在全基因關聯分析中利用總體的基因表現量作為穩定表現型

Abstract

在生物學上，穩定表現型(endophenotype)和疾病有著相同的遺傳路徑，但穩定表現型卻比診斷上的表現型(phenotype)更為接近其相關的基因，這也顯示穩定表現型在複雜疾病上基因研究的重要性。穩定表現型為主的基因遺傳分析比表現型為主的基因遺傳分析更容易找到致病基因。由穩定表現型所發展的指標(PHE)，穩定表現型的基因遺傳性所佔比例，用在判別出有可能的穩定表現型。 在這篇報告裡，氣喘是一種基因間作用和環境因素複雜的疾病，我們利用基因表現量當作穩定表現型找尋可能的氣喘基因。我們利用指標(PHE)判斷哪些探針組的基因表現量是穩定表現型，接著作指標(PHE)的檢定。針對多重檢定的問題，我們利用q-值來控制錯誤發現率和調整。我們也對每一個基因表現量做全基因關聯分析，比較基因表現量指標(PHE)中有顯著和沒有顯著之間基因遺傳性的變化。最後，我們論文中有(1) 評估利用基因表現量當作穩定表現型找尋跟疾病有相關基因的適當性，(2) 檢驗從基因表現量為主的分析，辨別出的基因和文獻中提過疾病相關的基因重複的多寡，(3) 從這些基因表現量判定為穩定表現型中，評估它們基因遺傳的特徵。

Endophenotype, which involve the same biological pathways as diseases but presumably are closer to the relevant gene action than diagnostic phenotypes, have emerged as an important concept in the genetic studies of complex diseases. Endophenotype-based genetic analysis is more likely to succeed than phenotype-based one in terms of search for the susceptibility genes. The index, proportion of heritability explained (PHE), has been proven useful in identifying potential endophenotypes. In this report, we use global gene expression as endophenotypes in search for the susceptibility genes underlying asthma, which is a disease caused by complex interactions of genetic and environmental factors. We judge which gene expressions of probe sets are endophenotypes by using the index PHE and do hypothesis test of PHE. For the problem of multiple testing, we utilize the q-value to control for the false discovery rate (FDR) for significance judgment. We also perform genome-wide association tests for each gene expression and compare various genetic properties between gene expressions with and without significant PHE values. At the end, this thesis has (1) evaluated the appropriateness of using global gene expressing as endophenotypes in searching possible phenotype-related genes, (2) examined the overlap between genes identified by the gene-expression-based analysis and genes already identified in the literature, and (3) assessed genetic characteristics of gene expressions that are identified as the endophenotypes.