2015-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/646927摘要：背景：注意力不足過動症（attention-deficit/hyperactivity disorder，以下簡稱ADHD）的主要表徵包括注意力不足、過動和衝動，是對個人、家庭及社會具有極大衝擊之早發型、高遺傳性、臨床上異質性之疾病。根據我們團隊過去的研究結果，已經有充分證據支持空間工作記憶障礙(spatial working memory deficits) 是ADHD的重要神經心理學指標，不但具有轉譯研究的價值，而且也是ADHD的內表現型。儘管ADHD遺傳基因學已在西方國家被廣泛地研究，但針對此疾病的病因仍未有定論。在基因遺傳研究中，相較於研究ADHD本身，研究疾病的內表現型所得到的結果更直接與致病基因和腦功能異常有關，因此以內表現型為研究目標可以大幅提升統計檢定力，並且使得小樣本的全基因體關聯性研究成為可行，而截至目前為止，國際上仍未有針對ADHD的空間工作記憶障礙所進行的全基因體關聯性研究。目的：1. 使用全基因體掃瞄找出與ADHD病患空間工作記憶表現有關聯的基因變異；2. 使用全基因體掃瞄找出與健康受試者空間工作記憶表現有關聯的基因變異；3. 在一個獨立樣本中驗證前一階段全基因體關聯性研究的發現；4. 檢視與空間工作記憶相關的基因變異是否也與罹患ADHD有關。個案與方法：本研究為三年的研究計畫，過去我們已經收集了382位ADHD病患和150位健康受試者的血液檢體和空間工作記憶資料。在本研究計劃期間會新招募232位7到18歲的健康受試者，評估工具包括：(1)會談：中文版K-SADS-E；(2)量表：ADHD症狀之量表(SNAP-IV)；(3)神經心理學測驗：劍橋神經心理學自動化測驗之空間工作記憶。第一年期間會進行病患組的全基因體關聯性研究(n = 254)，第二年期間會進行對照組的全基因體關聯性研究(n = 254)，第三年則是在一獨立樣本(病患組與對照組各128位) 驗證前兩年全基因體關聯性研究的發現。預期結果：我們經過嚴謹的計算，382位ADHD病患組成的樣本可以提供有效的統計檢定力，以發現全基因體關聯性研究中顯著的基因變異，並且在獨立樣本中驗證全基因體關聯性研究的發現。我們預期將找出ADHD致病基因與空間工作記憶之內表現型的相關性，本研究結果對於探索ADHD是如何由基因、經內表現型、到臨床症狀的病理生理機轉將會有重要的貢獻。<br> Abstract: Background: Attention deficit hyperactivity disorder (ADHD), characterized by inattention,hyperactivity and impulsivity, is an early onset, highly heritable, clinically heterogeneous,long-term impairing disorder with tremendous impact on individuals, families, and societies.Our research team has conducted a series of biological studies on spatial working memorydeficits of ADHD, and substantial evidence has suggested spatial working memory deficits asthe important neuropsychological biomarker with translational values and favorableendophenotypic properties for ADHD. Despite the abundance of molecular genetic studies onADHD, the genetic etiologies of ADHD have been non-conclusive. Because genetic studieson endophenotypes can offer more information on genetic and brain process, endophenotypicapproach can efficiently enhance the statistical power and make genome-wide associationstudies (GWAS) applicable in much smaller sample. To date, there has been no GWAS studyon spatial working memory deficits of ADHD.Specific Aims:1. To find the genetic variations associated with spatial working memory performance inpatients with ADHD by using GWAS;2. To find the genetic variations associated with spatial working memory performance inhealthy subjects by using GWAS;3. To recruit a validation sample and to replicate the findings from the initial GWAS;4. To test whether genetic variations significantly associated with spatial working memory arealso associated with ADHD.Subjects and Methods: This is a 3-year project. Our previous studies have collected bloodsamples and spatial working memory data of 382 patients with ADHD and 150 healthysubjects. In this 3-year project, we will recruit 232 healthy subjects, aged 7-18 years. Themeasures include (1) interviews for psychopathology (K-SADS-E), (2) questionnaires tomeasures ADHD symptoms (SNAP-IV), and (3) neuropsychological tests: Spatial WorkingMemory task of the CANTAB. In the first year, a case-only GWAS on spatial workingmemory (n = 254) will be conducted. In the second year, a control-only GWAS on spatialworking memory (n = 254) will be conducted. In the third year, findings from the initial twoGWAS will be replicated in a validation sample composed of 128 patients with ADHD and128 healthy controls.Anticipated Results: By careful calculation, a sample size of 382 ADHD subjects willprovide adequate power to detect genome-wide significant genetic variations and replicate thefindings in an independent validation sample. We anticipate to identify the relationshipbetween genetic variations of ADHD and the endophenotype of spatial working memory. Ourfindings will significantly contribute to our understanding of the pathophysiologicalmechanisms of ADHD, especially the pathological pathway from genes, throughendophenotype, to behavioral phenotypes.注意力不足過動症空間工作記憶內表現型分子遺傳基因學全基因體關 聯性研究Attention-deficit/hyperactivity disorderspatial working memoryendophenotypemolecular geneticsgenome-wide association studies