精神分裂症遺傳負荷、內在表現型以及慣用手側之探討

The relationship between genetic loading for schizophrenia, sustained attention deficits, schizotypy, and handedness

莊慧君(Hui-Chun Tsuang)

指導教授 ： 陳為堅

共同指導教授 ： 胡海國

國立臺灣大學/公共衛生學院/流行病學研究所/博士(2007年)

https://doi.org/10.6342/NTU.2007.01183

摘要

論文以下列三個子研究探討持續注意力缺失、精神分裂症之遺傳負荷、精神分裂性人格特質與慣用手側之關聯性。

研究一：單發性及多發性精神分裂症非精神病性家屬之持續注意力缺失
　　藉由連續性表現測驗所測量之持續注意力缺失被許多研究者視為精神分裂症之內在表現型。然而，現今對於持續注意力缺失於精神分裂症患者一等親是否與精神分裂症之遺傳負荷有所關聯之了解仍相當有限。本研究檢視來自單發精神分裂症家庭的107位雙親和84位無病手足，以及多發家庭的72位雙親和56位無病手足。使用的測量工具包括「遺傳研究診斷會談」與「連續性表現測驗」。知覺負荷一變項，是以「連續性表現測驗」有遮蔽及無遮蔽兩個版本之分數進行迴歸分析所得之殘差來估計。對於兩類家族成員之「連續性表現測驗」結果進行比較時，採用的統計方式能將家族相關予以調整。結果顯示，來自多發家庭之手足，在有遮蔽之「連續性表現測驗」之表現，較來自單發家庭之手足來得差。同樣的，多發家庭之手足在知覺負荷的表現，也不如來自單發家庭之手足。然而，來自多發和單發家庭之雙親，在「連續性表現測驗」及知覺負荷的表現則無顯著差異。根據上述研究發現，我們得到以下結論：伴隨有知覺負荷之持續注意力此一能力，於具有較高家族遺傳負荷之精神分裂症無病手足，會出現較嚴重的損傷。此研究之發現，可能有助於未來的精神分裂症遺傳研究。

研究二：精神分裂症患者之無精神病性家屬在精神分裂性人格特質的多重面向分析及其與持續注意力之關聯性
　　本研究致力於檢視具有不同遺傳負荷之精神分裂症患者之家屬，於精神分裂性人格特質的多重面向。並且，將進一步以持續注意力缺失來驗證之。本研究共納入203名單發精神分裂症家庭之一等親及1,310名多發家庭之一等親。所有參加研究的親屬，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」。同時，受訪者亦均接受遮蔽與無遮蔽兩種版本之「連續性表現測驗」。本研究所進行之探索性及驗證性因素分析，均以Mplus進行分析。對於持續注意力缺失和精神分裂性人格特質關聯性進行分析時，家族相關會予以校正。探索性因素分析，以單發精神分裂症家庭之家屬為研究對象，結果抽取出四個因子，分別為負性因子、正性因子、人際敏感度以及社會退縮/內向性。上述結果，再以多發精神分裂症家庭之家屬的資料，進行驗證性因素分析。結果顯示此四因子構成之結構，在各項適合度的指標上，都顯示足夠的適切性。四個因子當中，只有負性因子能一致地鑑別單發家庭和多發家庭的家屬。此外，此四個因子與「連續性表現測驗」的幾項指標呈現不同的關聯性：正性因子和人際敏感度兩因子與假警報率成正相關；負性因子和社會退縮/內向性兩因子則與正確率、敏感度呈現負相關。根據上述研究結果，我們得到以下結論：精神分裂性人格特質的四因子結構穩定的存在於具不同遺傳負荷之非精神病性家屬。而這些因子與「連續性表現測驗」的關聯性對於精神分裂症病因之探討，可以提供研究設計方面之建議。

研究三：慣用手側與精神分裂性人格特質於精神分裂症患者家屬之關聯性
　　相當多的證據均指出精神分裂症患者較常非慣用右手。然而，探討慣用手側與精神分裂性人格特質關聯性的研究卻得到不一致的研究結果。此外，這些研究幾乎都是以大學生為研究對象，因此其外推性受到相當的質疑。本研究檢視慣用手側與四個精神分裂性人格因子於精神分裂症患者家屬之關連性。本研究共納入850名雙親及334名手足。所有參加研究的親屬，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」。同時，這些親屬亦完成了「Annett慣用手側問卷」。研究中對於慣用手側採取了類別和連續兩類的指標。研究結果顯示，若使用Annett的分類方式將慣用手側分為慣用右手與非慣用右手，則非慣用右手的手足相較於慣用右手者，較常出現正性的精神分裂性人格特質。當慣用手側被視為連續變項，或者採用Briggs-Nebes之分類方式，慣用手側和精神分裂性人格特質之關聯性均不顯著。此外，若是以雙親為研究對象，不論使用何種方式界定慣用手側，其與精神分裂性人格特質之關聯性均不顯著。強烈反對使用左手應該是在雙親此一世代普遍存在的社會壓力，而此社會壓力可能使欲觀察的關聯性被低估，而無法達到統計顯著之水準。總結來說，本研究所提供的證據顯示，過去僅僅在大學生或社區樣本觀察到的慣用手側和正性精神分裂性人格特質之關聯性，也可以在精神分裂症患者之手足觀察到。此外，本研究之結果點出在進行相關研究時，必須要留意所使用之慣用手側的指標。至於究竟採用類別變項或連續變項來界定慣用手側，才更能釐清慣用手側和精神分裂性人格特質之關係，則需要後續研究來繼續探討之。

關鍵字

精神分裂症 ； 持續注意力缺失 ； 連續性表現測驗 ； 內在表現型 ； 遺傳負荷 ； 精神分裂性人格特質 ； 慣用手側

並列摘要

Three studies were conducted to investigate the relationship between sustained attention deficits, genetic loading for schizophrenia, schizotypy, and handedness in non-psychotic first-degree relatives of schizophrenic patients.
Study 1. More severe sustained attention deficits in nonpsychotic siblings of multiplex schizophrenia families than in those of simplex ones
Sustained attention deficits measured by the Continuous Performance Test (CPT) have been proposed as an endophenotype of schizophrenia. However, little is known about whether sustained attention deficits in first-degree relatives of schizophrenic patients are associated with familial loading for schizophrenia. We examined 107 parents and 84 siblings of simplex schizophrenia families as well as 72 parents and 56 siblings of multiplex schizophrenia families, all nonpsychotic, using the Diagnostic Interview for Genetic Studies and two sessions of the CPT (undegraded and degraded). The effect of perceptual load was assessed using the residual of the regression of the degraded score on the undegraded one. Statistical models that can adjust for familial correlations were used to compare the CPT performance of relatives between the two types of families. Siblings from multiplex families exhibited worse performance on the degraded CPT and less proficiency in processing the perceptual load than those from simplex families. No such difference was observed for the parents on either CPT version. We concluded that sustained attention along with perceptual load processing is more impaired in the siblings of schizophrenic patients with high familial loading and that this finding might be useful for future genetic dissection of schizophrenia.

Study 2. The Multidimensionality of Schizotypy in Nonpsychotic Relatives of Patients with Schizophrenia and Its Relations with Sustained Attention
Objective. To examine the multidimensionality of schizotypy in relatives from families with different genetic loading and to validate the structure using sustained attention deficits measured by the Continuous Performance Test (CPT).
Method. 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 section of the modified Structured Interview for Schizotypy, and completed two sessions on the CPT. Both exploratory and confirmatory factor analyses were performed using the Mplus program with categorical factor indicators. The relationship between sustained attention performance and schizotypal factors was assessed by means of linear mixed effect regression analysis to adjust for within-family correlation.
Results. A four-factor model, containing Negative Schizotypy, Positive Schizotypy, Interpersonal Sensitivity, and Social Isolation/Introversion, was extracted by exploratory factor analysis from relatives of simplex families and the results of confirmatory factor analysis in relatives of multiplex families indicated a good fit. Among the four factors, only the Negative Schizotypy factor consistently discriminated relatives of the simplex families from those of the multiplex ones. The four factors further displayed differential relations to performance indexes on the CPT, with Positive Schizotypy and Interpersonal Sensitivity positively associated with false alarm rate, whereas Negative Schizotypy and Social Isolation/Introversion inversely associated with hit rate and sensitivity.
Conclusions. A consistent four-factor model of schizotypy could be derived in non-psychotic relatives across families of different genetic loadings, and their differential relations to CPT indexes have etiological implications.

Study 3. Handedness and schizotypy in nonpsychotic first-degree relatives of schizophrenic patient
Convincing evidence showed excess of non-right handedness in schizophrenic patients. However, existing studies have found the relationship between handedness and schizotypy to be inconsistent and were limited regarding to generalization since only highly homogeneous groups have been investigated. This study examined the relation between handedness and the four schizotypal factors identified in a previous confirmatory factor analysis in 850 parents and 334 siblings of schizophrenic patients. All participants were interviewed with the Diagnostic Interview for Genetic Studies, which contains a section of the modified Structured Interview for Schizotypy, and the 12-item Annett handedness questionnaire. Both categorical and continuous indicators for handedness were examined. Non-right handed siblings of schizophrenic patients displayed more positive schizotypal features than their right handed counterparts when the two-way Annett’s handedness classification was adopted. No association was found when handedness was treated as continuous or when the Briggs-Nebes’ classification was used. The relationship between handedness and schizotypy was insignificant for parents probably due to the strong social pressure against left-handedness in that generation. In conclusion, the relationship between handedness and positive schizotypy has been confirmed in siblings of schizophrenic patients. Additionally, the study highlights the importance of taking into account the effect of handedness indicators on relating studies. Whether categorical or continuous approach of handedness better identify people with high positive schizotypy warrants further investigation.

並列關鍵字

Schizophrenia ； Sustained attention deficits ； Continuous Performance Test (CPT) ； Endophenotypes ； Genetic loading ； Schizotypy ； Handedness

參考文獻

1. Baron M: Genetics of schizophrenia and the new millennium: progress and pitfalls. Am J Hum Genet 2001; 68:299-312

2. Tsuang M: Schizophrenia: genes and environment. Biol Psychiatry 2000; 47:210-220

3. Altmuller J, Palmer LJ, Fischer G, Scherb H, Wjst M: Genomewide scans of complex human diseases: true linkage is hard to find. Am J Hum Genet 2001; 69:936-50

4. Gottesman, II, Gould TD: The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160:636-45

5. Gottesman I, Shields J: Schizophrenia: The Epigenetic Puzzle. New York, Cambridge University Press, 1982