Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene. Knauff EA et al. BACKGROUND: Spontaneous premature ovarian failure (POF) occurs in 1% of women and has major implications for their fertility and health. Besides X chromosomal aberrations and fragile X premutations, no common genetic risk factor has so far been discovered in POF. Using high-density single nucleotide polymorphism (SNP) arrays, we set out to identify new genetic variants involved in this condition. METHODS: A genome-wide association study involving 309 158 SNPs was performed in 99 unrelated idiopathic Caucasian POF patients and 235 unrelated Caucasian female controls. A replication study on the most significant finding was performed. We specifically focused on chromosomal areas and candidate genes previously implicated in POF. RESULTS: Suggestive genome-wide significant association was observed for rs246246 (allele frequency P = 6.0 x 10(-7)) which mapped to an intron of ADAMTS19, a gene known to be up-regulated in the female mouse gonads during sexual differentiation. However, replication in an independent Dutch cohort (60 POF patients and 90 controls) could not confirm a clear association (P = 4.1 x 10(-5) in a joint analysis). We did not observe strong evidence for any of 74 selected POF candidate genes or linkage regions being associated with idiopathic POF in Caucasian females, although suggestive association (P < 0.005) was observed for SNPs that mapped in BDNF, CXCL12, LHR, USP9X and TAF4B. CONCLUSION: We observed a possible association between POF and a SNP in a biologically plausible candidate gene. Although limited by sample size, this proof-of-principle study's findings reveal ADAMTS19 as a possible candidate gene for POF and thus a larger follow-up study is warranted.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Epistasis between IGF2R and ADAMTS19 polymorphisms associates with premature ovarian failure. Pyun JA 2013 et al. STUDY QUESTION Do single nucleotide polymorphisms (SNPs) or synergistic interactions between SNPs and diplotypes within the insulin-like growth factor 2 receptor (IGF2R) and ADAM metallopeptidase with thrombospondin type 1 motif, 19 (ADAMTS19), contribute to premature ovarian failure (POF)? SUMMARY ANSWER Synergistic interactions were detected between SNPs, including a non-synonymous SNP, and diplotypes within IGF2R and ADAMTS19 which may contribute to POF; however, there was no correlation with POF in a single SNP model after Bonferroni correction. WHAT IS KNOWN ALREADY IGF2R regulates free IGF2 level, which is involved in steroidogenesis in bovine granulosa cells. ADAMTS19 expression is higher in the murine embryonic ovary than in the embryonic testis during sexual differentiation, and an ADAMTS19 SNP (rs246246) showed a possible association with POF in a genome-wide association study in Caucasian women. STUDY DESIGN, SIZE, DURATION This study analyzed interactions between SNPs and diplotypes within IGF2R and ADAMTS19 as well as SNPs within the two genes. In Stage I, a total of 120 patients with POF and 152 female controls were recruited. All patients were diagnosed with POF at the CHA hospital in Seoul, Korea, and were recruited between 1994 and 2004. The 152 controls were recruited from Chungju, Korea, as part of another study that was conducted from April 2002 to March 2004. For Stage II, we obtained genotype data for an additional 1641 female controls, recruited in Ansung and Ansan from 2001 to 2008, from the Korean Genome Epidemiology Study (KoGES). PARTICIPANTS/MATERIALS, SETTING, METHODS In Stage I, the GoldenGate assay with VeraCode technology was used to genotype SNPs in IGF2R and ADAMTS19. In Stage II, we obtained genotype data for IGF2R and ADAMTS19 using Affymetrix Genome-Wide Human SNP array 5.0 and imputed data by the IMPUTE program from the KoGES. To identify POF-associated SNPs, logistic regression analysis in an additive model was performed using the PLINK tool. Synergistic interactions between SNPs and diplotypes within IGF2R and ADAMTS19 were analyzed by logistic regression analysis in three alternative models. MAIN RESULTS AND THE ROLE OF CHANCE In Stage I, 13 combinations of SNPs showed significant synergistic interactions after Bonferroni correction [the strongest association had odds ratio (OR) = 5.77, 95% confidence interval (CI): 2.26-14.75, P = 0.00025]. In Stage II and combined analyses, two and four combinations, respectively, of the significant results in Stage I showed significant synergistic interactions after Bonferroni correction. For interactions between diplotypes in block 2 of IGF2R and block 3 of ADAMTS19 in Stage I, we found 17 synergistic interactions with P < 0.0001, but there was no significant interaction after Bonferroni correction. In Stage II and combined analyses, we found that three and seven combinations in the same blocks, respectively, showed significant synergistic interactions after Bonferroni correction (strongest association: OR = 4.12, 95% CI: 2.22-7.62, P = 6.74E-06). LIMITATIONS, REASONS FOR CAUTION The sample size for patients with POF in this study was small but, compared with recent reports describing associations between SNPs and POF and considering the low prevalence of POF (1%), the sample size is considered to be reasonable. These results should be confirmed in large-scale studies involving different ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS Our results may ultimately provide predictive markers for women at a high risk of POF. STUDY FUNDING/COMPETING INTERESTS This study was supported by grants from Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (2009-0093821, 2011-0010637). There are no competing interests. /////////////////////////