Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene.
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.


CONCLUSIONS
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.
Knauff
Erik A H
EA
Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. knauff@gmail.com
Franke
Lude
L
van Es
Michael A
MA
van den Berg
Leonard H
LH
van der Schouw
Yvonne T
YT
Laven
Joop S E
JS
Lambalk
Cornelius B
CB
Hoek
Annemieke
A
Goverde
Angelique J
AJ
Christin-Maitre
Sophie
S
Hsueh
Aaron J
AJ
Wijmenga
Cisca
C
Fauser
Bart C J M
BC
D051722:ADAM Proteins / Q000235:genetics*; D000071096:ADAMTS Proteins; D000328:Adult; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D016649:Primary Ovarian Insufficiency / Q000235:genetics*
D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C544648:ADAMTS19 protein, human