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Genetic variation and reproductive timing: African American women from the Population Architecture using Genomics and Epidemiology (PAGE) Study.

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Citation: PLoS ONE [Electronic Resource]. 8(2):e55258, 2013.PMID: 23424626Institution: MedStar Washington Hospital CenterDepartment: Obstetrics and Gynecology/Female Pelvic Medicine and Reconstructive SurgeryForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, N.I.H., ExtramuralSubject headings: *African Americans/ge [Genetics] | *African Americans/sn [Statistics & Numerical Data] | *Epidemiologic Studies | *Genetic Variation | *Genomics | *Reproduction/ge [Genetics] | Adolescent | Female | Humans | Menarche/eh [Ethnology] | Menarche/ge [Genetics] | Menarche/ph [Physiology] | Menopause/eh [Ethnology] | Menopause/ge [Genetics] | Menopause/ph [Physiology] | Middle AgedLocal holdings: Available online through MWHC library: 2006 - presentISSN:

1932-6203

Name of journal: PloS oneAbstract: Age at menarche (AM) and age at natural menopause (ANM) define the boundaries of the reproductive lifespan in women. Their timing is associated with various diseases, including cancer and cardiovascular disease. Genome-wide association studies have identified several genetic variants associated with either AM or ANM in populations of largely European or Asian descent women. The extent to which these associations generalize to diverse populations remains unknown. Therefore, we sought to replicate previously reported AM and ANM findings and to identify novel AM and ANM variants using the Metabochip (n=161,098 SNPs) in 4,159 and 1,860 African American women, respectively, in the Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study. We replicated or generalized one previously identified variant for AM, rs1361108/CENPW, and two variants for ANM, rs897798/BRSK1 and rs769450/APOE, to our African American cohort. Overall, generalization of the majority of previously-identified variants for AM and ANM, including LIN28B and MCM8, was not observed in this African American sample. We identified three novel loci associated with ANM that reached significance after multiple testing correction (LDLR rs189596789, p=5x10-08; KCNQ1 rs79972789, p=1.9x10-07; COL4A3BP rs181686584, p=2.9x10-07). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, p=1.6x10-06). While most associations were identified in either AM or ANM, we did identify genes suggestively associated with both: PHACTR1 and ARHGAP42. The lack of generalization coupled with the potentially novel associations identified here emphasize the need for additional genetic discovery efforts for AM and ANM in diverse populations.All authors: Brennan K, Buyske S, Carlson CS, Carty CL, Cheng I, Chunyuanwu, Crawford DC, Fernandez-Rhodes L, Franceschini N, Haiman CA, Hindorff LA, Malinowski J, Matise TC, Park A, Rajkovic A, Ritchie MD, Spencer KL, Wilkens L, Young ADigital Object Identifier:

http://dx.doi.org/10.1371/journal.pone.0055258

Date added to catalog: 2013-09-17

Holdings ( 1 )
Title notes ( 3 )

Holdings
Item type	Current library	Collection	Call number	Status	Date due	Barcode
Journal Article	MedStar Authors Catalog	Article		Available		23424626

Available online through MWHC library: 2006 - present

Age at menarche (AM) and age at natural menopause (ANM) define the boundaries of the reproductive lifespan in women. Their timing is associated with various diseases, including cancer and cardiovascular disease. Genome-wide association studies have identified several genetic variants associated with either AM or ANM in populations of largely European or Asian descent women. The extent to which these associations generalize to diverse populations remains unknown. Therefore, we sought to replicate previously reported AM and ANM findings and to identify novel AM and ANM variants using the Metabochip (n=161,098 SNPs) in 4,159 and 1,860 African American women, respectively, in the Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study. We replicated or generalized one previously identified variant for AM, rs1361108/CENPW, and two variants for ANM, rs897798/BRSK1 and rs769450/APOE, to our African American cohort. Overall, generalization of the majority of previously-identified variants for AM and ANM, including LIN28B and MCM8, was not observed in this African American sample. We identified three novel loci associated with ANM that reached significance after multiple testing correction (LDLR rs189596789, p=5x10-08; KCNQ1 rs79972789, p=1.9x10-07; COL4A3BP rs181686584, p=2.9x10-07). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, p=1.6x10-06). While most associations were identified in either AM or ANM, we did identify genes suggestively associated with both: PHACTR1 and ARHGAP42. The lack of generalization coupled with the potentially novel associations identified here emphasize the need for additional genetic discovery efforts for AM and ANM in diverse populations.

English