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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.

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.

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