精神分裂症易感受性基因座在染色體6p24.3和6p22.3的精細輿圖分析：以家族為基礎之相關性研究

Abstract

本論文以下列兩個研究探討精神分裂症易感受性基因座在染色體6p24.3和6p22.3的精細輿圖分析，同時以神經心理測驗作為內在表現型的策略來協助研究。 研究一：精神分裂症易感受性基因座在染色體6p24.3和6p22.3的精細輿圖分析:以家族為基礎之兩階段相關性研究 目的：使用單核甘酸多型性標記的精細輿圖分析去尋找位於D6S296和D6S274區域附近的精神分裂症脆弱性基因。 方法：我們對216個多發性精神分裂症的家庭在D6S296和D6S274區域使用64個單核甘酸多型性標記進行研究，並分別使用持續注意力缺失和執行功能障礙的神經心理測驗(CPT和WCST)將研究個案分成性質較相近的子群，再去做兩階段相關分析。 結果：發現位在BMP6-TXNDC5的半套型rs1225934-rs13878在全部樣本和同質性子群的分析中皆和疾病有顯著相關。同時rs1225934-rs13878分別在兩個神經心理功能缺失(遮蔽式CPT的d'和WCST的完成類別個數)的子群中具有更顯著的相關性。 結論：BMP6和TXNDC5這兩個基因可能和精神分裂症的病因有關，尤其是在持續注意力缺失和執行功能障礙的個別子群中，這值得日後做進一步的研究。 研究二：利用神經心理功能所分群出來的家庭集群進行精神分裂症易感受性基因座在染色體6p24.3和6p22.3的精細輿圖分析 目的：由於精神分裂症遺傳研究的不一致發現和異質性，使用內在表現型去幫助分析的方法已經被提倡。因此本研究想要利用神經心理測驗得到功能缺失和功能沒缺失的家庭集群，並進行候選基因與疾病的相關分析。 方法：我們利用155個有作神經心理測驗(使用CPT和WCST的其中八個指標)的多發性精神分裂症家庭去進行集群分析，分成功能缺失和功能沒缺失的家庭集群之後，再分別去做兩階段相關分析。 結果：功能缺失和功能沒缺失的家庭集群在八個神經心理測驗指標都有明顯差別，並發現位在BMP6-TXNDC5的半套型rs1225934-rs13878在功能缺失的家庭集群中和疾病有顯著相關。 結論：我們所採用的分群方法能幫助研究得到同質性的家庭集群群去進行遺傳相關研究。本研究結果支持與神經心理功能障礙有關的精神分裂症之易感受基因可能很靠近位在BMP6-TXNDC5的rs1225934-rs13878。

Two studies were to conduct a fine mapping of the schizophrenia susceptibility loci near the D6S296 and D6S274 regions using single nucleotide polymorphism (SNP) markers by neuropsychological measures as endophenotypes of the disease. Study 1. Fine Mapping of the Schizophrenia Susceptibility Loci on Chromosome 6p24.3 and 6p22.3: A Two-Stage Family-Based Association Study Objective. To identify vulnerability genes of schizophrenia near D6S296 region of chromosome 6p24.3 and D6S274 region of chromosome 6p22.3 using SNP fine mapping study. Methods. We used the 64 SNPs around 2 cM of the D6S296 and D6S296 to analyze both the single locus and haplotype markers in 216 schizophrenic families with at least 2 affected siblings. The two-stage association analyses have further carried out in the subgroups of schizophrenia defined by neuropsychological deficits of sustained attention and executive function, respectively. Results. We found that haplotype rs1225934-rs13878 on BMP6-TXNDC5 genes was significant in the whole sample as well as the subgroups of schizophrenia defined by the Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test (WCST) deficits, respectively. In particular, the association of rs1225934-rs13878 with schizophrenia became more pronounced for the subgroups with neuropsychological deficits (i.e., deficits in d' on the degraded CPT and deficits in the Categories Achieved on the WCST). Conclusions. We consider these two genes may have etiological roles in schizophrenia, especially in the subgroup defined by CPT and WCST deficits, respectively and are worth for further replication studies. Study 2. Family-Based Clustering by Neruopsychological Functioning for Fine-Mapping of the Schizophrenia Susceptibility Loci on Chromosome 6p24.3 and 6p22.3 Objective. Because of the heterogeneity and inconsistent findings regarding genetic research of schizophrenia, using endophenotypes to refine the phenotype characterization has been advocated. The aim of the study was to obtain deficit and non-deficit family clusters by means of neuropsychological measures for genetic association analyses. Methods. Eight neuropsychological test scores of the Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test (WCST) from 155 schizophrenic families comprising at least two affected siblings and were performed in a cluster analysis with data visualization. Then the deficit and non-deficit family clusters from the cluster approach were used in fine mapping of D6S296 and D6S274. Results. The scores of the deficit cluster were more impaired than those of the non-deficit cluster in all neuropsychological measures. We found rs1225934-rs13873 on BMP6-TXNDC5 genes was significant in deficit cluster by the two-stage association analysis. Conclusions. The classification strategy may provide for selecting more homogeneous groups of families into subsequent genetic analyses. The results support that a susceptibility locus conferring vulnerability to schizophrenia with neuropsychological impairment may be near rs1225934-rs13878 on BMP6-TXNDC5.