情感性疾患臨床表型的遺傳學洞察： 探索台灣樣本中的常見與罕見變異負擔

Abstract

背景： 持續性注意力缺陷與自殺企圖 (Suicide Attempt, SA)是常見於情感性疾病患者（如重度憂鬱症(Major Depressive Disorder, MDD)與雙相情感障礙 (Bipolar Disorder, BP)）的嚴重臨床議題。了解這些特徵背後的遺傳因子有助於釐清其生物機制，並提升風險預測能力。本論文分為兩個部分：（1）使用持續性注意力測驗（Continuous Performance Test, CPT）資料進行全基因組關聯分析 （GWAS）及多基因風險分數 (Polygenic Risk Score, PRS）分析，探討其與持續注意力的關聯性；（2）利用全外顯子定序進行針對自殺企圖的罕見變異負荷檢定。 方法： 第一部分，我們分析了804位完成CPT測驗的情感性疾患患者的SNP資料（個案為雙相情感障礙，對照為重度憂鬱症）。針對CPT的各項指標（hit rate, false alarm rate, sensitivity 及 response criterion indices）進行GWAS分析，並利用Genome-wide Complex Trait Analysis（GCTA）方法估算其SNP遺傳力。我們亦依據MDD、失眠與SA等外部GWAS資料計算PRS，以探討其對注意力表現的影響。 第二部分，我們分析了來自台灣646位參與者的全外顯子定序(Whole Exome Sequencing, WES)資料，比較BP病人中自殺企圖者與非企圖者之間的差異。為探討罕見功能性變異對SA風險的貢獻，我們使用Firth邏輯斯迴歸進行WES的負荷分析，並進一步以Firth邏輯斯迴歸與Sequence Kernel Association Test（SKAT）進行基因層級的負荷檢定，評估各基因對SA風險的影響。此外，我們進行基因集富集分析以檢驗功能性相關基因群，並建構結合PRS與罕見變異攜帶狀態的聯合模型，以評估其對SA風險的整體效應。 結果： 在CPT分析中，GWAS結果未發現達到全基因體顯著性的位點，且各指標的SNP遺傳力估算值皆偏低。然而，MDD、失眠與SA的PRS與特定注意力指標（特別是false alarm rate與sensitivity）呈現顯著關聯，顯示注意力缺陷與情感性疾患風險可能具有共同的遺傳架構。 在罕見變異負荷檢定中，雖無單一基因或基因集達顯著性門檻，但蛋白截斷變異（Protein-Truncating Variants, PTVs）表現出較高的效應量，可能對SA風險具有較強影響。ANKRD60、PACS2 與 MYLK 等訊號較強之基因於基因層級分析中被識別出，與電壓閘控離子通道活性與血清素路徑相關的基因集亦呈現中等程度的富集現象。在聯合模型中，PRS與罕見變異攜帶狀態結合後與SA的關聯性更為穩定且顯著，顯示在本研究族群中，常見變異可能較罕見變異在自殺風險中扮演更重要的角色。相對地，罕見變異的效應可能受限於樣本數與統計力不足。 結論： 經本研究分析，發現MDD、失眠與SA的PRS與BP患者的持續性注意力表現有顯著關聯，結果顯示不同情感性疾患在神經認知功能的遺傳架構上可能具備異質性。特別是在BP患者中，遺傳風險對注意力缺陷的影響可能更為直接，進一步突顯未來評估認知功能時應考量疾病類型的遺傳背景。 針對自殺企圖之罕見變異分析，雖整體未達統計顯著，但觀察到PTVs可能具有相對較高的效應值，部分基因與神經發育路徑有潛在連結。此外，PRS與SA之間的穩定關聯，亦提示在現階段族群樣本中，常見變異可能較罕見變異更具預測價值。 總結而言，本研究強調整合常見與罕見變異分析對掌握精神疾病複雜遺傳特徵的重要性。雖然樣本數有限且具特定族群侷限性，本論文為東亞地區罕見的遺傳資料庫提供了寶貴的資料，並初步揭示與持續性注意力與自殺風險相關的生物路徑。未來研究應結合更大規模、更多元族群的資料與功能性後續驗證，以推動情感性疾患的精準醫療發展。

Background Sustained attentional deficits and Suicide attempt (SA) are serious clinical issues frequently observed in individuals with mood disorders such as major depressive disorder (MDD) and bipolar disorder (BP). Understanding the genetic factors underlying these traits may help clarify their biological mechanisms and support the prediction of risk. This thesis includes two parts: (1) a genome-wide association study (GWAS) and polygenic risk score (PRS) analysis of sustained attention using Continuous Performance Test (CPT) data, and (2) a series of rare variants burden tests of SA using whole-exome sequencing (WES). Materials and Methods For Part 1, we analyzed genome-wide single-nucleotide polymorphism (SNP) data from 804 patients with mood disorders (case: BP, control: MDD) who completed the CPT. GWAS was performed on CPT measures (hit rate, false alarm rate, sensitivity, and response criterion indices), followed by SNP-based heritability estimation using Genome-wide Complex Trait Analysis (GCTA). We also computed PRS based on external GWAS of MDD, insomnia, and SA to examine their association with sustained attention performance. For Part 2, we analyzed WES data from 646 Taiwanese individuals, comparing suicide attempters and non-attempters. To investigate the role of rare functional variants in SA risk, we conducted exome-wide burden tests using Firth’s logistic regression. We also performed gene-based burden tests with both Firth’s logistic regression and the Sequence Kernel Association Test (SKAT) to assess each gene's contribution to SA risk. Additionally, gene set enrichment tests were used to examine functionally grouped genes, and a joint model was developed to evaluate the combined effects of rare variant carrier status and PRS based on a large SA GWAS. Results In the CPT study, GWAS results did not reveal genome-wide significant loci. SNP-based heritability estimates were low across CPT traits. However, PRS for MDD, insomnia, and SA showed significant associations with certain attention measures, particularly false alarm rate and sensitivity, indicating shared genetic architecture between sustained attention deficits and mood disorders risk. In the rare variant burden tests, no individual gene or gene set reached statistical significance. However, PTVs showed higher effect sizes than other variant categories, suggesting a potentially more substantial impact on SA risk. Genes such as ANKRD60, PACS2, and MYLK were identified as top associations with SA, and gene sets related to voltage-gated ion channel activity and the serotonin pathway demonstrated modest enrichment. In the joint model, PRS showed stronger and more consistent associations with SA relative to rare variant carrier status. This suggests that common variants may play a more substantial role in suicide risk within this cohort. In contrast, the effect of rare variants may be limited by sample size and statistical power. Conclusion Based on our analysis, PRS for MDD, insomnia, and SA were significantly linked to sustained attention performance in patients with BP compared to those with MDD. These findings suggest potential differences in the genetic markers of neurocognitive function across various mood disorders. Specifically, genetic risk might have a more direct influence on attention deficits in BP patients, emphasizing the need to consider disorder-specific genetic backgrounds when assessing cognitive impairments.

In the rare variant analysis of SA, although no findings reached statistical significance, PTVs appeared to exhibit relatively higher effect sizes, and some of the top-ranked genes may be implicated in neurodevelopmental pathways. Additionally, the more consistent association between PRS and SA supports the possibility that, within the current sample, common variants may offer greater predictive value for suicide risk than rare variants. In conclusion, these findings highlight the importance of combining both rare and common variant analyses to capture the full range of genetic influences on complex psychiatric traits. While limited by a modest sample size and population-specific factors, this thesis adds valuable genetic data from an underrepresented East Asian group. It offers initial insights into the biological pathways related to both sustained attention and suicide risk. Future research with larger, more diverse samples and functional follow-up studies will be essential for validating these findings and advancing precision psychiatry in mood disorders.