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Identifying genes associated with premature ovarian failure through two‐stage association study
Author(s) -
Kwack KyuBum,
Lee Seung Ku,
Kim Hyoun Geun,
Kim KyoungYeon,
Kim Jeong Geun,
Oh Ah Reum,
Pyun Jung A,
Kim MinHo,
Won SeongSik,
Kang Eun Joo,
Lee SookHwan,
Kang HyunJun
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1123.1
Subject(s) - single nucleotide polymorphism , linkage disequilibrium , haplotype , genome wide association study , genetic association , biology , genetics , premature ovarian failure , snp , gene , tag snp , allele , genotype , endocrinology
Premature ovarian failure (POF) is a complex and heterogeneous disorder influenced by multiple genetic components. Therefore, the goal of this study was to identify genes or genetic regions associated with POF through two‐stage association study. In the first stage with small sample size, genome‐wide association study (GWAS) based on linkage disequilibrium (LD) mapping was performed with high‐throughput single nucleotide polymorphisms (SNPs) distributed in gene‐centric and evenly‐spaced manner. In the second stage, association study in larger sample sizes was conducted with target gene adding putative causal SNPs, which was selected from the first stage association. Among many of regions associated with POF, a part of chromosome 7p14 containing parathyroid hormone responsive‐B1 (PTHB1) gene revealed the strong association with POF‐susceptible haplotype; ht1, ‘GAAAG’ (p=0.00034) and also identified the POF‐resistant haplotype; ht2, ‘TGTGC’ for POF in the first stage. In the second stage, the association between POF and two SNPs, and a part of ht1 was repeated with additional SNP, which was considered as putative causal variants causing amino acid change, Ala to Thr. For the first time, we showed that the PTHB1 gene revealed strong association with ht1 as susceptible risk for POF. Although causative SNPs were not identified, repeated association of ht1 suggest that variants in PTHB1 gene are associated with POF.