臺灣人基因組的大規模拷貝數變異研究

Abstract

拷貝數變異 (Copy number variation; CNV) 是 DNA 序列上一種基因變異，可能影響表現型或造成疾病，這種基因變異不只在病人的基因序列上存在，在正常人的基因序列上也可以發現。在此情況下，我們需要建立一個可信的拷貝數變異基準，藉此得知不同的拷貝數變異在正常族群中出現的頻率，即可比較篩選出真正對疾病有影響的拷貝數變異。本篇研究中，我們使用居住於臺灣的15,995位健康受測者的基因晶片，針對臺灣族群建立了一個拷貝數變異基準的資料庫，也針對整體族群拷貝數變異的特徵進一步分析。本篇研究分析所得之臺灣族群拷貝數變異及基因相關資訊，可由我們建立的 TWCNV 網頁型資料庫中獲取，以利未來的研究加以比較使用。 在這些用來建立拷貝數變異基準的樣本中，我們也進一步分析拷貝數變異與肥胖之間的關聯，使用的統計方法為費雪精確度檢定 (Fisher’s exact test) 和邏輯式迴歸檢定分析 (Logistic regression test) ，分別找出對脂肪率 (Body fat percentage; BFP) 和身體質量指數 (Body mass index; BMI) 顯著相關的拷貝數變異片段，並進一步做生物功能路徑分析。路徑分析的結果顯示，能量代謝、神經訊號傳遞及神經發育等功能可能與肥胖相關，由結果中也發現，在我們台灣族群的樣本中，脂肪率相較於身體質量指數可以得到較顯著相關的功能路徑。本篇研究分析所得的結果有助於連結拷貝數變異在相關功能中對於肥胖的影響，也對未來肥胖相關的主題提供可能的研究方向。本篇研究多層面探討拷貝數變異在臺灣族群的基因組中扮演的角色，同時建立了臺灣族群拷貝數變異的基準供未來的研究比較參考。

Copy number variation (CNV) is a type of genetic variation that is the underlying cause for genetic diversity, phenotypic changes and susceptibility to certain diseases. While they can overlap with disease-related genes, these variants exist in healthy individuals too; hence the construction of a reliable CNV baseline is essential towards selecting the truly influential CNVs for diseases. In this study, 15,995 microarray samples from healthy Taiwanese individuals were included to generate the Taiwanese-specific CNV baseline database and characterize the CNV profiles in the general Taiwanese population. All the CNV information is stored in a web-based TWCNV database and is retrievable through an openly accessible user friendly platform. Association of CNVs with obesity is further explored and investigated to find putative CNVs specific to Taiwanese populations. Candidate CNVs are identified with Fisher's exact tests and logistic regression tests. Functional analysis of the significant CNVs indicates that body fat percentage performs better than body mass index while detecting obesity-related significant pathways and that CNV might have an influence on the obesity rates through its association to nutrient metabolisms, neuronal signal transduction, or neural development. The findings aid to connect the dots from previous studies and suggest potential pathways for future obesity-related studies. Comprehensive CNV analysis in the genomes of general Taiwanese populations serves as a solid foundation for future CNV studies specific to Taiwanese populations.