首发精神分裂症的神经认知功能和分子遗传学研究
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摘要
研究目的1．对首发精神分裂症患者、父母、子女和同胞进行神经认知功能的评定，研究神经认知功能的家族聚集性。寻找可能代表精神分裂症遗传特征的“内表型”；2．采用候选基因策略，在病例对照和家系的定性分析中研究5号染色体q31区的8个候选基因与精神分裂症的关系；3．将候选“内表型”作为数量性状进行定量的传递不平衡研究，对精神分裂症的易感基因进行精细定位。
研究方法1．采用成套神经心理测评工具(包括利手、知识、算术、数字符号、数字广度、木块拼图、逻辑记忆、视觉记忆、Stroop测试、连线测试、言语流畅测试、汉诺塔、威斯康星卡片分类测试和连续操作任务测试)，完成了首发精神分裂症患者232例，精神分裂症父母355例，精神分裂症患者同胞、子女273例和正常对照465例的神经认知功能的测评。采用多水平线性混合模式对神经认知功能进行分析，筛选出可以作为“内表型”的神经认知功能指标；2．对142例患者和449例正常受试者进行候选基因的病例对照研究；3．在142个核心家系中进行定性的传递不平衡研究；4．以神经认知功能为数量性状，在以上核心家系中进行定量的传递不平衡研究，探讨候选基因作为精神分裂症致病基因的可能性。
结果1．精神分裂症患者存在广泛的神经认知功能的损害，患者一级亲属存在相似神经认知功能的损害，但损害的维度更狭窄；2．将其中神经认知功能损害程度存在患者组＞子女同胞组＞父母组＞正常对照组的关系者作为“内表型”的指标，包括知识、算术、木块拼图、Stroop的读字错误数，即刻视觉记忆和逻辑记忆、以及延迟的视觉记忆和逻辑记忆，汉诺塔的计划时间、执行时间和得分，CPT的反应时间；3．在病例对照的遗传学研究中，NMU2R基因的SNPs rs1051566的等位基因A的OR值为1.70(x~2=4.670，P＜0.03)，有增高精神分裂症患病风险的趋势；在单体型分析中，rs3792906和rs1051566构建的单体型C-A的OR值为30.22(x~2=36.07，P＜1.9×10~(-9))、T-G的OR值为12.49(x~2=16.16，P＜5.83×10~(-5))和单体型T-A的OR值为30.6(x~2=25.16，P＜3.92×10~(-7))；rs1051566和rs12658265构建的单体型T-G的OR值为34.53(x~2=48.17，P＜3.92×10~(-19))，以及单体型A-T的OR值为52.35(x~2=21.37，P＜3.98×10~(-6))；rs3792906、rs1051566和rs12658265构建的单体型C-A-A的OR值为39.65(x~2=39.13，P＜3.97×10~(-10))和T-A-T的OR值为65.21(x~2=23.38，P＜1.33×10~(-6))；rs1051566、rs12658265和rs6875501构建的单体型A-A-G的OR值为13.82(x~2=11.86，P＜5.73×10~(-4))，单体型A-A-T的OR值为19.31(x~2=27.1，P＜1.93×10~(-7))和单体型A-T-G的OR为23.22(x~2=20.96，P＜4.70×10~(-6))；rs3792906、rs1051566、rs12658265和rs6875501构建的单体型C-A-A-G的OR值为11.34(x~2=8.238，P＜4.08×10~(-3))、单体型C-A-A-T的OR值为14.77(x~2=26.47，P＜2.68×10~(-7))和单体型T-A-T-G的OR值为23.22(x~2=20.96，P＜4.70×10~(-6))，提示NMU2R基因可能是精神分裂症的致病基因；3．在定性的传递不平衡研究中，没有发现候选基因的单体型同精神分裂症存在关联；4．在定量的传递不平衡研究中，SYNPO基因的单体型T-G-T-T(x~2=-2.786，P＜0.005339)和T-T-G-T-T(x~2=-3.164，P＜0.001555)与即刻逻辑记忆存在关联；SNPs rs3756579和rs33412构建的单体型T-T(x~2=-2.811，P＜0.004944)；rs3756579、rs33412和rs3733932构建的单体型T-T-G(x~2=-2.847，P＜0.004419)：rs3756579、rs33412、rs3733932和rs3733931构建的单体型T-T-G-T(x~2=-2.843，P＜0.004472)：rs33412、rs3733932、rs3733931和rs931055构建的单体型T-G-T-T(x~2=-2.670，P＜0.007577)：s3756579、rs33412、rs3733932、rs3733931和rs931055构建的单体型T-T-G-T-T(x~2=-3.312，P＜0.000927)同延迟逻辑记忆存在关联：SLC6A7基因的SNPs rs3776084和rs731376构建的单体型A-A(x~2=2.852，P＜0.004341)；rs3776084、rs731376和rs2240795构建的单体型A-A-T(x~2=2.644，P＜0.008203)同词汇流畅性正确数存在关联；NMU2R基因的rs12658265和rs6875501构建的单体型A-G(x~2=2.667，p＜0.007659)；rs3792906、rs10515666和rs12658265构建的单体型T-A-A(x~2=3.220，p＜0.00128)；rs10515666、rs12658265和rs6875501构建的单体型A-A-G(x~2.631，p＜0.0085)；rs3792906、rs10515666、rs12658265和rs6875501构建的单体型T-G-T-T(x~2=3.272，p＜0.0011)与WCST分类数存在关联。
结论本研究的结果提示神经认知功能损害在精神分裂症家系中存在家族聚集性，可以作为精神分裂症的“内表型”；NMU2R基因明显增高精神分裂症的患病风险，可能是精神分裂症的致病基因；SYNPO基因同延迟逻辑记忆存在关联；SLC6A7同词汇流畅和执行功能(WCST分类数)关联；NMU2R同执行功能(WCST分类数)存在关联；其中NMU2R基因rs10515666、rs12658265和rs6875501构建的单体型A-A-G在病例对照研究中发现同精神分裂症相关，OR值为13.82(x~2=11.86，P＜5.73×10~(-4))，在定量传递不平衡研究中，同WCST分类数存在关联。
Objects: 1. To investigate if neurocognitive deficits would be suitable to beused as a quantitative "endophenotype" for susceptibility gene searching of schizophrenia by analyzing familial cluster in first episode schizophrenic patients and their first degree relatives; 2. By using case-control and family-based association designs, to analyze the relationship between eight candidate genes on 5q31 and schizophrenia; 3. By using selected neurocognitive function assessments as quantitative "endophentypic" traits to study the association between these candidate genes and neurocognitive functions of schizophrenia.
Methods: 1. 232 first-episode schizophrenic patients, 355 parents, 273offspring and siblings and 472 normal controls were assessed by using a battery of neuropsychological tests, which includes information, arithmetic, digital symbol, digital span, block design, logical memory, visual memory, Stroop test, Trail Making test A and B, verbal fluency, tower of HANOI, modified version of Wisconsin Card Sorting Tests and CPT (continuous performance test). The differences of neurocognitive functions between schizophrenic patients, offspring and siblings, parents and normal controls were compared by using Multiple Linear Mixed Model, and then the neurocognitive function which met criteria of "endophenotype" were later used in family-based association analysis. 2. Single nucleotide polymorphism (SNP) markers from eight candidate genes on 5q31 were analyzed using single and haplotypic analysis methods in 142 patients and 449 normal controls by using COCAPHASE program and Chi-squared tests, in 142 schizophrenic TRIOS by using PDTPHASE program.
Results: 1.We found that first episode schizophrenic patients generallyperformed much worse on neuropsychological tests than normal controls, and the relatives of schizophrenic patients also had selective neurocognitive deficits. 2. Some of neurocognitive function showed different level in four different subjects groups: patientscontrols, which suggested they could be served as "endophenotype" of schizophrenia. These neurocogitive tests included information, arithmetic, block design, Stroop test, immediate visual memory and logical memory, delayed visual memory and logical memory, planning time, execute time and scores of tower of HANOI and reaction time of CPT. 3. In case-control association analysis, we found that NMU2R gene was associated with schizophrenia. However, family-based association analysis did not support this finding. 4. Using family-based quantitative trait analysis, we found that some genes were associated with selective neurocognitive function, which included SYNPO gene (immediate logical memory and delayed logical memory), SLC6A7 gene (verbal fluency), NMU2R gene (WCST).
Conclusion: This study provided further evidence that neurocognitivedeficits are familial cluster in schizophrenia and can be served as "endophenotype" in molecular genetic study; NMU2R is associated with schizophrenia and their executive function, SYNPO associated with delayed logical memory, and SLC6A7 associated with verbal fluency and execute function. Further work is needed to confirm our findings.
研究方法1．采用成套神经心理测评工具(包括利手、知识、算术、数字符号、数字广度、木块拼图、逻辑记忆、视觉记忆、Stroop测试、连线测试、言语流畅测试、汉诺塔、威斯康星卡片分类测试和连续操作任务测试)，完成了首发精神分裂症患者232例，精神分裂症父母355例，精神分裂症患者同胞、子女273例和正常对照465例的神经认知功能的测评。采用多水平线性混合模式对神经认知功能进行分析，筛选出可以作为“内表型”的神经认知功能指标；2．对142例患者和449例正常受试者进行候选基因的病例对照研究；3．在142个核心家系中进行定性的传递不平衡研究；4．以神经认知功能为数量性状，在以上核心家系中进行定量的传递不平衡研究，探讨候选基因作为精神分裂症致病基因的可能性。
结果1．精神分裂症患者存在广泛的神经认知功能的损害，患者一级亲属存在相似神经认知功能的损害，但损害的维度更狭窄；2．将其中神经认知功能损害程度存在患者组＞子女同胞组＞父母组＞正常对照组的关系者作为“内表型”的指标，包括知识、算术、木块拼图、Stroop的读字错误数，即刻视觉记忆和逻辑记忆、以及延迟的视觉记忆和逻辑记忆，汉诺塔的计划时间、执行时间和得分，CPT的反应时间；3．在病例对照的遗传学研究中，NMU2R基因的SNPs rs1051566的等位基因A的OR值为1.70(x~2=4.670，P＜0.03)，有增高精神分裂症患病风险的趋势；在单体型分析中，rs3792906和rs1051566构建的单体型C-A的OR值为30.22(x~2=36.07，P＜1.9×10~(-9))、T-G的OR值为12.49(x~2=16.16，P＜5.83×10~(-5))和单体型T-A的OR值为30.6(x~2=25.16，P＜3.92×10~(-7))；rs1051566和rs12658265构建的单体型T-G的OR值为34.53(x~2=48.17，P＜3.92×10~(-19))，以及单体型A-T的OR值为52.35(x~2=21.37，P＜3.98×10~(-6))；rs3792906、rs1051566和rs12658265构建的单体型C-A-A的OR值为39.65(x~2=39.13，P＜3.97×10~(-10))和T-A-T的OR值为65.21(x~2=23.38，P＜1.33×10~(-6))；rs1051566、rs12658265和rs6875501构建的单体型A-A-G的OR值为13.82(x~2=11.86，P＜5.73×10~(-4))，单体型A-A-T的OR值为19.31(x~2=27.1，P＜1.93×10~(-7))和单体型A-T-G的OR为23.22(x~2=20.96，P＜4.70×10~(-6))；rs3792906、rs1051566、rs12658265和rs6875501构建的单体型C-A-A-G的OR值为11.34(x~2=8.238，P＜4.08×10~(-3))、单体型C-A-A-T的OR值为14.77(x~2=26.47，P＜2.68×10~(-7))和单体型T-A-T-G的OR值为23.22(x~2=20.96，P＜4.70×10~(-6))，提示NMU2R基因可能是精神分裂症的致病基因；3．在定性的传递不平衡研究中，没有发现候选基因的单体型同精神分裂症存在关联；4．在定量的传递不平衡研究中，SYNPO基因的单体型T-G-T-T(x~2=-2.786，P＜0.005339)和T-T-G-T-T(x~2=-3.164，P＜0.001555)与即刻逻辑记忆存在关联；SNPs rs3756579和rs33412构建的单体型T-T(x~2=-2.811，P＜0.004944)；rs3756579、rs33412和rs3733932构建的单体型T-T-G(x~2=-2.847，P＜0.004419)：rs3756579、rs33412、rs3733932和rs3733931构建的单体型T-T-G-T(x~2=-2.843，P＜0.004472)：rs33412、rs3733932、rs3733931和rs931055构建的单体型T-G-T-T(x~2=-2.670，P＜0.007577)：s3756579、rs33412、rs3733932、rs3733931和rs931055构建的单体型T-T-G-T-T(x~2=-3.312，P＜0.000927)同延迟逻辑记忆存在关联：SLC6A7基因的SNPs rs3776084和rs731376构建的单体型A-A(x~2=2.852，P＜0.004341)；rs3776084、rs731376和rs2240795构建的单体型A-A-T(x~2=2.644，P＜0.008203)同词汇流畅性正确数存在关联；NMU2R基因的rs12658265和rs6875501构建的单体型A-G(x~2=2.667，p＜0.007659)；rs3792906、rs10515666和rs12658265构建的单体型T-A-A(x~2=3.220，p＜0.00128)；rs10515666、rs12658265和rs6875501构建的单体型A-A-G(x~2.631，p＜0.0085)；rs3792906、rs10515666、rs12658265和rs6875501构建的单体型T-G-T-T(x~2=3.272，p＜0.0011)与WCST分类数存在关联。
结论本研究的结果提示神经认知功能损害在精神分裂症家系中存在家族聚集性，可以作为精神分裂症的“内表型”；NMU2R基因明显增高精神分裂症的患病风险，可能是精神分裂症的致病基因；SYNPO基因同延迟逻辑记忆存在关联；SLC6A7同词汇流畅和执行功能(WCST分类数)关联；NMU2R同执行功能(WCST分类数)存在关联；其中NMU2R基因rs10515666、rs12658265和rs6875501构建的单体型A-A-G在病例对照研究中发现同精神分裂症相关，OR值为13.82(x~2=11.86，P＜5.73×10~(-4))，在定量传递不平衡研究中，同WCST分类数存在关联。
Objects: 1. To investigate if neurocognitive deficits would be suitable to beused as a quantitative "endophenotype" for susceptibility gene searching of schizophrenia by analyzing familial cluster in first episode schizophrenic patients and their first degree relatives; 2. By using case-control and family-based association designs, to analyze the relationship between eight candidate genes on 5q31 and schizophrenia; 3. By using selected neurocognitive function assessments as quantitative "endophentypic" traits to study the association between these candidate genes and neurocognitive functions of schizophrenia.
Methods: 1. 232 first-episode schizophrenic patients, 355 parents, 273offspring and siblings and 472 normal controls were assessed by using a battery of neuropsychological tests, which includes information, arithmetic, digital symbol, digital span, block design, logical memory, visual memory, Stroop test, Trail Making test A and B, verbal fluency, tower of HANOI, modified version of Wisconsin Card Sorting Tests and CPT (continuous performance test). The differences of neurocognitive functions between schizophrenic patients, offspring and siblings, parents and normal controls were compared by using Multiple Linear Mixed Model, and then the neurocognitive function which met criteria of "endophenotype" were later used in family-based association analysis. 2. Single nucleotide polymorphism (SNP) markers from eight candidate genes on 5q31 were analyzed using single and haplotypic analysis methods in 142 patients and 449 normal controls by using COCAPHASE program and Chi-squared tests, in 142 schizophrenic TRIOS by using PDTPHASE program.
Results: 1.We found that first episode schizophrenic patients generallyperformed much worse on neuropsychological tests than normal controls, and the relatives of schizophrenic patients also had selective neurocognitive deficits. 2. Some of neurocognitive function showed different level in four different subjects groups: patients
Conclusion: This study provided further evidence that neurocognitivedeficits are familial cluster in schizophrenia and can be served as "endophenotype" in molecular genetic study; NMU2R is associated with schizophrenia and their executive function, SYNPO associated with delayed logical memory, and SLC6A7 associated with verbal fluency and execute function. Further work is needed to confirm our findings.
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