Newly identified gene variants associated with the age at which females experience their first menstrual period and the onset of menopause may help shed light on the prevention of breast and endometrial cancer, osteoporosis, and cardiovascular disease.

In a new study, researchers from Harvard School of Public Health (HSPH), Brigham and Women’s Hospital (BWH), National Cancer Institute (NCI), and the Broad Institute of Harvard and MIT report that they have identified 10 genetic variants in two chromosomal regions associated with age at menarche (the first menstrual period), and 13 genetic variants in four chromosomal regions associated with age at natural menopause. The paper, “Genome-wide association studies identify loci associated with age at menarche and at natural menopause,” will publish online in Nature Genetics on May 17, 2009 ( http://www.nature.com/ng/journal/vaop/ncurrent/index.html ).

Menarche and natural menopause are two important physiological events in a woman’s life. An early onset of menarche and later menopause are well-established risk factors for the development of breast cancer and endometrial cancer, the researchers explain. On the other hand, early menopause increases risk of osteoporosis and cardiovascular disease.

Previous studies have suggested both menarche and menopause may be partially under genetic control. To identify common genetic variants influencing these states, the researchers analyzed more than 317,000 gene variants in a total of 17,438 women from the Nurses’ Health Study (NHS) and the Women’s Genome Health Study (WGHS) based at BWH.

“At these newly identified loci, fine mapping or sequencing might lead to identification of the causal variants, and thus expand our knowledge of the underlying physiology and biological regulation of these traits,” said lead author Chunyan He, who was a doctoral student in the HSPH Department of Epidemiology while conducting the research. “Insights into the genetic factors influencing the timing of menarche and natural menopause might shed light on normal reproductive function and the prevention of the diseases associated with these two traits.”

Daniel Chasman, Director of Computational Biology in the Center for Cardiovascular Disease Prevention at BWH, said: “The collaboration of the WGHS and the NHS represents a great example of how large cohorts with genome-wide data can complement each other. While only one locus reached near genome-wide significance in the NHS alone, the meta-analysis of combined data had much more statistical power and revealed a total of two loci for timing of menarche and four for timing of menopause.” Chasman, also an assistant professor at Harvard Medical School, added, “Of the loci for timing of menopause, three were already strong but not proven candidates in the NHS; these loci reached genome-wide significance in the WGHS alone, supplementing the meta-analysis by a second mode of validation through replication. The remaining locus, for timing of menopause, would not have been identified, even as a candidate, without the joint power of these two cohorts working together. Future collaborations will hopefully continue to leverage the combined power of the two cohorts for association studies directed at other clinical characteristics.”

The NHS was begun in 1976 to investigate the potential long term consequences of the use of oral contraceptives. The studies were soon expanded to include diet and nutrition, in recognition of their roles in the development of chronic diseases. The research continues today with more than 116,000 women enrolled in the study.

The WGHS was announced in 2006 as a survey of genetic differences among 28,000 initially healthy American women who had already been tracked for over a decade for the development of heart disease, stroke, diabetes, and other common health disorders. Stored genetic samples from each participant undergo a fully confidential “genome-wide scan” evaluating more than 317,000 potential genetic differences.

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Contact: Christina Roache
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“Genome-wide association studies identify loci associated with age at menarche and at natural menopause,” Chunyan He, Peter Kraft, Constance Chen, Julie Buring, Guillaume Pare´, Susan Hankinson, Stephen Chanock, Paul Ridker, David Hunter, and Daniel Chasman, Nature Genetics, online May 17, 2009, http://www.nature.com/ng/journal/vaop/ncurrent/index.html

The Women’s Genome Health Study (WGHS) is supported by the National Heart, Lung, and Blood Institute, National Cancer Institute, Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. The Nurses’ Health Study (NHS) is supported by the National Cancer Institute (NCI). The NHS genome-wide association study was performed as part of the Cancer Genetic Markers of Susceptibility initiative of the NCI.

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