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Heritability of Age at Natural Menopause in the Framingham Heart Study

National Heart, Lung, and Blood Institute’s Framingham Heart Study (J.M.M., Q.Y., C.F., L.A.C.), Framingham, Massachusetts 01702; Section of General Internal Medicine (J.M.M.), Boston University School of Medicine, Boston, Massachusetts 02118; Departments of Biostatistics and Neurology (Q.Y., L.A.C.), Boston University Schools of Public Health and Medicine, Boston, Massachusetts 02118; National Heart, Lung, and Blood Institute (C.F.), Bethesda, Maryland 20892; Department of Endocrinology, Diabetes, and Hypertension (C.F.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; and Departments of Endocrinology, Diabetes, and Medical Genetics (P.W.F.W.), Medical University of South Carolina, Charleston, South Carolina 29425

Address all correspondence and requests for reprints to: Joanne Murabito, M.D., Sc.M., National Heart, Lung, and Blood Institute’s Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, Massachusetts 01702-5827. E-mail: Murabito{at}bu.edu.

	Abstract

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Background: Twin registries and family history studies provide evidence that genetic factors contribute to the onset of menopause, but heritability estimates in population-based samples are limited. We sought to estimate heritability of age at natural menopause in women participating in the multigenerational Framingham Heart Study, a community-based epidemiological study.

Methods: A total of 1500 original cohort and 932 offspring cohort women from 1296 extended families reported a natural menopause defined as the natural cessation of menses for 1 yr or more. Correlation coefficients were calculated using family correlations in Statistical Applications for Genetic Epidemiology for mother-daughter, sister-sister, and aunt-niece pairs. Heritability was estimated using variance-components methods in the Sequential Oligogenic Linkage Analysis Routines (SOLAR) computer package. Covariates in the multivariable models included generation, number of cigarettes smoked, body mass index, and parity.

Results: The mean age at natural menopause was 49.1 and 49.4 yr in original cohort and offspring women, respectively. The multivariable-adjusted correlation coefficients for mother-daughter, sister-sister, and aunt-niece pairs were 0.21, 0.22, and 0.12, respectively. The crude and multivariable-adjusted heritability estimates for age at natural menopause were 0.49 (0.37, 0.61) and 0.52 (0.35, 0.69).

Conclusions: Our data suggest that at least 50% of the interindividual variability in menopausal age appears to be attributable to genetic effects.

	Introduction

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MENOPAUSAL AGE INFLUENCES risk for death and many serious illnesses in women. For each year that menopause is delayed, cardiovascular disease mortality has been estimated to fall by 2% (1). Menopausal age varies widely, between 40 and 60 yr, and appears to be modulated by both environmental and genetic factors (2, 3, 4, 5, 6, 7). Smoking is one of the most important environmental factors influencing menopausal age with smokers experiencing menopause on average 0.8–2.0 yr earlier than nonsmokers (8, 9, 10, 11). However, it has been suggested that only a small proportion of the large variation in age at natural menopause can be explained by environmental factors (12).

Family history studies and heritability estimates of menopausal age provide support for genetic factors contributing significantly to the onset of menopause. Women reporting a mother with an early age at menopause had a 6-fold increase in odds of a premature or early menopause (3, 4). Volunteer twin registries have reported substantial heritability estimates for age at menopause that range from 0.31–0.53 in an Australian sample (5) and 0.63 in a United Kingdom sample (6). In a population-based sample of women from The Netherlands participating in a breast cancer screening project, heritability estimates for menopausal age were even higher (0.71–0.72 for twin sisters and 0.85–0.87 for singleton sisters) (7). Recent work using the same Netherlands population sample examining mother-daughter pairs found heritability of age at natural menopause to be 0.44 (13). However, heritability estimates of menopausal age have not been examined in unselected population-based samples in the United States. We hypothesized that age at natural menopause is heritable, and we sought to test this in the population-based sample of women participating in the Framingham Study cohorts. Furthermore, we sought to examine the effect of important environmental factors on heritability estimates in this sample of women.

	Subjects and Methods

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Study sample and definitions

Study sample. The Framingham Heart Study was established in 1948, when 5209 residents of Framingham, MA, including 2873 women, aged 28–62 yr, were enrolled in a prospective cohort study. Original cohort members have undergone follow-up examinations every 2 yr. In 1971, 5124 offspring of the original cohort members and offspring spouses were enrolled in the Framingham Offspring Study. Of the offspring cohort, 2641 were female ranging in age from 5–70 yr at study enrollment. These participants have undergone follow-up examinations approximately every 4 yr. Study design and entry criteria have been reported elsewhere (14, 15). The Institutional Review Board at Boston Medical Center approved the examination content for all examinations.

Of the 2873 original cohort and 2641 offspring women, 618 original cohort and 833 offspring women were excluded because they were not part of a biological family. An additional 755 original cohort and 876 offspring women were excluded because none of the women underwent a natural menopause. The final study sample is composed of 1296 families that include 1500 original cohort and 932 offspring women reporting natural menopause. The study sample includes 622 mother-daughter pairs, 474 sister-sister pairs, 29 grandmother-granddaughter pairs, 258 avuncular, and 165 first-cousin pairs. For multivariable analyses, the sample was reduced to 1022 families that include 984 original cohort and 680 offspring women after excluding women with missing covariate data.

Definition of age at natural menopause

At each examination, women were queried as to their menopausal status with the following questions: whether her periods had stopped for 1 yr or more, age periods stopped, cause periods stopped (natural, surgical, or other), hysterectomy (yes or no), and number of ovaries removed (0, 1, 2, or unknown). For the purposes of this study, natural menopause occurred after a woman had ceased menstruating naturally for 1 yr, and the age at natural menopause was the self-reported age at last menstruation. Offspring women who attended more than one examination after the onset of natural menopause may have reported different ages at which periods stopped at each postmenopausal examination attended. We used the age periods stopped at the first report to minimize recall error if the reported stop ages varied by five or fewer years (16). If the reported stop ages varied by more than 5 yr, one investigator (J.M.M.), blinded to family relationship, reviewed each woman’s research chart to ascertain the best report of age at natural menopause.

Potential environmental factors related to age at natural menopause

At each examination, height and weight were obtained and body mass index was defined as the weight in kilograms divided by the height in meters squared. Women were asked whether they smoked cigarettes regularly in the year preceding each examination, and if yes, the number of cigarettes smoked per day was recorded. Women were asked to report the average number of alcoholic drinks consumed per week. Parity was dichotomized as zero (nulliparous) vs. one or more live births (parous). Offspring women were queried about age at menarche at exam 2 and about oral contraceptive use at every exam.

Statistical analysis

Analyses were performed on crude age at natural menopause and standardized residuals from multiple linear regressions in SAS (SAS/STAT Software, Version 8.2, 1999, SAS Institute, Cary, NC) that adjusted age at natural menopause for covariates of interest. Thus, crude and multivariable-adjusted age at natural menopause were used as phenotypes in subsequent analyses. Because the crude trait was skewed and the variance component method assumes normality, we also computed heritability for the Winsorized crude trait. Winsorization is a widely accepted methodology for reducing skewness and kurtosis (17, 18). In this study, we replaced values that were four times the SD above or below the mean by the mean plus/minus four times the SD. Covariates in the multivariable models included mean number of cigarettes smoked, mean body mass index, and mean alcohol intake measured across attended examinations, parity (0 vs. 1 or more live births), oral contraceptive use ever, and age at menarche.

Heritability was calculated using two methods. First, we examined familial aggregation of age at natural menopause by calculating correlations for relatives of different types. We used the family correlations procedure in Statistical Applications for Genetic Epidemiology (SAGE, release 3.1; Case Western Reserve University, Cleveland, OH) to calculate the intraclass correlations for mother-daughter pairs, sibling pairs, and aunt-niece pairs using equal weights for each pedigree. A simple estimate of heritability is obtained by doubling the correlation coefficients for first-degree relative pairs using the equation h² = 2r (h² indicates heritability and r correlation among first-degree relative pairs). To estimate heritability from second-degree relatives, the correlation coefficient is quadrupled using the equation h² = 4r (h² indicates heritability and r correlation among aunt-niece pairs). Next, heritability of age at natural menopause was calculated using the variance-components methods implemented in the Sequential Oligogenic Linkage Analysis Routines (SOLAR) computer package (19) because it takes into account all familial relations together. The variance-components model assumes that variation in the trait can be partitioned into genetic and random environmental components. Heritability was estimated as the ratio of genetic variance to total phenotypic variance via a maximum likelihood method.

Heritability was calculated separately for offspring women and original cohort women first, and then calculated for a pooled sample of offspring and original cohort women.

	Results

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Clinical characteristics

The distribution of menopausal ages in our study sample is shown in Fig. 1. The mean age at natural menopause was similar in original cohort and offspring women, 49.1 yr (range, 29–60 yr) and 49.4 yr (range, 25–61 yr), respectively. No important differences were noted with respect to body mass index, cigarette smoking, alcohol intake, or parity.

View larger version (16K): [in this window] [in a new window]   FIG. 1. Distribution of age at natural menopause in the study sample.

Correlation coefficients for mother-daughter pairs, sister-sister pairs, and aunt-niece pairs were calculated using Statistical Applications for Genetic Epidemiology family correlations. For crude and multivariable-adjusted analyses, the correlation coefficients for age at natural menopause were 0.21 and 0.21, respectively, for mother-daughter pairs, 0.32 and 0.22, respectively, for sister-sister pairs, and 0.03 and 0.12, respectively, for aunt-niece pairs. Using the multivariable-adjusted mother-daughter, sister-sister, and aunt-niece correlation coefficients, the estimate of heritability is similar 0.42, 0.44, and 0.48, respectively.

Heritability estimates

Heritability estimates using variance components for age at natural menopause are shown in Table 1. The crude model resulted in heritability estimates of 0.65 [95% confidence interval (CI), 0.42, 0.89] in original cohort, 0.59 (95% CI, 0.37, 0.81) in offspring, and 0.49 (95% CI, 0.37, 0.61) in the pooled offspring and cohort sample. The heritability estimate for the multivariable-adjusted age at natural menopause in the original cohort was 0.74 (95% CI, 0.31, 1.00), for the offspring was 0.48 (95% CI, 0.15, 0.81), and for the pooled sample of offspring and cohort women was 0.52 (95% CI, 0.35, 0.69). Therefore, at least 50% of the interindividual variability in menopausal age appears to be attributable to genetic effects.

In offspring, the contribution of genetic factors to overall variation in age at natural menopause was 45% (heritability), and the contribution of the covariates accounted for 8% of the total variation, leaving a residual of 47%. In the original cohort, the genetic factors accounted for 74% (heritability) of the variation in age at natural menopause, whereas the covariates accounted for 4% of the total variation, leaving a residual of 22%.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have found that about 50% of the variation in age at natural menopause can be explained by genetic factors in women in Framingham families. Family history studies have focused on women with early-onset or premature menopause (3, 4), and almost all previous reports of heritability focused on twin registries, which may overestimate heritability because heritability estimates cannot effectively distinguish between genetic factors and the early shared environmental influences that are more similar among twins (20). Our data demonstrate that heritability estimates using correlation coefficients and variance-components methodology are comparable, and the magnitude of the heritability for natural menopausal age (48–74%) is similar to reports from twin registries in Australia, the United Kingdom, and The Netherlands. The similarities between our estimates of heritability and those derived from twin registries supports our finding that the environmental contribution to age at natural menopause is relatively small. Our estimate of heritability of age at natural menopause for mother-daughter pairs (0.42) is almost identical to the only other report of mother-daughter pairs derived from a Dutch sample (0.44) (13).

Limitations

Our study has several important limitations. First, our sample is primarily Caucasian, limiting the generalizability of our findings. Most national survey data have not reported an association between race or ethnicity and menopause (21, 22), but other studies have found menopause to occur later in some racial/ethnic groups (10, 23). Second, age at natural menopause was ascertained by self-report, raising the concern of recall bias. This is most challenging for women who are menopausal on study entry. We did not remove these women because this would have resulted in removing women with younger ages at menopausal onset. Third, parity is higher in the original cohort women in our study sample (95%) than in U.S. population estimates for women born at the same general time period. Because nulliparity is associated with earlier menopause, it is possible that the distribution of menopausal ages in our sample is shifted toward later onset. Fourth, some offspring women remain premenopausal. Therefore, our sample may not include as many women at more extreme ages of menopausal onset with a greater likelihood of an underlying genetic mechanism. This may result in an underestimation of heritability. Last, family studies are not able to distinguish between genetic factors and shared environmental factors within families. It is possible that lifestyle factors such as diet and exercise or other household exposures shared among family members might have influenced menopausal age.

Conclusions

A substantial proportion of the variability in age at natural menopause is explained by genetic factors. Additional studies of genetic linkage and candidate gene association are warranted to identify the specific genetic variants associated with menopausal onset. Confirmation of the first report of linkage analysis in sibling pairs with extreme concordance or discordance for age at menopause is needed (24). Determining the genetic factors associated with age at menopause may have important clinical implications because of the potential ability to intervene early in many diseases in postmenopausal women.

	Footnotes

 
National Heart, Lung, and Blood Institute’s Framingham Heart Study is supported by contract number N01-HC-25195.

First Published Online March 15, 2005

Abbreviation: CI, Confidence interval.

Received January 27, 2005.

Accepted March 4, 2005.

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