Hum. Reprod. Advance Access originally published online on June 9, 2009
Human Reproduction 2009 24(9):2372-2378; doi:10.1093/humrep/dep197
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Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene
1 Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands 2 Department of Genetics, University Medical Centre Groningen, 9700 RB, Groningen, The Netherlands 3 Centre for Gastroenterology, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK 4 Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands 5 Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands 6 Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, 3000 CA Rotterdam, The Netherlands 7 Department of Reproductive Medicine, Free University Medical Centre (VUmc), 1007 MB Amsterdam, The Netherlands 8 Section of Reproductive Medicine, Department of Obstetrics and Gynaecology, University Medical Centre Groningen, Groningen, The Netherlands 9 Reproductive Endocrine Unit, Hôpital Saint-Antoine, Université Paris VI, EA 1533 Paris, France 10 Divison of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
11 Correspondence address. Tel: +31-88-755-7524; Fax: +31-88-755-5433; E-mail: knauff{at}gmail.com
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.
Key words: premature ovarian failure/genome-wide association study/ADAMTS19/candidate gene/single nucleotide polymorphism
These authors contributed equally to this manuscript. Submitted on October 29, 2008; resubmitted on March 24, 2009; accepted on April 2, 2009.