透過候選基因的方法探討具季節模式之鬱症患者的遺傳變異研究

Identifying Genetic Variants for Depressive Patients with Seasonal Patterns: a Candidate Gene Approach

范騰畬(Teng-Yu Fan)

指導教授 ： 郭柏秀

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/碩士(2018年)

https://doi.org/10.6342/NTU201803901

摘要

相較於其他的精神疾病，憂鬱症具有較高的盛行率與症狀表現的歧異性，因而造成它在基因研究上的困難度。現在認為藉由疾病的同質性將患者分群，可能增加發現致病基因的機會。在部分憂鬱症及躁鬱症的患者中，都發現有在特定季節中重複發作的現象，稱為季節模式。季節模式有機會作為基因檢測時分類的依據，因具有季節模式者，相較於沒有季節模式的患者，在過去的研究中被發現具有不同的特徵。然而，究竟是哪些特徵在兩群間產生差異仍沒有明確定論，在不同種族文化中，其特徵是否會相同也仍然未知。於是本研究的目的，包括（1）了解台灣漢人具有季節模式鬱症患者的特性。（2）透過候選基因的方法，以類別和連續兩種季節模式的定義方式，尋找可能在患者中造成季節模式的基因位點。（3）透過前述的候選基因，更進一步探討其中是否有會造成季節性憂鬱的基因位點。
本研究自台灣的醫學中心共納入了977位被診斷為憂鬱症或躁鬱症的患者，類別的季節模式定義方法，是透過中文版的終生精神疾病診斷晤談手冊(the schedule of affective disorders and schizophrenia, SADS)的半結構式訪談，其中一題詢問「一年中哪一個季節你覺得最不好？」請患者回憶其在第一次、最嚴重及一年內的憂鬱陣發期當中的情形。若患者在三次陣發期中有兩次都回答特定季節的話，我們便將其定義為具有季節模式(SP+)，反之則無(SP-)。在本次研究中我們發現具季節模式者相較於無季節模式者，其一生中有較多次的鬱症發作、較長的陣發期，與較低的生活品質。在憂鬱症狀的表現上，有季節模式的患者相較於沒有季節模式的患者，有較高的比例食慾增加，渴求碳水化合物，精神運動性激動，疲勞，及無價值感。
在基因檢測的部分，除了前段提及的類別（SP+，SP-）季節定義外，我們使用季節性問卷(seasonal pattern assessment questionnaire, SPAQ)計算出的季節分數(the global seasonality score, GSS)作為季節模式的連續性定義。我們總共檢驗了40個選自「血清素與褪黑激素的生物合成 (serotonin and melatonin biosynthesis)」與「晝夜節律(circadian rhythm)」途徑的基因，並發現晝夜節律途徑中的PRKAA1 rs29743(empirical P= 4*10-4), rs249429 (empirical P= 5*10-4)位點和血清素接受器HTR5A rs1017488 (empirical P= 2.6*10-3)位點與鬱症季節模式有關。在結合多位點以基因為單位(gene base)作檢測時也呈現了相同的結果。其中NPAS2的rs72816926與rs2043534位點在兩種不同的季節模式定義下，都與季節模式有關，並取得方向一致的結果。
接著我們將來自台灣生物人體資料庫的樣本，去除其中具有憂鬱傾向者，共16349人的基因資料作為控制組，與SP+的患者比較。結果發現NPAS2 rs76376883 (empirical P= 9*10-4)位點與季節性憂鬱具有相關性，顯示NPAS2的位點除了做為調節基因，可能在鬱症患者中造成季節模式外，也可能導致季節性憂鬱的發生。
本研究為第一個在亞洲鬱症患者中進行的季節模式遺傳變異研究，具季節模式的患者被發現具有特定特徵，擁有成為一同質性族群的潛力。我們發現在患者是否具季節模式，及季節性憂鬱的成因當中，皆可能具有基因效應的存在。在本次研究中，我們初步探討了鬱症季節模式的可能病因，期盼在結合後續的研究成果後，能進一步推進季節模式鬱症患者的早期診斷治療。

關鍵字

情感性疾患 ； 鬱症 ； 季節模式 ； 血清素 ； 晝夜節律 ； 基因研究

並列摘要

There have been challenges in finding genes associated with major depression due to its high heterogeneity and high prevalence comparing to other psychiatric disorders, while subgrouping may be a strategy for improving detection. Seasonal pattern (SP), the recurrence of depression in a specific season, was reported in depressive patients of both bipolar disorder (BD) and major depressive disorder (MDD). In previous studies, patients with (SP+) or without seasonal pattern (SP-) was found with different characteristics which may form a distinct group for examining genetic contribution. However, the divergence of features between SP+ and SP- patients still remain inconsistencies, whether characteristics disparities exist across regions were also unknown. In this study, we aim to (1) examine the difference of clinical features between SP+ and SP- in depressive patients of Taiwan. (2) To further identify the variants of depression, we investigate the genetic markers through comparing between the categorical (SP+ and SP-) and dimensional seasonality from candidate pathway genes. (3) By using the candidate genes, we search for susceptible genes for seasonal depression in Taiwanese Han population.
We recruited 977 BP and MDD patients from psychiatric departments in Taiwan. SP of depressive episode were defined according to interview questions from the schedule of affective disorders and schizophrenia (SADS) as “Which season do you feel the worst?” in their first, the most serious, and the most recent episode within a year. Subjects answered a specific season in two of the three episode categories were considered SP+, while others were categorized as non-SP (SP-). We have defined SP+ patients, comparing to SP-, with more numbers and longer duration of disease episodes followed by lower quality of life. The SP+ group have higher percentage than SP- in expressing depressive symptoms such as increase of appetite, carbohydrate craving, fatigue, psychomotor agitation, and feelings of worthlessness.
In genetic association tests, the global seasonality score (GSS) of the seasonal assessment questionnaire (SPAQ) serves as a dimensional assessment of seasonal pattern. 40 genes were examined from susceptible pathway genes, including genes from the “serotonin and melatonin biosynthesis” and “circadian rhythm” pathway. Association analyses of categorical SP identified the circadian pathway PRKAA1 SNPs, rs29743 (empirical P= 4*10-4), rs249429 (empirical P= 5*10-4), and the serotonin pathway gene HTR5A rs1017488 (empirical P= 2.6*10-4) as the markers with the strongest association. These associations were further confirmed by gene bases tests. 2 SNPs in NPAS2 were found to be associated with seasonality in both SP criteria.
After excluding those with depression tendency, 16349 community samples from the Taiwan Biobank served as controls in search for susceptible genes of seasonal depression. While comparing against SP+, the SNP rs76376883 (empirical P= 9*10-4) located in the NPAS2 gene was found to be associated with seasonal depression. Showing the potential role of NPAS2 gene variants as a seasonal pattern modifier, as well as a susceptible gene for seasonal depression.
To our best knowledge, this is the first genetic study in seasonal pattern of depressive patients conducted in Asian population. Through this study, we gain evidence that depressive patients with seasonal pattern were with shared characteristics, which may form a more homogenous subgroup and exist genetic effects. The results may provide information on etiology and benefit identification of seasonal depression patients to aid early treatments in clinical practices.

並列關鍵字

Mood disorder ； depression ； seasonal pattern ； circadian rhythm ； serotonin ； genetic studies

參考文獻

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