Genetic Variation and Reproductive Timing: African American Women from the Population Architecture Using Genomics and Epidemiology (PAGE) Study
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...
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| Published in | PloS one Vol. 8; no. 2; p. e55258 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
12.02.2013
Public Library of Science (PLoS) |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1932-6203 1932-6203 |
| DOI | 10.1371/journal.pone.0055258 |
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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. |
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| AbstractList | 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. 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. 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. 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.sup.-08 ; KCNQ1 rs79972789, p = 1.9x10.sup.-07 ; COL4A3BP rs181686584, p = 2.9x10.sup.-07). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, p = 1.6x10.sup.-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. 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.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. |
| Audience | Academic |
| Author | Park, Amy Rajkovic, Aleksandar Fernández-Rhodes, Lindsay Matise, Tara C. Cheng, Iona Wilkens, Lynne Carlson, Christopher S. Hindorff, Lucia A. Carty, Cara L. Ritchie, Marylyn D. ChunyuanWu Malinowski, Jennifer Young, Alicia Buyske, Steven Franceschini, Nora Spencer, Kylee L. Haiman, Christopher A. Brennan, Kathleen Crawford, Dana C. |
| AuthorAffiliation | 6 Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America 2 Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America 7 University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, United States of America 9 Department of Obstetrics and Gynecology, School of Medicine, Georgetown University, Washington, DC, United States of America 5 Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America 8 Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, California, United States of America 12 Department of Biology and Environmental Science, Heidelberg University, Tiffin, Ohio, United States of America 1 Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America 11 Office of Population Genomics, National Human Genome |
| AuthorAffiliation_xml | – name: 8 Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, California, United States of America – name: 9 Department of Obstetrics and Gynecology, School of Medicine, Georgetown University, Washington, DC, United States of America – name: 13 Biochemistry and Molecular Biology, Penn State University, University Park, Maryland, United States of America – name: 4 Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America – name: 3 Department of Statistics, Rutgers University, Piscataway, New Jersey, United States of America – name: 6 Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America – name: 5 Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America – name: 1 Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America – name: 2 Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America – name: Peninsula College of Medicine and Dentistry, University of Exeter, United Kingdom – name: 7 University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, United States of America – name: 10 Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America – name: 11 Office of Population Genomics, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America – name: 12 Department of Biology and Environmental Science, Heidelberg University, Tiffin, Ohio, United States of America |
| Author_xml | – sequence: 1 givenname: Kylee L. surname: Spencer fullname: Spencer, Kylee L. – sequence: 2 givenname: Jennifer surname: Malinowski fullname: Malinowski, Jennifer – sequence: 3 givenname: Cara L. surname: Carty fullname: Carty, Cara L. – sequence: 4 givenname: Nora surname: Franceschini fullname: Franceschini, Nora – sequence: 5 givenname: Lindsay surname: Fernández-Rhodes fullname: Fernández-Rhodes, Lindsay – sequence: 6 givenname: Alicia surname: Young fullname: Young, Alicia – sequence: 7 givenname: Iona surname: Cheng fullname: Cheng, Iona – sequence: 8 givenname: Marylyn D. surname: Ritchie fullname: Ritchie, Marylyn D. – sequence: 9 givenname: Christopher A. surname: Haiman fullname: Haiman, Christopher A. – sequence: 10 givenname: Lynne surname: Wilkens fullname: Wilkens, Lynne – sequence: 11 surname: ChunyuanWu fullname: ChunyuanWu – sequence: 12 givenname: Tara C. surname: Matise fullname: Matise, Tara C. – sequence: 13 givenname: Christopher S. surname: Carlson fullname: Carlson, Christopher S. – sequence: 14 givenname: Kathleen surname: Brennan fullname: Brennan, Kathleen – sequence: 15 givenname: Amy surname: Park fullname: Park, Amy – sequence: 16 givenname: Aleksandar surname: Rajkovic fullname: Rajkovic, Aleksandar – sequence: 17 givenname: Lucia A. surname: Hindorff fullname: Hindorff, Lucia A. – sequence: 18 givenname: Steven surname: Buyske fullname: Buyske, Steven – sequence: 19 givenname: Dana C. surname: Crawford fullname: Crawford, Dana C. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23424626$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | COPYRIGHT 2013 Public Library of Science 2013 Spencer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2013 Spencer et al 2013 Spencer et al |
| Copyright_xml | – notice: COPYRIGHT 2013 Public Library of Science – notice: 2013 Spencer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. – notice: 2013 Spencer et al 2013 Spencer et al |
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| DOI | 10.1371/journal.pone.0055258 |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Competing Interests: Co-author Dana C. Crawford is a PLOS ONE Editorial Board member. This membership does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. Conceived and designed the experiments: KLS CLC NF LFR AY IC MDR CAH LW CW TCM CSC KB AP AR LAH SB DCC. Performed the experiments: KLS CLC NF LFR AY IC MDR CAH LW CW TCM CSC KB AP AR LAH SB DCC. Analyzed the data: KLS JM CLC NF LFR AY IC MDR CAH LW CW TCM CSC KB AP AR LAH SB DCC. Contributed reagents/materials/analysis tools: KLS JM CLC NF LFR AY IC MDR CAH LW CW TCM CSC KB AP AR SB DCC. Wrote the paper: KLS JM CLC NF LFR LAH SB DCC. |
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| SubjectTerms | Adolescent African American women African Americans Apolipoprotein E Architecture Arteriosclerosis Atherosclerosis Biology Black or African American - genetics Black or African American - statistics & numerical data Breast cancer Cancer Cardiovascular disease Cardiovascular diseases Epidemiologic Studies Epidemiology Female Genetic aspects Genetic diversity Genetic variance Genetic Variation Genome-wide association studies Genomes Genomics Health promotion Health risk assessment Hormone replacement therapy Humans KCNQ1 protein Life span Lipoprotein (low density) receptors Medical research Medicine Menarche Menarche - ethnology Menarche - genetics Menarche - physiology Menopause Menopause - ethnology Menopause - genetics Menopause - physiology Middle Aged Obesity Populations Potassium channels (voltage-gated) Reproduction - genetics Single-nucleotide polymorphism Type 2 diabetes Women's health |
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| Title | Genetic Variation and Reproductive Timing: African American Women from the Population Architecture Using Genomics and Epidemiology (PAGE) Study |
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