한국 여아를 대상으로 한 전장유전체분석을 통한 새로운 성조숙증 연관 유전변이의 동정
Identification of novel genetic variants associated with precocious puberty by genome-wide association analysis in Korean girls
- 주제(키워드) precocious puberty , girl , early diagnosis , genetic biomarker , genetic variants , single nucleotide polymorphism (SNP) , genome-wide association study (GWAS) , gene expression , hypothalamus , gonadotrophin-releasing hormone (GnRH)
- 발행기관 아주대학교 대학원
- 지도교수 정선용
- 발행년도 2019
- 학위수여년월 2019. 2
- 학위명 석사
- 학과 및 전공 일반대학원 의생명과학과
- 실제URI http://www.dcollection.net/handler/ajou/000000028663
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Precocious puberty results from the activation of the hypothalamus-pituitary-gonadal axis at an early stage, which lead to the secretion of gonadotrophin-releasing hormone (GnRH) and can lead to physical and psychological problems such as loss of adult height, breast cancer, type 2 diabetes, and depression. Precocious puberty is caused by both genetic and environmental factors. Early diagnosis is very important for the effective treatment of the disease, because highly effective drugs are available for its treatment. The use of genetic biomarkers of precocious puberty might be a good solution could enable its early diagnosis. Although several genes, such as KISS1, KISS1R, and MKRN3 are known to be involved in precocious puberty, no genetic variants associated with precocious puberty have been identified yet using a genome-wide association study (GWAS). To identify genetic biomarker(s) for the early diagnosis of precocious puberty, I analyzed the genotype and clinical data of 696 Korean girls with precocious puberty and 300 Korean age-matched normal controls. After performing a case-control GWAS, I found eight genetic variants that are significantly associated with precocious puberty (p < 1.0 × 10-5), viz., rs10900855 (OR = 2.21 and p = 1.10 × 10-8), rs13187637 (OR = 2.006 and p = 7.07 × 10-7), rs373629 (OR = 0.5839 and p = 1.94 × 10-6), rs3849046 (OR = 1.959 and p = 2.24 × 10-6), rs56252016 (OR = 0.1212 and p = 3.48 × 10-6), rs62579679 (OR = 2.493 and p = 3.66 × 10-6), rs4680885 (OR = 0.4638 and p = 6.41 × 10-6), and rs4891764 (OR = 0.5933 and p = 8.66 × 10-6). The most significant SNP, rs10900855, exhibited a p- value at the GWAS-level of significance (p ≤ 5.0 × 10-8) and an extremely high OR value. By annotating and performing a signal plot analysis of the identified SNPs, I found that the SNPs were closely located to six genes: EGR1, HSPA9, ETF1, MAGI2, MPPED2, and DOK6. The gene expression patterns of the six genes in the hypothalamus tissue of female mice indicated a significant increase (EGR1) or a significant decrease (HSPA9, ETF1, MAGI2, MPPED2, and DOK6) in levels during the puberty period. In silico pathway analysis revealed that all six genes are closely associated with precocious puberty via two (EGR1) or three nodes (HSPA9, ETF1, MAGI2, MPPED2, and DOK6). These results indicate that the SNPs identified in these six genes were also closely associated with precocious puberty in girls.
more목차
I. INTRODUCTION 1
II. MATERIALS AND METHODS 8
A. Subject 8
B. DNA extraction and quality check 8
C. SNP Genotyping 9
D. Mouse tissue preparation 10
E. RNA extraction and cDNA synthesis 10
F. Quantitative RT-PCR analysis 11
G. Network analysis 11
H. Statistical analysis 12
III. RESULTS 14
A. Establishment of a study cohort for analyzing precocious puberty in Korean girls 14
B. Genome-wide association study in Korean cohort for precocious puberty 16
C. Candidate-gene association analysis of the previously identified genes
26
D. Gene expression patterns of the six identified genes during the puberty period in female mouse tissues 28
E. Gene expression patterns of previously known genes during the puberty period in female mouse tissues 43
F. Network analysis 48
IV. DISCUSSION 53
V. CONCLUSION 58
REFERENCES 59
국문요약 68
