偏执型与未分化型精神分裂症家系两个靶染色体易感位点的连锁分析

目的 探讨中国人群中精神分裂症亚型与1号染色体长臂1q21-25和6号染色体短臂6p21-25易感基因位点的相关性.方法 在染色体1q21-25区域中选择5个微卫星标记和6p21-25区域中选择8个微卫星标记对36个来自中国河南省的精神分裂症家系(19个偏执型和17个未分化型)中的242个个体进行基因分型及参数和非参数连锁分析.结果 36个精神分裂症家系的1号染色体参数分析时,在显性遗传模式下,D1S484得到多点异质性对数优势记分法(heterogeneity Log of odds score method,HLOD)值为1.33 (α=0.38).非参数分析时,在D1S484得到多点非参数连锁(nonparametric linkage,NPL)值为1.89(P=0.0188);D1S2878单点NPL值为2.11(P=0.0111),多点NPL值为2.41(P=0.0053);D1S196多点NPL值为1.59(P=0.0383).提示以上3个位点存在连锁.在17个未分化型家系中,D1S484多点NPL值为1.60(P=0.0367);D1S2878单点 NPL值为1.95(P=0.0145),多点NPL值为2.39(P=0.0041); D1S196多点NPL值为 1.74(P=0.0255).这与以上36个家系提示连锁的位点相同.在19个偏执型家系中,5个微卫星标记位点均未提示连锁.36个精神分裂症家系的6号染色体分析发现,除19个偏执型精神分裂症家系参数连锁分析在隐性模式下D6S289位点单点HLOD值为1.26(α=0.40),多点HLOD值为1.12(α=0.38)和非参数连锁分析在D6S289位点单点NPL值为1.52(P=0.0402),多点NPL值为1.92(P=0.0206)之外,36个精神分裂症家系总体分析和其中17个未分化型家系分型分析的结果显示8个微卫星标记位点均未提示有连锁.结论 在染色体1q23.3 和1q24.2区域可能存在与中国河南省未分化型精神分裂症相关的易感基因;在6p23区域可能存在与偏执型精神分裂症相关的易感基因.

Abstract：

Objective To investigate the relationship of susceptibility loci in chromosomes 1q21-25 and 6p21-25 and schizophrenia subtypes in Chinese population. Methods A genomic scan and parametric and non-parametric analyses were performed on 242 individuals from 36 schizophrenia pedigrees, including 19 paranoid schizophrenia and 17 undifferentiated schizophrenia pedigrees, from Henan province of China using 5 microsatellite markers in the chromosome region 1q21-25 and 8 microsatellite markers in the chromosome region 6p21-25, which were the candidates of previous studies. All affected subjects were diagnosed and typed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised (DSM-Ⅳ-TR; American Psychiatric Association, 2000). All subjects signed informed consent. Results In chromosome 1, parametric analysis under the dominant inheritance mode of all 36 pedigrees showed that the maximum multi-point heterogeneity Log of odds score method (HLOD) score was 1.33 (α=0.38). The non-parametric analysis and the single point and multi-point nonparametric linkage (NPL) scores suggested linkage at D1S484, D1S2878, and D1S196. In the 19 paranoid schizophrenias pedigrees, linkage was not observed for any of the 5 markers. In the 17 undifferentiated schizophrenia pedigrees, the multi-point NPL score was 1.60 (P=0.0367) at D1S484. The single point NPL score was 1.95 (P=0.0145) and the multi-point NPL score was 2.39 (P=0.0041) at D1S2878. Additionally, the multi-point NPL score was 1.74 (P=0.0255) at D1S196. These same three loci showed suggestive linkage during the integrative analysis of all 36 pedigrees. In chromosome 6, parametric linkage analysis under the dominant and recessive inheritance and the non-parametric linkage analysis of all 36 pedigrees and the 17 undifferentiated schizophrenia pedigrees, linkage was not observed for any of the 8 markers. In the 19 paranoid schizophrenias pedigrees, parametric analysis showed that under recessive inheritance mode the maximum single-point HLOD score was 1.26 (α=0.40) and the multi-point HLOD was 1.12 (α=0.38) at D6S289 in the chromosome 6p23. In nonparametric analysis, the single-point NPL score was 1.52 (P=0.0402) and the multi-point NPL score was 1.92 (P=0.0206) at D6S289. Conclusion Susceptibility genes correlated with undifferentiated schizophrenia pedigrees from D1S484, D1S2878, D1S196 loci, and those correlated with paranoid schizophrenia pedigrees from D6S289 locus are likely present in chromosome regions 1q23.3 and 1q24.2, and chromosome region 6p23, respectively.

Linkage analysis of susceptibility loci in 2 target chromosomes in pedigrees with paranoid schizophrenia and undifferentiated schizophrenia

Objective To investigate the relationship of susceptibility loci in chromosomes 1q21-25 and 6p21-25 and schizophrenia subtypes in Chinese population. Methods A genomic scan and parametric and non-parametric analyses were performed on 242 individuals from 36 schizophrenia pedigrees, including 19 paranoid schizophrenia and 17 undifferentiated schizophrenia pedigrees, from Henan province of China using 5 microsatellite markers in the chromosome region 1q21-25 and 8 microsatellite markers in the chromosome region 6p21-25, which were the candidates of previous studies. All affected subjects were diagnosed and typed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised (DSM-Ⅳ-TR; American Psychiatric Association, 2000). All subjects signed informed consent. Results In chromosome 1, parametric analysis under the dominant inheritance mode of all 36 pedigrees showed that the maximum multi-point heterogeneity Log of odds score method (HLOD) score was 1.33 (α=0.38). The non-parametric analysis and the single point and multi-point nonparametric linkage (NPL) scores suggested linkage at D1S484, D1S2878, and D1S196. In the 19 paranoid schizophrenias pedigrees, linkage was not observed for any of the 5 markers. In the 17 undifferentiated schizophrenia pedigrees, the multi-point NPL score was 1.60 (P=0.0367) at D1S484. The single point NPL score was 1.95 (P=0.0145) and the multi-point NPL score was 2.39 (P=0.0041) at D1S2878. Additionally, the multi-point NPL score was 1.74 (P=0.0255) at D1S196. These same three loci showed suggestive linkage during the integrative analysis of all 36 pedigrees. In chromosome 6, parametric linkage analysis under the dominant and recessive inheritance and the non-parametric linkage analysis of all 36 pedigrees and the 17 undifferentiated schizophrenia pedigrees, linkage was not observed for any of the 8 markers. In the 19 paranoid schizophrenias pedigrees, parametric analysis showed that under recessive inheritance mode the maximum single-point HLOD score was 1.26 (α=0.40) and the multi-point HLOD was 1.12 (α=0.38) at D6S289 in the chromosome 6p23. In nonparametric analysis, the single-point NPL score was 1.52 (P=0.0402) and the multi-point NPL score was 1.92 (P=0.0206) at D6S289. Conclusion Susceptibility genes correlated with undifferentiated schizophrenia pedigrees from D1S484, D1S2878, D1S196 loci, and those correlated with paranoid schizophrenia pedigrees from D6S289 locus are likely present in chromosome regions 1q23.3 and 1q24.2, and chromosome region 6p23, respectively.