態(tài)功能數(shù)據(jù)進行預(yù)處理,預(yù)處理過程包括：時間校正、頭動校正、空間標準化、重采樣到3mm×3mm×3mm的立方體素及空間平滑。對于時間校正、頭動校正、空間標準化后得到的靜息態(tài)功能圖像,我們用Tomasi等人提出的FCD方法計算全腦灰質(zhì)mask內(nèi)每個體素的短程(local FCD)和長程功能連接密度(long-range FCD)值,再用每個體素local FCD和long-range FCD值除以全腦的平均local FCD和long-range FCD值,得到每個受試者標準化的local FCD和long-range FCD圖,最后進行空間平滑。 3.采用預(yù)處理后的高分辨率結(jié)構(gòu)像數(shù)據(jù),研究COMT基因?qū)Υ竽X灰質(zhì)體積影響的主效應(yīng)及基因-性別交互效應(yīng)。然后,我們將有顯著差異的腦區(qū)作為感興趣區(qū)進行基于種子區(qū)的全腦功能連接計算。同樣地,我們研究COMT基因?qū)Ω信d趣區(qū)與全腦功能連接影響的主效應(yīng)以及基因-性別交互效應(yīng)。 4.在控制受試年齡、性別、教育年限后,FCD數(shù)據(jù)在SPM8軟件中進行統(tǒng)計分析,研究COMT及DRD2基因?qū)θX功能連接密度調(diào)控的主效應(yīng)及基因-基因交互效應(yīng)。 5.統(tǒng)計分析采用雙因素方差分析(COMT基因型-性別或COMT基因型-DRD2基因型),采用AlphaSim或FWE方法對結(jié)果進行多重比較校正。 結(jié)果： 1.通過COMT、DRD2基因分型檢測,基因型分布頻率符合Hardy-Weinberg分布。 2.雙因素方差分析發(fā)現(xiàn)右側(cè)后扣帶區(qū)的灰質(zhì)體積存在顯著COMT基因主效應(yīng),即Val純合子右側(cè)后扣帶的灰質(zhì)體積比Met等位基因攜帶者要小。左內(nèi)側(cè)額上回區(qū)灰質(zhì)體積存在顯著的COMT基因型-性別交互效應(yīng),即男性Val純合子的左內(nèi)側(cè)額上回的灰質(zhì)體積比男性Met等位基因攜帶者要小,在女性中則不存在這一現(xiàn)象。 3.以右側(cè)后扣帶區(qū)及左內(nèi)側(cè)額上回區(qū)為種子區(qū)進行全腦功能連接計算。單樣本t檢驗(校正后P0.05)顯示右后扣帶與左內(nèi)側(cè)額上回表現(xiàn)出類似的功能連接模式,它們均與默認網(wǎng)絡(luò)內(nèi)的主要腦區(qū)呈正功能連接。這表明右側(cè)后扣帶區(qū)和左內(nèi)側(cè)額上回均屬于默認網(wǎng)絡(luò)的一部分。 4.當以右側(cè)后扣帶區(qū)作為種子區(qū)進行全腦功能連接,右后扣帶與左內(nèi)側(cè)額極的功能連接存在顯著的COMT基因主效應(yīng)。當以左內(nèi)側(cè)額上回作為種子區(qū)進行全腦功能連接,左內(nèi)側(cè)額上回與左內(nèi)側(cè)額極的功能連接同樣存在顯著的COMT基因主效應(yīng)。它們均表現(xiàn)為Val純合子的功能連接強度比Met等位基因攜帶者小。 5.在控制種子區(qū)的灰質(zhì)體積后我們重復(fù)了功能連接分析。我們發(fā)現(xiàn)新得到的結(jié)果與控制灰質(zhì)體積之前的結(jié)果沒有顯著差異,表明功能連接的變化與結(jié)構(gòu)變化不存在顯著關(guān)聯(lián)。 6.雙因素方差分析發(fā)現(xiàn)右側(cè)顳極上部、左側(cè)舌回的local FCD以及右側(cè)殼核、左內(nèi)側(cè)前額葉皮層的long-range FCD存在顯著的COMT-DRD2基因交互效應(yīng)。FCD與各基因型之間的關(guān)系呈系統(tǒng)依賴型非線性變化。 結(jié)論： 1. COMT Val158Met基因多態(tài)性調(diào)控默認網(wǎng)絡(luò)腦區(qū)的結(jié)構(gòu)及相關(guān)的功能連接強度；這可能是由于不同人群中COMT活性差異導(dǎo)致部分腦區(qū)多巴胺濃度不同而引起的。 2. COMT Vall58Met基因多態(tài)性對默認網(wǎng)絡(luò)腦區(qū)結(jié)構(gòu)及功能的調(diào)控是相對獨立的過程,不存在直接關(guān)聯(lián)性。 3. COMT Vai158Met基因多態(tài)性對前額葉形態(tài)的調(diào)控具有性別依賴性。 4. COMT與DRD2基因多態(tài)性對大腦功能連接密度的調(diào)控具有系統(tǒng)依賴性。
[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.

【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R445.2

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本文編號：1766799