Menopause, Natural, Age At, Quantitative Trait Locus 1

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Age at natural menopause has been associated with variation on chromosome Xp21.3. Other quantitative trait loci (QTLs) for age at natural menopause include MENOQ2 (612884) on chromosome 19q13.4, MENOQ3 (612885) on chromosome 20p12.3, and MENOQ4 (612886) on chromosome 5q35.2.

Inheritance

Several studies have suggested that genetic factors are involved in the age at natural menopause. Cramer et al. (1995) reported a familial component to the occurrence of early menopause. Among 551 women who did not use hormone replacement therapy (HRT) and did not have a hysterectomy, Torgerson et al. (1997) found that women with premature menopause (less than 40 years) and early menopause (less than 45 years) reported significantly lower maternal menopausal ages than women with normal menopausal ages (43.8, 45.4, and 48.4 for premature, early, and normal, respectively). The odds of a woman having an early or premature menopause if her mother had experienced an early menopause was 6.02, indicating a strong relationship between mothers' and daughters' menopausal age.

In a study of 275 monozygotic and 353 dizygotic female twin pairs, Snieder et al. (1998) used a model specifying additive genetic and unique environmental factors to yield a 63% heritability score for age at menopause. No correlation was found between age at menopause and age at menarche, suggesting different genetic mechanisms.

In an Australian twin sample, Treloar et al. (1998) estimated heritability of age at natural menopause to be 31 to 53%. De Bruin et al. (2001) reported heritability estimates of 70% and 85% in twin and sister pairs, respectively.

Murabito et al. (2005) studied the heritability of age at natural menopause in women participating in the multigenerational Framingham Heart Study. The mean age at natural menopause was 49.1 and 49.4 years in the original cohort and offspring women, respectively. The authors concluded that at least 50% of interindividual variability in menopausal age appears to be attributable to genetic effects.

Mapping

To identify quantitative trait loci for age at normal menopause, van Asselt et al. (2004) performed a genomewide linkage study in 165 Dutch sister pairs. Two chromosomal regions showed suggestive linkage: Xp21.3 (lod score of 3.1) and 9q21.3 (lod score of 2.6). The authors noted that premature ovarian failure has been linked to a region on Xq (311360).

Associations Pending Confirmation

Weel et al. (1999) investigated whether genetic variation in the ESR gene contributes to the variability in the onset of menopause in 900 postmenopausal women, 55 to 80 years of age, of the Rotterdam Study, a population-based cohort study in the Netherlands. Gynecologic information was obtained, and if women reported surgical menopause, validation of type and indication of surgery was accomplished by checking medical records. The ESR1 (133430) genotypes PP, Pp, and pp representing the anonymous intronic PvuII RFLP (133430.0004) were assessed by PCR using the PvuII endonuclease. Compared with women carrying the pp genotype, homozygous PP women had a 1.1 year (P less than 0.02) earlier onset of menopause. Furthermore, an allele dosage effect was observed, corresponding to a 0.5 year (P less than 0.02) earlier onset of menopause per copy of the P allele. The risk of surgical menopause was 2.4 (95% confidence interval, 1.5 to 3.8) times higher for women carrying the PP genotype compared to those in the pp group, with the most prominent effect in women who underwent hysterectomy due to fibroids or menorrhagia. The authors concluded that genetic variations of the ESR gene are related to the onset of natural menopause and the risk of surgical menopause, especially hysterectomy.

Stolk et al. (2009) conducted a 2-stage genomewide association study for age at natural menopause in 2,979 European women and identified significant association with rs7333181 (p = 2.5 x 10(-8)) on chromosome 13q34. The authors subsequently conducted fine mapping using metaanalysis of imputed data from the stage 1 study and found 3 additional SNPs with more or equal significance compared to that of the initially reported SNP, rs1361542, rs1163623, and rs1756091 (p = 4.00 x 10(-4) for each), all of which are located in the same LD block as rs7333181.

In a genomewide association study of 17,438 women, He et al. (2009) found significant association of age at natural menopause with rs2153157 (p = 5.1 x 10(-8)), located within intron 4 of the SYCP2L gene (616799) on chromosome 6p24.2.