2011-01-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/656962摘要：精神分裂症具有遺傳與表現型的異質性，藉由具有較高遺傳負荷量的次表現型所定義的具同質性之子集家庭，也許可以協助研究者找到更高的遺傳連鎖信號。在過去以分佈全台灣研究中心收案的大型研究中，我們已經有收案完成的557 個精神分裂病患家庭（罹病人數為 1,207 人，未罹病人數為1,035 人），其收案準則為家中至少有兩位罹病手足。在我們使用 386 個微衛星多型性遺傳標記所進行的精神分裂症全基因掃瞄研究中，最高的無母數連鎖標準分數 (nonparametric linkage z [NPL-Z] scores) 為 2.88。在此三年計畫的申請書，我們將針對我們使用較早的發病年齡與較多的持續注意力測驗 (Continuous Performance Test , CPT) 或威斯康辛卡片分類測驗 (Wisconsin Card Sorting Test) 作為次表現型所進行全基因排序子集連鎖分析而得到的連鎖信號，進行後續的追蹤研究。在我們的初步研究中，最高的NPL-Z 分數為 4.12 位於 2q22.1，是以發病年齡遞增排序所定義的295 個家庭而得到此連鎖訊號。根據此295 個家庭，以未遮蔽及已遮蔽版本的CPT 的假警報率進一步進行分群所得到的巢式子集中得到更高的NPL-Z 分數，分別是5.36 於228 個家庭，5.50 於243 個家庭。針對此珍貴的線索，我們將執行一個多階段精細輿圖分析來進一步找到更精細的遺傳訊號： (1) 在第一年，我們計畫針對160 精神分裂症患者（80 位具有早發病與具有認知缺損的病人與80 位未具有早發病與具有認知缺損的病人）進行Affymetrix Genome-Wide Human SNP Array 6.0 實驗；(2) 同樣在第一年，我們計畫進行遺傳關連分析，聚焦於 23.1 Mb 的基因區域 （D2S1328 at 133 cM to D2S1399 at 152 cM, the support interval surrounding D2S442）；(3)在第二年，我們計畫在一個獨立樣本中的病人樣本 (150 位具有早發病與具有認知缺損的病人與150 位未具有早發病與具有認知缺損的病人) 重現與疾病具有關連性的單核甘酸多型性；(4) 在第三年，針對被確認的單核甘酸多型性附近區域進行序列分析，期待能找到針對早發性與具認知缺損的精神分裂症的罕見遺傳變異。我們藉由此研究計畫能解碼與跟早發病與更多的 CPT 錯誤訊號有關遺傳變異。<br> Abstract: As schizophrenia is genetically and phenotypically heterogeneous, targeting subphenotypes with possible greater genetic loadings may help dissect genetic structure of schizophrenia. We have recruited a large sample of 557 families of sib-pairs co-affected with schizophrenia (1,207 affected individuals and 1,035 unaffected individuals) throughout Taiwan and genome-wide linkage scan using 386 microsatellitemarkers revealed a maximum nonparametric linkage z (NPL-Z) score of 2.88. In this 3-year grant application, we propose to follow-up a linkage signal derived from a genome-wide ordered subset linkage analyses for schizophrenia using earlier age at onset or greater Continuous Performance Test (CPT) deficits or Wisconsin Card Sorting Test (WCST) as subphenotypes. In a preliminary study, a maximum NPL-Z score of 4.12 (empirical P = 0.007) at 2q22.1 was found in 295 families ranked by increasing ageat onset. Based on this subset, a further subsetting by false alarm rate on the degraded CPT achieved further increase in the NPL-Z scores on 2q22.1, with a score of 5.50 in 243 families. Following this precious clue, we will conduct a multi-stage fine mapping to further narrow down this signal: 1) to applythe Affymetrix Genome-Wide Human SNP Array 6.0 in a sample of 180 schizophrenia patients (80 patients with early onset and cognitive deficits vs. 80 patients without such features) in the first year; 2) to conduct association analysis with focus on a region of 23.1 Mb (D2S1328 at 133 cM to D2S1399 at 152cM, the support interval surrounding D2S442) in the first year too; 3) to replicate the tentatively associated SNP markers in an independent sample of schizophrenia patients (150 deficit patients vs. 150 non-deficit ones) in the second year; and 4) to re-sequence the areas around the confirmed SNPs to lookfor rare coding variants for schizophrenia with early age at onset and neurocognitive deficits in the third year. We expect that genetic variants related to schizophrenia with younger age at onset and more CPT false alarm rates can be deciphered in this proposal.精神分裂症