Genetic Variation and Reproductive Timing: African American Women from the Population Architecture Using Genomics and Epidemiology (PAGE) Study

Kylee L. Spencer, Jennifer Malinowski, Cara L. Carty, Nora Franceschini, Lindsay Fernández-Rhodes, Alicia Young, Iona Cheng, Marylyn D. Ritchie, Christopher A. Haiman, Lynne Wilkens, ChunyuanWu, Tara C. Matise, Christopher S. Carlson, Kathleen Brennan, Amy Park, Aleksandar Rajkovic, Lucia A. Hindorff, Steven Buyske, Dana C. Crawford

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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.

Original languageEnglish (US)
Article numbere55258
JournalPloS one
Volume8
Issue number2
DOIs
StatePublished - Feb 12 2013

Fingerprint

menarche
menopause
Epidemiology
Menarche
African Americans
Menopause
Genomics
epidemiology
Genes
genomics
genetic variation
Population
Testing
women's health
ovarian neoplasms
Genome-Wide Association Study
Women's Health
atherosclerosis
breast neoplasms
Ovarian Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Spencer, Kylee L. ; Malinowski, Jennifer ; Carty, Cara L. ; Franceschini, Nora ; Fernández-Rhodes, Lindsay ; Young, Alicia ; Cheng, Iona ; Ritchie, Marylyn D. ; Haiman, Christopher A. ; Wilkens, Lynne ; ChunyuanWu ; Matise, Tara C. ; Carlson, Christopher S. ; Brennan, Kathleen ; Park, Amy ; Rajkovic, Aleksandar ; Hindorff, Lucia A. ; Buyske, Steven ; Crawford, Dana C. / Genetic Variation and Reproductive Timing : African American Women from the Population Architecture Using Genomics and Epidemiology (PAGE) Study. In: PloS one. 2013 ; Vol. 8, No. 2.
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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.",
author = "Spencer, {Kylee L.} and Jennifer Malinowski and Carty, {Cara L.} and Nora Franceschini and Lindsay Fern{\'a}ndez-Rhodes and Alicia Young and Iona Cheng and Ritchie, {Marylyn D.} and Haiman, {Christopher A.} and Lynne Wilkens and ChunyuanWu and Matise, {Tara C.} and Carlson, {Christopher S.} and Kathleen Brennan and Amy Park and Aleksandar Rajkovic and Hindorff, {Lucia A.} and Steven Buyske and Crawford, {Dana C.}",
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Spencer, KL, Malinowski, J, Carty, CL, Franceschini, N, Fernández-Rhodes, L, Young, A, Cheng, I, Ritchie, MD, Haiman, CA, Wilkens, L, ChunyuanWu, Matise, TC, Carlson, CS, Brennan, K, Park, A, Rajkovic, A, Hindorff, LA, Buyske, S & Crawford, DC 2013, 'Genetic Variation and Reproductive Timing: African American Women from the Population Architecture Using Genomics and Epidemiology (PAGE) Study', PloS one, vol. 8, no. 2, e55258. https://doi.org/10.1371/journal.pone.0055258

Genetic Variation and Reproductive Timing : African American Women from the Population Architecture Using Genomics and Epidemiology (PAGE) Study. / Spencer, Kylee L.; Malinowski, Jennifer; Carty, Cara L.; Franceschini, Nora; Fernández-Rhodes, Lindsay; Young, Alicia; Cheng, Iona; Ritchie, Marylyn D.; Haiman, Christopher A.; Wilkens, Lynne; ChunyuanWu; Matise, Tara C.; Carlson, Christopher S.; Brennan, Kathleen; Park, Amy; Rajkovic, Aleksandar; Hindorff, Lucia A.; Buyske, Steven; Crawford, Dana C.

In: PloS one, Vol. 8, No. 2, e55258, 12.02.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic Variation and Reproductive Timing

T2 - African American Women from the Population Architecture Using Genomics and Epidemiology (PAGE) Study

AU - Spencer, Kylee L.

AU - Malinowski, Jennifer

AU - Carty, Cara L.

AU - Franceschini, Nora

AU - Fernández-Rhodes, Lindsay

AU - Young, Alicia

AU - Cheng, Iona

AU - Ritchie, Marylyn D.

AU - Haiman, Christopher A.

AU - Wilkens, Lynne

AU - ChunyuanWu,

AU - Matise, Tara C.

AU - Carlson, Christopher S.

AU - Brennan, Kathleen

AU - Park, Amy

AU - Rajkovic, Aleksandar

AU - Hindorff, Lucia A.

AU - Buyske, Steven

AU - Crawford, Dana C.

PY - 2013/2/12

Y1 - 2013/2/12

N2 - 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.

AB - 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.

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