title: Genetic variation and reproductive timing: African American women from the Population Architecture using Genomics and Epidemiology (PAGE) Study.
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.
authors: Department of Biology and Environmental Science, Heidelberg University, Tiffin, Ohio, United States of America.
authors: Kylee L
authors: KL
authors: Spencer
authors: Jennifer
authors: J
authors: Malinowski
authors: Cara L
authors: CL
authors: Carty
authors: Nora
authors: N
authors: Franceschini
authors: Lindsay
authors: L
authors: Fernández-Rhodes
authors: Alicia
authors: A
authors: Young
authors: Iona
authors: I
authors: Cheng
authors: Marylyn D
authors: MD
authors: Ritchie
authors: Christopher A
authors: CA
authors: Haiman
authors: Lynne
authors: L
authors: Wilkens
authors: Chunyuanwu
authors: Tara C
authors: TC
authors: Matise
authors: Christopher S
authors: CS
authors: Carlson
authors: Kathleen
authors: K
authors: Brennan
authors: Amy
authors: A
authors: Park
authors: Aleksandar
authors: A
authors: Rajkovic
authors: Lucia A
authors: LA
authors: Hindorff
authors: Steven
authors: S
authors: Buyske
authors: Dana C
authors: DC
authors: Crawford
mesh_terms: D000293:Adolescent; D001741:Black or African American / Q000235:genetics* / Q000706:statistics & numerical data*; D016021:Epidemiologic Studies; D005260:Female; D014644:Genetic Variation; D023281:Genomics; D006801:Humans; D008572:Menarche / Q000208:ethnology / Q000235:genetics / Q000502:physiology; D008593:Menopause / Q000208:ethnology / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D012098:Reproduction / Q000235:genetics*