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 × 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 × 10-5in 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.

ADAMTS19, Candidate gene, Genome-wide association study, Premature ovarian failure, Single nucleotide polymorphism,
Human Reproduction
Erasmus MC: University Medical Center Rotterdam

Knauff, E.A.H, Franke, L, van Es, M.A, van den Berg, L.H, van der Schouw, Y.T, Laven, J.S.E, … Hoek, A. (2009). Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene. Human Reproduction, 24(9), 2372–2378. doi:10.1093/humrep/dep197