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Title: | 利用全基因體關聯掃描探討與多發性思覺失調症及其較早發病年齡相關之遺傳變異 Investigation of Genetic Variants Associated with Multiplex Schizophrenia and Its Early Age at Onset using Genome-Wide Association Studies |
Authors: | Annemarie Lee Woolston 李佳螢 |
Advisor: | 陳為堅(Wei J. Chen) |
Keyword: | 多發性思覺失調症,家族病史,發病年齡,易感受性,全基因體關聯性研究,多基因遺傳風險評分,基因基礎分析,基因群富集分析, multiplex schizophrenia family history,age at onset,susceptibility,GWAS,polygenic risk scores,gene-based analysis,gene set enrichment analysis, |
Publication Year : | 2017 |
Degree: | 博士 |
Abstract: | 背景:思覺失調症是個由複雜遺傳因子構成致病機轉之精神疾病,其高度多基因遺傳架構包含了易感受性與修飾基因,構成此疾病之遺傳異質性。全基因體關聯性研究之間不一致的結果顯示,有數百個遺傳基因座與思覺失調症之易感受性之間有關聯性,此議題已被認為是相當大的隱憂。根據和遺傳負荷相關的特徵將患者分組的關聯性分析,可以提供有效的方法來尋找與台灣漢人之思覺失調症相關的修飾及易感受性基因。
研究目的:此研究的主旨在於,1)辨識與思覺失調症較早發年齡相關之修飾基因座;2)在台灣漢人族群中尋找與思覺失調症易感受性相關之單核苷酸多型性、基因、基因群、以及路徑;3)在思覺失調症較早發病多發家庭中以常見及罕見變異探討與易感受性相關的遺傳因子。 方法:本篇論文建構三種研究設計來達到不同的目的。第一、從557個多發性家庭中挑選出來的94個最早發病與91個最晚發病之思覺失調症指標患者,被用來進行一個只有病例的全基因體關聯性研究。接著在這些沒有親屬關係之患者的共病手足中,進行候選單核苷酸多型性的基因定型。由候選基因座所組成的多基因遺傳風險評分,被用來區別最早發病與最晚發病之指標患者。第二、這185個指標患者接下來被混合成為一群病例,將其與925個正常對照組座,進行單核苷酸多型性基因型的比較。包括1)個別單核苷酸多型性關聯檢驗;2)基因基礎分析;3)基因群富集分析等三種策略,被用來詮釋思覺失調症易感受性之全基因體關聯性研究資料。第三、運用針對精神疾病設計的基因型定序晶片,較早發病的思覺失調症多發性家庭中,檢測常見與罕見遺傳因子,並進行家族遺傳研究。 結果:在與思覺失調症較早發病年齡相關之修飾基因座方面,由14個單核苷酸多型性組成之風險分數,可以區分最早發病指標患者之90位共病手足與最晚發病指標患者之91位共病手足。當132次早發病患者與158為次晚發病患者皆被納入分析後,在最早、次早、次晚、最晚發病年齡等四組家庭群體之間,此由14個單核苷酸多型性組成之風險分數具有一個顯著的趨勢。這些基因座初步的網絡分析顯示PARK2這個經常在思覺失調症被報導的,被認為是導致帕金森氏症較早發病的基因之參與。而與思覺失調症易感受性有關之遺傳組成方面,在一開始的全基因體基因關聯性研究中,辨識出四個通過全基因體顯著水準。而LINC01215、 IFT57、及CD47等三個有最強訊號的基因可在Psychiatric Genomics consortium – Schizophrenia 2 (PGC-SCZ2)中重現,一個京都基因與基因组百科全書路徑(KEGG pathway)- 細胞附著分子(Cell adhesion molecules,CAM),以及十四個集中在神經元細胞形成、離子閥門通道、免疫反應活性等基因本體論關係(GO terms)也在基因組富集分析中被找到。在家族相關性研究方面,根據思覺失調症遺傳架構的多基因概念,超過兩百個基因全基因體相關性研究被篩選出來,進行路徑與網絡分析。常見與罕見變異都被納入考量,同時對較早發病年齡的多發性家庭之思覺失調症易感受性具有貢獻。 結論:在本論文中包含的這些研究辨識出,1)與思覺失調症的較早發病年齡相關之修飾基因座,2)在臺灣漢人族群中,與思覺失調症易感受性相關的單核苷酸多型性、基因、基因群、生物路徑,3)於較早發病的多發性家庭中,許多潛在與思覺失調症易感受性相關的基因、路徑、網絡等。許多個不同面向的遺傳因子,可能可以進一步幫助闡釋思覺失調症的致病機轉。 Background: Schizophrenia is a mental disorder resulted from complex genetic components underpinning the pathogenesis. The highly polygenic architecture, including susceptibility and modifier genes, results in genetic heterogeneity of schizophrenia. Inconsistent results between genome-wide association studies (GWAS) have reported possible associations between hundreds of genetic loci with variants and susceptibility of schizophrenia. This issue has been a major concern in recent genomic studies. Association analyses based on subgrouping patients according to characteristics related to genetic loadings may provide an efficient way to search for modifier and susceptibility genes in multiplex schizophrenia in Taiwanese Han population. Aims: This study aimed 1) to identify modifier loci associated with an earlier AAO of schizophrenia; 2) to search for single nucleotide polymorphisms (SNPs), genes, and gene sets associated with susceptibility for schizophrenia among Taiwanese population; and 3) to investigate susceptibility-related genetic components using both common and variants among multiplex families with early age at onset of schizophrenia. Methods: Three study designs were conducted to achieve different aims. First, a case-only GWAS was conducted in 94 schizophrenia probands with the earliest AAO and 91 with the latest AAO selected from 557 multiplex families. Candidate single nucleotide polymorphisms (SNPs) were then genotyped in the co-affected siblings and unrelated probands. Multi-SNP risk scores composed of the candidate loci were used to distinguish patients with an early or late AAO. Second, the 185 probands were then pooled together to be a group of cases and compared the SNP genotypes with a total of 925 normal controls. Three analytic methods including 1) individual SNP association tests; 2) gene-based analysis; and 3) gene set enrichment analysis were used to interpret the GWAS dataset for susceptibility for schizophrenia. Third, family-based association tests on genome-wide common and rare variants, utilizing genotyping microarray designed for psychiatric diseases, were performed among multiplex families with earlier age at onset of schizophrenia. Results: For modifier loci associated with AAO of schizophrenia, the 14-SNP risk score could distinguish the co-affected siblings (n = 90) of the earliest AAO probands from those (n = 91) of the latest AAO probands. When 132 patients with an earlier AAO and 158 patients with a later AAO were included, a significant trend in the 14-SNP risk score was detected among those unrelated probands from 4 family groups with the earliest, earlier, later, and latest AAO. Preliminary network analysis of these loci revealed the involvement of PARK2, a gene known as main cause of early-onset Parkinson’s disease and intensively reported in schizophrenia research. For genetic components related to susceptibility for schizophrenia, 4 SNPs passed genome-wide significance (p < × 10-8) in the initial GWAS. Three genes, LINC01215, IFT57, and CD47 with associations (p < 0.001) in Taiwanese population were replicated in the Psychiatric Genomics consortium – Schizophrenia 2 (PGC-SCZ2) samples. A KEGG pathway, Cell adhesion molecules (CAM) and 14 gene ontology (GO) terms focusing on neural formation, ion-gated channels, and immune response activities were identified overlapping with the PGC-SCZ2 dataset. For the family-based association analyses, over two hundred genes were shortlisted from the GWAS results based on the concept of the polygenic architecture of schizophrenia. Both common or rare variants were considered having contribution to the susceptibility within multiplex families with early age at onset. The pathway analysis and network analysis according to these genes revealed 17 significant (P < 0.05) biological pathways and 8 networks each included more than 10 genes out of the gene lists. Conclusion: The studies included in this doctoral dissertation have identified 1) modifier loci associated with an earlier AAO of schizophrenia; 2) associations of SNPs, genes, gene sets, and pathways with susceptibility for schizophrenia among the Taiwanese Han population; and 3) a long list of genes, pathways, and networks potentially associated with susceptibility for schizophrenia among multiplex families with early age at onset. The genetic components with different dimensions may help further illuminate the pathogenesis of schizophrenia. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/68814 |
DOI: | 10.6342/NTU201703657 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 流行病學與預防醫學研究所 |
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