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Pathway Analysis Using Genome-wide Association Study of Polycystic Ovary Syndrome

Title
Pathway Analysis Using Genome-wide Association Study of Polycystic Ovary Syndrome
Authors
심은진
Issue Date
2014
Department/Major
대학원 의학과
Publisher
이화여자대학교 대학원
Degree
Doctor
Advisors
성연아
Abstract
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. PCOS is influenced by environmental and genetic factors, and genetic studies in PCOS are recently focusing on the identification of susceptibility loci through genome-wide associations studies (GWAS). However, GWAS largely focuses on individual single nucleotide polymorphisms (SNPs) achieving a stringent statistical significance and most identified SNPs lack a functional relevance. To further elucidate the data obtained from the GWAS, pathway based approaches are being applied. The aim of this study was to elucidate the disease associated genes involved in the biological pathways related to insulin secretion and action, and to ovulatory dysfunction using the GWA dataset of PCOS. Two thousand non-pregnant premenopausal women who volunteered for evaluation of PCOS were recruited. After eliminating invalid data through the quality control procedures, 636,797 autosomal SNPs representing 1,221 individuals (432 PCOS and 789 control women) were obtained. Pathway based approach was conducted using meta-analysis gene-set enrichment of variant association (MAGENTA). Top ranking pathways or gene sets associated with PCOS were identified, and significant genes within the pathways were also determined. Significant pathways related with ovulation and insulin secretions were identified, including oocyte meiosis, regulation of insulin secretion by acetylcholine and regulation of insulin secretion by free fatty acids (all nominal gene set enrichment analysis (GSEA) Ps < 0.05). In addition, INS, GNAQ, STXBP1, PLCB3, PLCB2, SMC3 and PLCZ1 were some of the significant genes observed within the biological pathways (all Gene Ps < 0.05). Through pathway analysis of PCOS, significant biological pathways and genes related with ovulation and insulin secretion were identified. Further studies will be needed to elucidate the pathogenesis of PCOS.;연구배경: 다낭난소증후군 (polycystic ovary syndrome, PCOS)은 가임여성에서 발생하는 흔한 내분비 질환이며 여성 불임의 가장 흔한 원인 중 하나이다. 이는 유전적 요인과도 중요한 연관성이 있으며 전장유전체연관분석 (genome-wide association study, GWAS)을 통해 다양한 유전체 및 단일유전자변이 (single nucleotide polymorphism, SNP) 발굴이 이루어지고 있다. 그러나 GWAS는 가장 유의성이 높은 몇 개의 SNP들에 대한 분석이 이루어지기 때문에 질환의 복합적인 연관성이나 생물학적 경로 (biological pathway)를 이해하는 데는 어려움이 있다. 이런 한계점으로 인해 최근에는 GWAS 데이터를 이용하여 다양한 생물학적 경로, 질환들의 연관성을 발굴하는 경로기반 단일염기다형성 분석 (pathway based SNP analysis)의 중요성이 강조되고 있다. 본 연구는 젊은 PCOS 여성의 GWAS 데이터를 이용하여 pathway analysis를 시행하고자 하였다. 실험방법: 1,221명의 여성들 (432명의 PCOS군과 789명의 대조군)의 데이터를 분석하였다. 정도관리 (quality control)를 통과한 636,797 autosomal SNP들은 MAGENTA (meta-analysis gene-set enrichment of variant association)라는 pathway analysis 기법을 이용하여 분석을 진행하였고, 이를 통해 PCOS와 연관성이 높은 pathway 또는 유전자 세트 (gene set) 그리고 각 pathway 안에서 유의한 상관성을 보이는 유전자들을 확인하였다. 실험결과: 배란 및 인슐린 분비와 관련성이 있는 oocyte meiosis, regulation of insulin secretion by acetylcholine, regulation of insulin secretion by free fatty acids가 PCOS와 가장 연관성이 높은 biological pathway들이였다. (gene set enrichment analysis (GSEA) P < 0.01). Pathway 안에서는 INS, GNAQ, STXBP1, PLCB3, PLCB2, SMC3 and PLCZ1와 같은 유전자들이 유의한 상관성을 보였다 (Gene P < 0.05). 결론: Pathway analysis를 통해 PCOS와 연관성이 높은 배란 및 인슐린 분비와 관련된 biological pathway들을 확인할 수 있었으며 이에 대해서는 앞으로 더 많은 연구가 필요할 것이다.
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