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

TitleGenetic variation and reproductive timing: African American women from the Population Architecture using Genomics and Epidemiology (PAGE) Study.
Publication TypeJournal Article
Year of Publication2013
AuthorsSpencer KL, Malinowski J, Carty CL, Franceschini N, Fernández-Rhodes L, Young A, Cheng I, Ritchie MD, Haiman CA, Wilkens L, Matise TC, Carlson CS, Brennan K, Park A, Rajkovic A, Hindorff LA, Buyske S
Secondary AuthorsCrawford DC
JournalPLoS One
Volume8
Issue2
Paginatione55258
Date Published2013
ISSN1932-6203
KeywordsAdolescent, African Americans, Epidemiologic Studies, Female, Genetic Variation, Genomics, Humans, Menarche, Menopause, Middle Aged, Reproduction
Abstract

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 = 5×10⁻⁰⁸; KCNQ1 rs79972789, p = 1.9×10⁻⁰⁷; COL4A3BP rs181686584, p = 2.9×10⁻⁰⁷). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, p = 1.6×10⁻⁰⁶). 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.

DOI10.1371/journal.pone.0055258
Alternate JournalPLoS One
PubMed ID23424626
PubMed Central IDPMC3570525
Grant ListN01WH22110 / WH / WHI NIH HHS / United States
U01CA98758 / CA / NCI NIH HHS / United States
N01WH42129-32 / WH / WHI NIH HHS / United States
T32 GM080178 / GM / NIGMS NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01WH32100-2 / WH / WHI NIH HHS / United States
U01CA136792 / CA / NCI NIH HHS / United States
N01WH32108-9 / WH / WHI NIH HHS / United States
U01HG004803 / HG / NHGRI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
U01HG004802 / HG / NHGRI NIH HHS / United States
N01WH42107-26 / WH / WHI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01WH32122 / WH / WHI NIH HHS / United States
U01HG004798 / HG / NHGRI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01WH32105-6 / WH / WHI NIH HHS / United States
N01WH32111-13 / WH / WHI NIH HHS / United States
N01WH32118-32119 / WH / WHI NIH HHS / United States
U01HG004801 / HG / NHGRI NIH HHS / United States
R37CA54281 / CA / NCI NIH HHS / United States
U01HG004790 / HG / NHGRI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01WH32115 / WH / WHI NIH HHS / United States
N01WH44221 / WH / WHI NIH HHS / United States
P01CA33619 / CA / NCI NIH HHS / United States
N01WH24152 / WH / WHI NIH HHS / United States
R01 CA63 / CA / NCI NIH HHS / United States