- 學位論文
與思覺失調症中減弱之菸鹼酸皮膚反應有關之遺傳變異
Genetic Variants Associated with Attenuated Niacin Flush Response in Schizophrenia
摘要
背景與目的: 菸鹼酸是維他命的一種 (vitamin B3)，時常作為降血脂藥物，但此物質無論口服或是皮膚接觸皆會使皮膚產生紅腫反應；然而在思覺失調症患者中，菸鹼酸所導致之皮膚紅腫反應明顯地減弱，而此減弱反應也同時在患者之一等親中有較高比例地出現，顯示遺傳基因對此特徵扮演著重要的角色，也暗示著減弱之菸鹼酸皮膚反應可能是思覺失調症的潛在內表型。此研究主要探討此內表型在基因型與表現型之間的關係，首先，我們試圖了解減弱之菸鹼酸皮膚反應是否和思覺失調症中之臨床特徵有關，進一步釐清此內表型在此疾病中所扮演的角色；再者，此研究進行全基因體關連性分析 (Genome-wide association study, GWAS)，試圖尋找和減弱之菸鹼酸皮膚反應有關之遺傳變異，並採用貝氏因子的統計方法以進行多基因關聯性分析。 方法: 此研究樣本來自於台灣思覺失調症之全基因體研究計畫 (Schizophrenia Trio Genomic Study of Taiwan, STOGET)，並從中納入1,866位思覺失調症患者，屬於全為病例設計之研究。每位病人皆會接受遺傳研究診斷問卷訪談 (Diagnostic Interview for Genetic Studies, DIGS)、神經認知功能測驗、以及菸鹼酸皮膚貼片測驗，並抽血以進行後續的基因型定型。在考量以基因標誌為基礎並對每個觀察值所估計的遺傳率後，我們決定以0.1M濃度下之三個時間點 (5, 10, 15分鐘) 的紅腫分數總和進行後續分析。首先，我們進行單點全基因體關聯性分析，並使用貝氏因子的排序來進行單點的選取，再者，我們進行貝氏多基因關聯性分析，試圖找到一組擁有最佳解釋力的遺傳變異，進一步對這些位點進行路徑分析 (Ingenuity Pathway Analysis, IPA)，試圖了解這些基因的功能與關連性。 結果: 在所有思覺失調症的病人中，菸鹼酸皮膚測驗反應較不敏感的病人相對於較敏感的病人，有較低的整體功能分數 (p=0.05)、較多的正向症狀 (p<0.0001)與負性症狀 (p=0.005)、以及較差的認知功能表現 (p<0.0001)，代表減弱之菸鹼酸皮膚反應確實和思覺失調症中的臨床症狀表現相關。在全基因體關連性分析中，沒有任何單點達到全基因體顯著水準，然而，當採用另一種指標“貝氏因子”時，貝氏因子最大的變異位置位於GRM7基因，過去曾被發現與思覺失調症有關；此外，貝氏多基因關聯性分析的結果顯示當貝氏因子大於120時，可以找出一組由74個位點所組成的遺傳變異並具有最佳的解釋力 (p=0.059)，並且成功對應到29個已知基因位置，路徑與網絡分析結果皆指出這些和減弱之菸鹼酸皮膚反應有關的基因主要可能和神經突觸與訊號傳導功能有關。 結論: 此研究發現減弱之菸鹼酸皮膚反應的確和思覺失調症中的臨床症狀有顯著關聯，意味著這種簡易、方便的菸鹼酸皮膚貼片測驗在未來也許能實際應用至臨床，並幫助醫師了解病人症狀，以給予更適當的藥物或治療。此外，我們利用貝氏多基因統計方法發現了一組解釋力最佳、並可能與思覺失調症中減弱之菸鹼酸皮膚反應有關的遺傳變異，從中去探索可能的功能與機制，進一步建立減弱之菸鹼酸反應如何修飾思覺失調症之基礎。
並列摘要
Background: Attenuated niacin flush response is consistently found in schizophrenia patients and their nonpsychotic relatives, but its relation to clinical features and genetic risk factors remain unclear. This study aimed to 1) examine the association between attenuated niacin flush response and clinical features in schizophrenia; and 2) identify the genetic variants related to attenuated niacin flush response. Methods: A total of 1866 schizophrenia patients who were interviewed with the Diagnostic Interview for Genetic Studies (DIGS) underwent a niacin skin patch test with three concentrations of aqueous methylnicotinate (0.1M, 0.01M, 0.001M) measured at 5, 10 ,15 minutes rated on a 4-point scale. Part of the sample (n=856) was genotyped to search for genome-wide genetic variants. A newly developed polygenic test called the Adaptive Combination of Bayes Factors (ADABF) was applied to select SNPs associated with attenuated niacin flush response. Ingenuity Pathway Analysis (IPA) was further applied to explore the biological mechanism of the selected genetic loci. Results: Patients with an attenuated niacin flush response score that exhibited robust SNP-based heritability showed lower global functional score (p=0.02), higher negative symptoms score (p=0.003), higher positive symptoms score (p<0.0001), and more cognitive impairment (p<0.0001). No single SNP reached genome-wide significance. However, based on another alternative measure, Bayes factor (BF), the strongest association signal with the highest BF was mapped at the GRM7 gene, which plays a vital role of glutamatergic neurotransmission and has been found associated with schizophrenia previously. Furthermore, Bayesian polygenic test (ADABF) was enriched by combing 74 SNPs each with a Bayes factor > 120 even though the association was not significant (p=0.059). Pathway analysis implied that the regulation of these selected genes was mainly correlated to the synaptic neurotransmitter signaling. Conclusions: Attenuated niacin flush response in schizophrenia is characterized by certain clinical features and is influenced by multiple genetic variants with small effects. Further investigation of the biological functions is warranted.