指導教授：鄭素芳臺灣大學：物理治療學研究所姚乃嘉Yao, Nai-JiaNai-JiaYao2014-11-262018-07-082014-11-262018-07-082014http://ntur.lib.ntu.edu.tw//handle/246246/262238背景與目的：雖然過去的研究發現多巴胺相關基因在認知、感覺動作和情緒行為等系統上扮演重要角色，但其與早產兒及足月兒發展有關的文獻則相當有限。本研究旨在檢驗多巴胺相關基因的單核苷酸多型性與早產兒及足月兒之早期認知與動作發展的關聯性，並且探討是否能使用基因風險分數預測早產兒發展預後。方法：本實驗共採集404名早產兒與118名足月兒之口腔檢體，其中201名早產兒與111名足月兒於年齡六、十二、十八、二十四以及三十六個月時已經完成貝萊氏嬰幼兒發展評估第二版之認知與動作發展評估。口腔檢體經萃取後針對多巴胺相關基因 (DRD2, DRD3, DAT1, COMT及MAOA)中的十五個單核苷酸多型性進行基因型分析檢驗。結果：長期追蹤分析與統計校正後，發現DRD3(rs167771)、DAT1(rs2550948)與屬MAOA基因的單核苷酸多型性(代表為rs12843268)與早產兒長期追蹤之認知發展原始分數有顯著的關聯性。而屬MAOA基因的八個單核苷酸多型性則呈現強的連鎖不平衡現象 (所有D’ > 0.9且r2 > 0.8)。綜合多巴胺相關基因之基因風險分數與早產兒學習組的認知發展分數有顯著關聯，但在驗證組則未呈現明顯關聯性。結論：DRD3、DAT1基因與MAOA基因在早產兒認知發展可能扮演重要的角色。Background and Purpose: Although dopamine-related genes may involve in the neurotransmission of cognitive, sensori-motor and behavioral systems, the information concerning their role in various developmental functions in preterm and term children has been limited. The purpose of this study was therefore to examine the associations of dopamine-related genes with mental and motor development in preterm and term children and to predict the development of preterm children using genetic risk scores. Methods: This study included 404 preterm children and 118 term children to collect their buccal cell samples of whom 201 preterm children and 111 term children have been prospectively assessed the mental and motor development using the Bayley Scales of Child Development-Second edition at 6, 12, 18, 24 and 36 months of age. The buccal cells samples were genotyped for 15 single-nucleotide polymorphisms (SNPs) of dopamine-related genes (DRD2, DRD3, DAT1, COMT and MAOA). Results: One SNP of DRD3 gene (rs167771), one SNP of DAT1 gene (rs2550948) and eight SNPs of MAOA gene (rs12843268 as the tagger) were significantly associated with the mental raw scores in preterm children between different genotypes with longitudinal analysis after false discovery rate corrections. The linkage disequilibrium (LD) block which covered all the eight markers of MAOA gene showed strong relationship (all D’ > 0.9 and r2 > 0.8). A genetic risk score formed by the dopamine-related genes was significantly associated with the mental development in learning set of preterm children, but such a relation did not reach statistical significance in testing set. Conclusions: The DRD3, DAT1 and MAOA genes may play a role in the mental development in preterm children.口試委員會審定書…………………………………………………………… i 誌謝…………………………………………………………………………… ii 中文摘要……………………………………………………………………… iii 英文摘要……………………………………………………………………… iv 1. Introduction………………………………………………………………… p.1 2. Methods……………………………………………………………………… p.5 2.1 Participants…………………………………………………………… p.5 2.2 Testing Procedures…………………………………………………… p.5 2.3 Genetic analyses……………………………………………………… p.6 2.4 Neurodevelopmental measures……………………………………… p.7 2.5 Statistical analysis………………………………………………… p.8 3. Results……………………………………………………………………… p.10 4. Discussion…………………………………………………………………… p.13 5. Conclusions………………………………………………………………… p.17 6. Acknowledgements…………………………………………………………… p.17 7. References…………………………………………………………………… p.18 Figure Legend…………………………………………………………………… p.24 Tables Table 1…………………………………………………………………… p.25 Birth and demographic characteristics of preterm and term children with available genetic data, Bayley data and both data Table 2…………………………………………………………………… p.26 Allele frequencies and deviation from the Hardy–Weinberg equilibrium for the 15 SNPs of dopamine-related genes Table 3…………………………………………………………………… p.27 Relations of genotype and age with mental index scores (in p-value) separately in preterm and term children Table 4…………………………………………………………………… p.28 Relations of genotype and age with motor index scores (in p-value) separately in preterm and term children Table 5…………………………………………………………………… p.29 The relationship between mental and motor development and genetic risk scores of preterm childre Figures Figure 1 ………………………………………………………………… p.30 Flow chart of allocation and follow-up in preterm children and term children among each cohort Figure 2 ………………………………………………………………… p.32 Haplotype and linkage disequilibrium plot of 15 SNPs Figure 3 ………………………………………………………………… p.33 Plot of model-based mental development of DRD3, DAT1 and MAOA markers at 5 age points in preterm children Appendix 1-10 ………………………………………………………… p.342540400 bytesapplication/pdf論文使用權限：同意有償授權(權利金給回饋本人)早產兒童發展多巴胺相關基因thesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/262238/1/ntu-103-R01428001-1.pdf