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Non-synonymous single nucleotide polymorphism in MCM8 decreased in a cohort of premature ovarian failure patients


Genome-wide association studies have identified genetic loci that may be involved in the onset and senescence of ovarian function. A non-synonymous single nucleotide polymorphism (SNP rs16991615), located in exon 9 of MCM8, was found to be associated with age at natural menopause in a recent GWAS analysis (He, 2009). We speculate that this mutation changes secondary protein structure sufficiently to affect the function of MCM8. Therefore, we hypothesize that this SNP may be present in more women with premature ovarian failure (POF) compared to controls.


Experimental laboratory study.


We collected genomic DNA from predominantly North-American Caucasian women with premature ovarian failure (defined as amenorrhea prior to age 40 with FSH > 20IU/L) and control patients of similar background. A primer set specific for the region of MCM8 containing exon 9 was used for polymerase chain reaction to amplify the segment of interest. Restriction enzyme AciI was used to cut the 597-bp product at the recognition site; cleaved products indicated wild-type, and intact products indicated a PCR product containing the SNP. Statistical comparison was performed using the Fisher exact test.


The frequency of SNP rs16991615 was lower in women with POF. Although there was a trend, it did not reach statistical significance. Of 60 women with POF, only 1 (1.6%) had the SNP rs16991615 identified, compared to 6 of 56 (10.7%) control women (P=0.055).


SNP rs16991615 is more common in our control women than those with POF. Our finding suggests that this SNP could confer a reproductive advantage to women or, at a minimum, provides supporting evidence for the association of MCM8 with genes influencing age at natural menopause. Overall frequency of this SNP was low in both groups of women. In future studies, an increased sample size may lead to a statistically significant difference in SNP frequencies.

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