精神分裂症之類別性與量性次表現型之全基因連鎖分析

本論文為一精神分裂症全基因連鎖分析研究。以下三個子研究分別從精神分裂症的不同面向，包含：人格特質、臨床表徵，以及神經認知表現，尋找精神分裂症的類別性與量性次表現型之易感受基因座。研究一、精神分裂症患者之非精神病性家屬在準精神分裂人格特質的多面向性及其在排序子集連鎖分析的應用本研究主要目的為檢視精神分裂症親屬其精神分裂性人格特質的不同面向，並且進一步使用以精神分裂症患者其症狀與其親屬的精神分裂性人格特質作為家庭分組依據所進行的排序子集連鎖分析 (ordered subset linkage analysis) 來驗證其多面向的架構。本研究共納入203名單發精神分裂症家庭與1,310名多發性家庭的一等親，所有參與研究的親屬均接受「遺傳研究診斷會談」，此一會談工具涵蓋了「準精神分裂症結構化問卷」。以Mplus使用類別因素指標所進行的探索性及驗證性因素分析得出四因子模式：負性因子、正性因子、人際敏感以及社會退縮/內向性。根據不同的「精神分裂症—精神分裂人格特質」因子所進行的排序子集分析 (ordered subset analysis, OSA) 得到不同的連鎖區域，因此提供證據支持本四因子模式。六個具有顯著增加無母數連鎖標準分數 (nonparametric linkage z [NPL-Z] scores) 的染色體區域如下：「負性精神分裂症—負性精神分裂人格特質」於15q21.1 (NPL-Z = 3.60)，「負性精神分裂症—社會退縮/內向性人格特質」於10q22.3 (NPL-Z = 3.83) 以及 15q21.3 (NPL-Z = 3.36)，「正性精神分裂症—正性精神分裂人格特質」於5q14.2 (NPL-Z = 3.20) 以及11q23.3 (NPL-Z = 3.31)，「正性精神分裂症—人際敏感人格特質」於4q32.1 (NPL-Z = 3.31)。其中，由不同分組家庭所得出的最高的 NPL-Z 為3.83位於10q22.3，顯著高於由全部樣本所得出的NPL-Z，其值為2.88 (empirical p value = 0.04)。上述結果提供精神分裂人格特質之四因子模式的可能遺傳病因證據。研究二、以發病年齡與神經認知缺損所定義的精神分裂症亞型所尋找到的遺傳連鎖證據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，也許可以協助找到更高的遺傳連鎖信號。本研究目的在於檢驗以較早發病年齡與較嚴重神經認知缺損所定義的精神分裂症之子集家庭的連鎖證據。精神分裂症病人與其一等親來自於分佈於全台灣的六個資料收集研究中心。本研究的557個精神分裂病患家庭其收案準則為家中至少有兩位罹病手足且具有中國漢族血統。收案樣本中，總計罹病人數為 1,207 人，未罹病人數為1,035人。每位研究個案將完成面對面半結構式訪談，持續注意力測驗(Continuous Performance Test , CPT)，及威斯康辛卡片分類測驗 (Wisconsin Card Sorting Test)。基因定型總計為386個微衛星標記。在進行一系列OSA後，相較於原先使用全部家庭所進行的連鎖分析，以較早發病年齡與認知神經缺損所定義的子集家庭中有四個染色體區域（2q22.1, 8q13.1, 8q21.1, 以及 9p13.3）在最大值的NPL-Z分數有顯著增加，並達到全基因顯著的標準。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，此二個連鎖分數亦同時達到全基因顯著。我們在以較年輕的發病與較多的CPT錯誤警報率所組成的家庭中找到2q22.1有顯著的連鎖證據。我們同時亦發現其他的遺傳連鎖證據在具特定認知神經功能缺損的家庭分別位於8q13.1, 8q21.1, 以及9p13.3。這些結果指出納入遺傳相關的次表現型在探討精神分裂症複雜遺傳病因的重要性。研究三、全基因掃瞄針對影響精神分裂症其神經認知表現型的連續性狀基因座認知神經缺損是精神分裂症的核心症狀。針對此性狀所進行的遺傳研究將可協助釐清精神分裂症其家族聚集性下的生理路徑。本研究目的在於尋找影響精神分裂症神經認知表現的易感受基因座。精神分裂症病人與其一等親來自於分佈於全台灣的六個資料收集研究中心。本研究的557個精神分裂病患家庭其收案準則為家中至少有兩位罹病手足且具有中國漢族血統。收案樣本中，總計罹病人數為 1,207 人，未罹病人數為1,035人。本研究針對罹病個案，進行一系列的全基因多點無母數量性基因座連鎖分析。全基因顯著水準是透過1,000次虛擬的全基因掃瞄而確定。NPL-Z分數高於3.0的染色體位置位於5q，6q，以及12q，分別與CPT的不同指標有關。其中，有兩個連鎖信號達到全基因顯著水準，為NPL-Z分數3.32，此乃針對未遮蔽版CPT的打擊率所找到位於12q24.32的D12S2078標誌 (genome-wide empirical p = 0.03)，以及NPL-Z分數3.28，此乃針對遮蔽版CPT的反應時間所找到位於5q14.2的D5S641標誌 (genome-wide empirical p = 0.046)。12q24.32在過去精神分裂症的連鎖研究中較少被發現，5q14.2則重疊於我們近來針對正性精神分裂症—正性準精神分裂人格特質的子集家庭所進行的連鎖研究而找到的染色體區域。本研究中不同的連鎖結果將有助於未來針對精神分裂症的遺傳研究上，提供功能性的假說。

關鍵字

精神分裂症；精神分裂性人格特質；發病年齡；神經認知缺損；全基因連鎖分析；排序子集連鎖分析；連續性狀連鎖分析

並列摘要

The dissertation is a research of genome-wide linkage analyses for schizophrenia. Three sub-studies were conducted to investigate the susceptibility loci linked with categorical and quantitative subphenotypes. These studies focused on different dimensions of this disorder, including personality traits, clinical manifestation, and neurocognitive performances. Study I. The Multidimensionality of Schizotypy in Nonpsychotic Relatives of Patients with Schizophrenia and Its Applications in Ordered Subsets Linkage Analysis of Schizophrenia This study aimed to examine the multidimensionality of schizotypy and validate the structure using ordered subset linkage analyses on information from both relatives’ schizotypy and probands’ schizophrenia symptoms. A total of 203 and 1,310 nonpsychotic first-degree relatives from simplex and multiplex schizophrenia families, respectively, were interviewed with the Diagnostic Interview for Genetic Studies, which contains a modified Structured Interview for Schizotypy. Using Mplus program with categorical factor indicators, a four-factor model (Negative Schizotypy, Positive Schizotypy, Interpersonal Sensitivity, and Social Isolation/Introversion) was extracted by exploratory factor analysis from relatives of simplex families and was confirmed in relatives of multiplex families. The validity of each factor was supported by distinct linkage findings resulting from ordered subset analysis based on different combinations of schizophrenia-schizotypy factors. Six chromosomal regions with significant increase in nonparametric linkage z score (NPL-Z) were found as follows: 15q21.1 (NPL-Z = 3.60) for Negative Schizophrenia-Negative Schizotypy, 10q22.3 (NPL-Z = 3.83) and 15q21.3 (NPL-Z = 3.36) for Negative Schizophrenia-Social Isolation/Introversion, 5q14.2 (NPL-Z = 3.20) and 11q23.3 (NPL-Z = 3.31) for Positive Schizophrenia-Positive Schizotypy, and 4q32.1 (NPL-Z = 3.31) for Positive Schizophrenia-Interpersonal Sensitivity. The greatest NPL-Z of 3.83 on 10q22.3 in the subset was significantly higher than the greatest one of 2.88 in the whole sample (empirical p value = 0.04). We concluded that a consistent four-factor model of schizotypy could be derived in non-psychotic relatives across families of patients with different genetic loadings in schizophrenia. Their differential relations to linkage signals have etiological implications and provide further evidence for their validity. Study II. Genetic Linkage Evidence for Distinct Subtypes of Schizophrenia Characterized by Age at Onset and Neurocognitive Deficits As schizophrenia is genetically and phenotypically heterogeneous, targeting subphenotypes with possible greater genetic loadings may help reveal a more homogeneous subset of families with greater linkage signals. This study aimed to evaluate the genetic linkage evidence for schizophrenia in subsets of families using earlier age at onset or greater neurocognitive deficits as subphenotypes. Patients with schizophrenia and their first-degree relatives recruited from six data collection research center throughout Taiwan. The sample comprised 1,207 affected individuals and 1,035 unaffected individuals of Han Chinese ethnicity from 557 sib-pair families co-affected with DSM-IV schizophrenia. Subjects completed a face-to-face semi-structured interview, the Continuous Performance Test (CPT), the Wisconsin Card Sorting Test, and were genotyped with 386 microsatellite markers across the genome. A series nested ordered subset genome-wide linkage analyses were conducted in this study. Four chromosomal regions (2q22.1, 8q13.1, 8q21.1, and 9p13.3 ) had significant increases in maximum nonparametric linkage z (NPL-Z) scores and reached genome-wide significance in subsets of families of patients with schizophrenia characterized by age at onset or neurocognitive deficits compared with those obtained in initial linkage analyses using all available families. A maximum NPL-Z score of 4.12 at 2q22.1 was found in 295 families ranked by increasing age at onset. Based on this subset, a further subsetting by false alarm rate on the undegraded and degraded CPT obtained further increase in the nested subset-based NPL-Z on 2q22.1, with a score of 5.36 in 228 families and 5.50 in 243 families, respectively, reaching genome-wide significance. We found strong evidence of linkage on chromosome 2q22.1 in families of schizophrenia patients with younger age at onset and more CPT false alarm rates. We also found evidence of linkage on 8q13.1, 8q21.1, and 9p13.3 in families with particular neurocognitive deficits. These results highlight the importance of incorporating genetic-related subphenotypes in unraveling the complex genetics of schizophrenia. Study III. A Genome-wide Scan for Quantitative Trait Loci Influencing Neurocognitive Phenotypes for Schizophrenia Neurocognitive impairment is the core symptoms of schizophrenia. Genetic studies of such traits may help to elucidate the biological pathways underlying familial liability to schizophrenia. This study aimed to identify regions containing susceptibility loci for the neurocognitive performances in schizophrenia. The sample comprised 1,207 affected individuals and 1,035 unaffected individuals of Han Chinese ethnicity from 557 sib-pair families co-affected with DSM-IV schizophrenia. Subjects completed a face-to-face semi-structured interview, the Continuous Performance Test (CPT), the Wisconsin Card Sorting Test, and were genotyped with 386 microsatellite markers across the genome. A series of autosomal genome-wide multipoint non-parametric quantitative trait linkage (QTL) analysis were performed in affected individuals only. Determination of genome-wide empirical significance was implemented using 1,000 simulated genome scans. Results for nonparametric linkage z (NPL-Z) scores greater than 3.0 were found on 5q, 6q, and 12q for particular CPT indices, respectively. Two linkage peaks reached genome-wide significance: NPL-Z scores of 3.32 for undegraded CPT hit rate on 12q24.32 at marker D12S2078 (genome-wide empirical p = 0.03) and NPL-Z scores of 3.28 (genome-wide empirical p = 0.046) on 5q14.2 at marker D5S641for degraded CPT reaction time. The identification of quantitative trait locus 12q24.32 has seldom been implicated in previous linkage studies of schizophrenia, while 5q14.2 overlaps the chromosomal region reported in our recent linkage studies for a subset of schizophrenia families with Positive Schizophrenia-Positive Schizotypy. The differential linkage results may inform functional hypotheses in further genetic analyses for schizophrenia.

並列關鍵字

Schizophrenia ； Schizotypy ； Age at onset ； Neurocognitive deficits ； Genome-wide linkage analyses ； Ordered subset analyses ； Quantitative trait linkage analyses

參考文獻

Chapter 1

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精神分裂症之類別性與量性次表現型之全基因連鎖分析

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