利用菸鹼酸皮膚漲紅反應進行精神分裂症之排序子集的遺傳連鎖分析

背景：先前的文獻指出，精神分裂症患者對於菸鹼酸所引起的皮膚漲紅反應相較於健康對照組的強度較弱或是反應受損，並且此現象並未在其他精神疾患中發現，具有專一性。近期的研究也顯示精神分裂症患者對於菸鹼酸的受損的皮膚漲紅反應具有家族聚集性，且此現象在遺傳負荷較高的多發性家庭當中更為明顯。目標：本研究的主要目的是以對於菸鹼酸的皮膚漲紅反應為基礎，利用排序子集之連鎖分析的方法進行精神分裂症的全基因掃瞄。方法：Taiwan Schizophrenia Linkage Study為一個全國性的樣本，由兩個以上的家庭成員依據DSM-IV診斷具有精神分裂症或抑鬱型情感性分裂疾患的家庭所組成。基因定型包含369個平均間隔為9-cM的微衛星標記。其中至少一位家庭成員具有菸鹼酸皮膚貼片試驗資料的家庭共190個，作為本次分析的樣本。每個家庭皆計算其成員的平均菸鹼酸漲紅反應分數，並以此分數作為排序子集之連鎖分析的排序依據。排序子集之連鎖分析將家庭樣本依序放入連鎖分析以提高樣本的均質性，而取得各染色體當中由特定子集所產生的最大無母數連鎖分析Z值。以排列檢定對於子集所產生的連鎖訊號上升進行統計顯著的檢定。而連鎖訊號的全基因顯著程度則透過兩步驟的方式進行校正。結果：菸鹼酸皮膚漲紅反應較正常的家庭所組成的子集，在5q35.2 (NPL-Z = 3.65, an increase of 2.97, empirical p = 0.006, nominal p = 0.00013)以及15q26 (NPL-Z = 3.08, an increase of 2.11, empirical p = 0.047, nominal p = 0.0011)位置的連鎖訊號上升達到統計顯著，並且達到全基因的統計顯著。而菸鹼酸皮膚漲紅反應較弱的家庭所組成的子集，在22q13.1 (NPL = 2.26, an increase of 2.09, empirical p = 0.043, nominal p = 0.012)位置的連鎖訊號上升達到統計顯著，但未達全基因的統計顯著。這些位置皆未曾出現在全基因掃瞄的顯著結果當中。結論：本研究結果顯示菸鹼酸的漲紅反應可以作為精神分裂症潛在異質性的標誌變項，可用於精神分裂症次群組的區分，以利於找尋不同的易感受基因。

關鍵字

精神分裂症；菸鹼酸皮膚漲紅反應；全基因掃瞄；子集排序之連鎖分析

並列摘要

Objective: Previous studies suggested that the attenuation of flush response to topically applied niacin was specific to patients with schizophrenia, showed familial aggregation in families of patients with schizophrenia, and was more impaired in both patients and non-psychotic relatives from families with higher familial loading for schizophrenia. This study aimed to evaluate the linkage signal for schizophrenia in genome scan by means of ordered subset analysis on the basis of the impaired niacin flush response. Methods: Subjects of this study were part of the participants of the Taiwan Schizophrenia Linkage Study, which collected a nation-wide family sample with at least two siblings fulfilling the DSM-IV criteria for schizophrenia or schizoaffective disorder, depressive type. The genotyping was conducted by the Center for Inherited Disease Research, with 369 microsatellite markers spaced at an average of 9-cM intervals. Among these families, 190 had at least one member with information on the niacin skin test and were included for this study. The mean niacin flush response score averaged over all the family members with the niacin skin test information was used as the covariate for each family. A series of ordered subset linkage analyses was then conducted to increase the homogeneity of the samples by ranking families according to the mean niacin flush response scores in each family, and generate a new maximum nonparametric linkage Z (NPL-Z) score on each chromosome for each subset of families. The statistical significance for a subset-derived increase in linkage signal was evaluated using permutations to obtain a chromosome-wide p value. Then the genome-wide significance level of the OSA linkage result was evaluated using a two-step correction procedure. Results: Two chromosomal regions were found to have significant increases in NPL-Z score by ranking families in descending order of niacin flush score, including 5q35.2 (NPL-Z = 3.65, an increase of 2.97, empirical p = 0.006) and 15q26 (NPL-Z = 3.08, an increase of 2.11, empirical p = 0.047). Both regions reached genome-wide significance level with a nominal p value of 0.00013 and 0.0011, respectively. Meanwhile, we also obtained a significant increase in linkage signal on chromosome 22q13.1 (NPL = 2.26, an increase of 2.09, empirical p = 0.043) by ranking families in ascending order of niacin flush score, through not reaching genome-wide significance (a nominal p value of 0.012). In contrast, there was little evidence of linkage on these regions in the original genome-wide analyses. Conclusions: These results suggest that the flush response to niacin may be a marker of underlying heterogeneity in schizophrenia and potentially useful to demarcate subgroups of the disorder with different susceptibility genes.

並列關鍵字

schizophrenia ； niacin flush response ； genome-wide analysis ； ordered subset analysis

參考文獻

Lee, H. J., Song, J. Y., Kim, J. W., Jin, S. Y., Hong, M. S., Park, J. K., Chung, J. H., Shibata, H. & Fukumaki, Y. (2005). Association study of polymorphisms in synaptic vesicle-associated genes, SYN2 and CPLX2, with schizophrenia. Behav Brain Funct 1, 15.

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利用菸鹼酸皮膚漲紅反應進行精神分裂症之排序子集的遺傳連鎖分析

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