Hum. Reprod. Advance Access published online on March 18, 2008
Human Reproduction, doi:10.1093/humrep/den086
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Parathyroid hormone-responsive B1 gene is associated with premature ovarian failure
1 Medical Genomics Laboratory, Pochon CHA University, Gyeonggi-do, Korea 2 Institute for Clinical Research, Pochon CHA University, Gyeonggi-do, Korea 3 Genome Research Center for Reproductive Medicine and Infertility of Korea Ministry of Health and Welfare, Seoul, Korea
4 Correspondence address. Tel: +82-31-725-8376; Fax: +82-31-725-8350; E-mail: kbkwack{at}cha.ac.kr/ kbkwack{at}gmail.com
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Abstract |
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BACKGROUND: Premature ovarian failure (POF) is a complex and heterogeneous disorder that is influenced by multiple genetic components. Here, we performed a two-stage association study to identify POF-associated genes.
METHODS: A first stage linkage disequilibrium (LD)-based genome-wide association study was performed using 24 pairs of patients with POF and matched controls and a high-throughput BeadChip assay with 109365 single-nucleotide polymorphisms (SNPs) that are scattered throughout the genome in an exon-centric and evenly spaced manner. A region that was shown to be strongly associated with POF was then tested again for POF association in the second stage by using a larger sample size (101 cases and 87 controls) and additional putative causal SNPs.
RESULTS: The first stage analysis revealed that many regions were associated with POF, with part of chromosome 7p14 that contains the parathyroid hormone responsive-B1 (PTHB1) gene showing the strongest association. A POF-susceptible haplotype of PTHB1 (ht1, ‘GAAAG’, P = 0.00034) and a POF-resistant haplotype (ht2, ‘TGTGC’) were also identified. The association between POF and two PTHB1 SNPs (rs3884597 and rs6944723) and part of ht1 was confirmed in the second stage analysis. The additional SNP, rs11773504, was considered as a putative causal variant causing an amino acid change, Ala to Thr.
CONCLUSIONS: We showed for the first time that PTHB1 is strongly associated with POF, and ht1 confers susceptibility to POF. While causative SNPs were not identified, the polymorphism of the non-synonymous SNP rs11773504 and the repeated association of ht1 with POF suggest that PTHB1 may contribute to POF pathogenesis.
Key words: POF/PTHB1 gene/LD mapping/SNP/haplotype
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Introduction |
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Premature ovarian failure (POF) is one of several causes of female infertility. It is clinically defined by amenorrhea, namely, the cessation of the menstrual cycle before the age of 40 years. In general,
1% of women suffer from POF during their reproductive life (Coulam et al., 1986
), and a similar prevalence has been observed in Korean women.
A number of conditions appear to influence the development of POF, including autoimmune, iatrogenic and chromosomal or genetic aberrations (Santoro, 2001). However, the exact pathogenetic mechanism leading to POF is unclear. Understanding the pathogenesis of POF is complicated by the fact that it is a complex idiopathic and heterogeneous disorder (Laml et al., 2000; Pal and Santoro, 2002) that involves many candidate genes (Findlay, 1993; Gougeon, 1994; Richards, 2001; Richards et al., 2002). Many association studies have been performed to determine whether various candidate genes may participate in the development of POF. These genes mainly include those involved in the reproductive system, namely, those encoding the various sex hormones and their receptors and the local ovarian regulators that participate in the endocrinological pathways [e.g. FSH-receptor (Aittomaki et al., 1995), inhibin-alpha (Harris et al., 2005), luteinizing hormone (LH)-receptor (Latronico et al., 1996), FSH-beta subunit (Matthews et al., 1993) and LH-beta subunit (Takahashi et al., 1999)]. However, while these genes have been found to be associated with POF in some studies, other association studies have failed to verify these associations (Layman et al., 1993; Conway et al., 1999; Jeong et al., 2004). These discrepancies may be due to ethnic-specific genetic variation (Phimister, 2003; Burchard et al., 2003) and because the few candidate genes examined cannot sufficiently account for the development of the complex and polygenic disease, that, is POF (Sham, 1998; Jones et al., 2005).
These problems with association studies can be overcome by performing a ‘two-stage association study’. The first stage involves a genome-wide indirect association study that relies on linkage disequilibrium (LD) mapping. This type of study can efficiently identify disease-causing gene variants even when small sample sizes are used and when these variants occur commonly and/or only play a modest role (Risch and Merikangas, 1996; Cheung et al., 2005) in the etiology of the disease in question. This type of study is thus appropriate for locating as-yet unknown candidate genes that are associated with complex and polygenic diseases (Collins et al., 1997; Hirschhorn and Daly, 2005). Once these genes have been identified by the indirect association study, they can be tested in second stage direct association studies. Such two-stage association studies have several advantages over other approaches, namely, they are cost-effective and have increased statistical power by confirming genotype repeats in subjects with the genotyping techniques (Satagopan and Elston, 2003; Hirschhorn and Daly, 2005; Ohashi and Clark, 2005).
Here, we performed a two-stage association study to identify gene variants that participate in the development of POF. In the first stage, we performed an LD-based genome-wide association study with 24 patient/control pairs and a high-throughput BeadChip assay with 109 365 single-nucleotide polymorphisms (SNPs) scattered throughout the human genome. In the second stage, we performed a direct association study for one of the genes that was found by the first stage analysis to be strongly associated with POF. This second stage analysis was conducted in a larger sample size, with additional SNPs which are considered as putative causal variants in the gene of interest.
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Materials and Methods |
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Collection of human blood samples and genomic DNA preparation
Human blood samples were collected from 101 patients with POF and 87 matched controls. All were ethnic Koreans. Of these, 24 patient/control pairs were subjected to first stage whole-genome genotyping, while all were subjected to second stage genotyping. Such repeated genotyping helps to identify technology-specific errors and confirm the disease-association of particular genetic variants. This study was approved by the Institutional Review Board (IRB) at Pochon CHA University. All patients with POF were <40 years old, had had amenorrhea for more than six months, and had serum FSH levels that exceeded 40 IU/l. Serum FSH levels were measured at two separate time-points in the preceding two months. For the measurement of serum FSH levels, we obtained the blood samples from subjects at the Day 3 or 4 after the start of menstruation. Sera were obtained by centrifugation and tested to measure the FSH level by ADVIA Centaur immunoassay system (Bayer Co., Tarrytown, NY, USA), which utilizes a two-site sandwich immunoassay using direct chemiluminometric technology. All matched controls had undergone menopause but had had regular menstrual cycles before they spontaneously reached menopause, and they had one or more offspring arising from spontaneous pregnancies. All subjects had the normal female karyotype (46, XX).
High-salt buffer methods were used to purify the human genomic DNAs (gDNAs) from the blood samples, after which the gDNA was diluted to 50 ng/µl with 1 x TE (pH 8.0); 15 µl of each sample was then subjected to first stage genome-wide genotyping while 5 µl was used in the second stage.
First stage genotyping for LD-based genome-wide association study
The InfiniumTM Assay I (Illumina, San Diego, CA, USA), which employs the Sentrix® Human-1 Genotyping BeadChip and allele-specific primer extension (ASPE) was used. The BeadChip is a commercial beaded microarray platform that contains 109,365 SNPs that are distributed in an exon-centric and evenly spaced manner and are thus suitable for whole-genome LD mapping. Each bead bears a probe consisting of 75 nucleotides: 25 nucleotides of the 5' end are attached to the bead and serve as the address sequence that distinguishes each SNP from the others. The other 50 nucleotides serve as an allele-specific primer that helps determine the allele types of each SNP (Gunderson et al., 2004, 2005). We performed genome-wide genotyping according to the manufacturer's protocol by using 750 ng/15 µl of gDNA. After scanning, an image file of each sample was obtained. The signal intensities of the image files were analyzed by using the BeadStudio III software; by using the clustering formulae for determining genotypes that was reported by Gunderson et al. (2005), we examined the clustering for each SNP and thereby determined the alleles in each patient.
Second stage genotyping for selected gene-association study
All 101 patients with POF and 87 controls were genotyped with regard to one gene that was shown by the first stage association study to be strongly associated with POF. The genotyping involved existing and additional SNPs and for this, the GoldenGateTM Assay kit for discriminating genotypes was used. This kit is also based on ASPE but involves a somewhat different genotyping procedure to that used in the InfiniumTM Assay I, as it employs 250 ng/5 µl gDNA per sample and a two color system where Cy3 and Cy5 are used to discriminate between the alleles of each SNP. After hybridization and staining, image files were obtained by scanning with a BeadArray Reader (Illumina, Inc.). The SNP genotypes of each sample were determined as described for the first stage genotyping.
Statistical analysis
Whether the genotypes of all SNPs deviated from the expected Hardy–Weinberg equilibrium (HWE) values was estimated by chi-square tests. The analysis of the first stage genotypes involved disease-association analysis for (i) the allele model that were performed by using chi-square test and for (ii) the genotype and haplotype distribution by using Fisher's exact test. All of the significant values were statistically corrected for multiple comparisons by using Monte Carlo Estimation (MCE) or permutation tests. By using Haploview 4.0 software (http://www.broad.mit.edu/mpg/haploview/index.php) (Barrett et al., 2005), LD analysis and haplotype inference were performed by using Gabriel's rule (Gabriel et al., 2002) and the expectation maximization algorithm (Stephens et al., 2001), respectively. Each of the haplotype blocks (HBs) were measured as |D'| and 
2 values. The analysis of the second stage genotypes involved disease-association analyses for (i) and (ii) models that were performed the same way as described in the first stage and additionally for three alternative genotype models (the co-dominant, dominant and recessive models for the rare allele of each genotype) that were evaluated by logistic regression. LD analysis and haplotype inference were performed as described above. All HWE and disease-association analyses were performed by using SAS/genetics software (ver 9.1.3). All differences were considered to be significant when the P-value was <0.05.
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The first stage: genome-association study based on LD mapping
The LD-based whole-genome association study revealed that many genomic regions were strongly associated with POF. One of the most strongly associated regions was the part of chromosome 7p14 that includes the parathyroid hormone responsive-B1 (PTHB1) gene (P < 0.01 in the haplotype association study). In total, 24 SNPs were distributed in the PTHB1 gene with a physical distance that was suitable for LD analysis and genotyping (Fig. 1). All observed genotypes were in HWE (P > 0.05) (Table I). The association study using the allele model revealed that five allele types, namely, G of rs3884597, A of rs4604335, A of rs6944723, A of rs6462477 and G of 10225698, were strongly associated with POF, even when the significance values were statistically corrected for multiple comparisons by using the permutation test with 100,000 repeats (Table I). The genotype distribution of nine SNPs in POF patients differed significantly from the distribution in the matched controls, even when these differences were corrected by using the MCE (Table I). Use of Gabriel's rule revealed two HBs, namely, HB1 and HB2. HB1 was in complete LD (|D'| = 1,
2 
1; Devlin and Risch, 1995) (Table IIA) and included five SNPs that represented POF-associated alleles (Fig. 1). Four haplotypes (hts) were reconstructed from HB1 (data not shown), two of which showed significantly different frequencies in the haplotype association study. Ht1 (GAAAG) consisted of the POF-associated alleles and was associated significantly with POF, whereas ht2 (TGTGC) was associated with resistance to POF (Table IIB). To identify the existence of causative polymorphisms and to confirm the repetition of association with POF in the results of the first stage, we subjected the PTHB1 gene to a direct association study by adding putative causal SNPs mainly in HB1 and by using a larger sample size.
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SNPs genotyped and analyzed at the only first stage. 
SNPs genotyped and analyzed at the only second stage. *Haplotype blocks formed by LD analysis with the first stage genotypes. #Haplotype blocks formed by LD analysis with the second stage genotypes
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The second stage: target gene-association study
Twelve SNPs in the PTHB1 gene were excluded from this analysis for the following reasons: one SNP was monomorphic, five SNPs were not PTHB1-specific, four SNPs showed no association with POF in the first stage analysis and two SNPs presented technical problems in terms of the study design of the second stage. Six putative causal SNPs were added to the analysis, namely, one SNP in the 5'-untranslated region (UTR), one SNP in the 3'-UTR and four SNPs in the different coding regions. In total, 18 SNPs were genotyped and analyzed for their association with POF (Fig. 1). The observed genotypes of all SNPs were in HWE except for the rs10225698 SNP (P = 0.00148). Significant associations were not found for the six putative causal SNPs and the POF-associations of only two SNPs (rs3884597 and rs6944723) were preserved when using allele and three alternative genotype models (Table III). When LD analysis was performed (the SNPs with MAF <0.1 were excluded from this analysis), two HBs were detected. Comparison to HB1 identified by the first stage analysis revealed that rs10225698 was not included (Fig. 1, Table IIC). However, the disease-susceptible haplotype ht1 (GGAA) maintained its significant association with the polymorphism of rs11773504, which was considered to be able to affect the amino acid change, but it showed no association (Table IIB and III). Further analysis revealed that ht1 affects the risk of developing POF in a dominant manner (Table III). The resistant effect of ht2 in the first stage study was not confirmed by the second stage study.
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Discussion |
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POF is a complex and heterogeneous disorder with many possible genetic contributors. To identify POF-associated genes in an unbiased fashion, we performed a two-stage set of association studies. In the first stage, a genome-wide association study was performed by high-throughput SNP genotyping of 24 patient–control pairs. PTHB1, the gene that showed the best association with POF (P < 0.001), was then subjected to second stage analysis by genotyping 12 of the SNPs genotyped in the first stage along with six putative causal SNPs in 101 POF patients and 87 control subjects. This strategy has several advantages, e.g. easy and rapid identification for disease causing genes from the whole genome and confirmation of technical genotypes and analytical associations repetition (Satagopan and Elston, 2003
; Hirschhorn and Daly, 2005).
PTHB1 was first identified in osteoblastic cells, where its expression is down-regulated early in response to parathyroid hormone exposure (Adams et al., 1999). Since then, it has been shown to be expressed in various tissues, including the heart, skeletal muscle, liver, kidney, placenta and brain (Adams et al., 1999). The physiological functions of this gene and how it interacts with other genes remain unknown. It has also not been associated previously with POF. LD mapping and association analysis for hts in the first stage revealed one POF-susceptible and one POF-resistant haplotype in the PTHB1 gene that we designated as ht1 and ht2, respectively (Table IIB). Ht1 was strongly associated with POF, which suggests that it may increase susceptibility to this disease. The hts reconstructed from HB1 in complete LD included seven exons from exon 13 to 19 (Fig. 1, Table IIA). The premise of LD (Kruglyak, 1999; Risch, 2000) suggests that causative genetic variants in HB1 may exist together with ht1. Thus, to identify the POF-causative SNPs, we also genotyped an SNP in 5'-UTR, and an SNP in the 3'-UTR and four non-synonymous SNPs in the second stage study. Of these, three were included in HB1 and are known to change the amino acid sequence. But, the second stage study with larger sample size failed to detect their association with POF. However, the association with susceptible ht1 was maintained in the second stage study (Table III). These findings suggest that certain variants in the ht1 region may affect the risk of developing POF.
Notably, many studies have shown that genetic variation in alternative splicing can denote the presence of haplotype-dependent mRNA isoforms (Hviid et al., 2003; Marchand and Polychronakos, 2007). In the PTHB1 gene, four transcription variants that result from alternative splicing of the primary mRNA at exon 14 or 15 are known to exist. Taken together with our findings, these observations suggest that the transcription of PTHB1 may occur in a haplotype-dependent manner.
On the basis of comparative genomic analysis, SNP homozygosity mapping and gene expression analysis, the PTHB1 gene was designated as a novel BBS9 gene that is associated with Bardet–Biedle Syndrome (BBS) (Nishimura et al., 2005). BBS is a genetically heterogeneous, autosomal recessive disorder (Ammann, 1970; Green et al., 1989). There is no evidence that suggests BBS and POF are directly associated. However, one of the main BBS symptoms is hypogonadism (Beales et al., 1999), which is also often observed in POF (Coulam, 1982). Furthermore, a review of several case reports has revealed that some patients with BBS suffer ovarian abnormalities (Slavotinek and Biesecker, 2000). These observations suggest that PTHB1/BBS9 may be a causative gene for both of these heterogeneous diseases. Notably, Forti et al. (2007) have shown that PTHB1 is expressed early during human adipogenesis. Obesity is a primary symptom of BBS (Schachat and Maumenee, 1982) and while POF has not been directly associated with obesity, several studies have indicated that maintaining a moderate body fat level may be important for the reproductive health of women (Sherman and Korenman, 1974; Grenman et al., 1986; Frisch, 1990; Santoro et al., 2004). These observations support the notion that certain PTHB1 variants may increase the risk of developing POF.
In conclusion, we performed a two-stage association study and showed for the first time that the PTHB1 gene is strongly associated with POF. Both stages showed that two SNPs and ht1, which contains the non-synonymous SNP, rs11773504, are associated with POF. This suggests that the PTHB1 gene may induce susceptibility to POF. These observations may help shed light on the molecular mechanisms that lead to POF.
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This study was supported by grants from Ministry of Health & Welfare, Republic of Korea (01-PJ10-PG6-01GN13-0002 and 0405-BC02-0604-0004).
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Submitted on August 17, 2007; resubmitted on February 12, 2008; accepted on February 26, 2008.
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