{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/78517"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/78517","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"Analysis of reproductive aging in African American women: A replication study and exome array analysis in the AMBER Consortium.","abstract":"Ph.D.","abstract_html":"Ph.D.","abstract_has_math":false,"creators":["Coignet, Marie; 0000-0002-1236-1722"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Yao, Song","Pathology and Anatomical Sciences"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-10-26T02:54:42Z","date_published":"2018-10-26T02:54:42Z","updated_at":"2026-07-27T19:05:12Z","subjects":["epidemiology","genetics"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/78517","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Yao, Song","Pathology and Anatomical Sciences"]},{"key":"dc:creator","label":"Author","values":["Coignet, Marie; 0000-0002-1236-1722"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2018-10-26T02:54:42Z","2018","2018-07-23 16:28:35"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["epidemiology","genetics"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/78517"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Ph.D.","Background. The two main hormonal events of a woman’s life, menarche and menopause, have a paramount impact on the duration of exposure to estrogen. Reproductive aging phenotypes, including age at menarche (AM) and age at natural menopause (ANM) have been consistently associated with breast cancer risk. Despite an estimated strong genetic component, genome-wide association studies (GWAS) for AM and ANM found that common variants identified to date account for only a small fraction of the variation of the two phenotypes. As those GWAS were conducted mostly in women of European ancestry (EA), studies are warranted to examine the genetic components of reproductive aging in African-American (AA) women, who have earlier AM and ANM than EA women. Hypothesis and specific aims. We hypothesize that rare and low-frequency coding variants explain a substantial proportion of the heritability for reproductive aging phenotypes (AM, ANM, and total reproductive lifespan (TRLS)) in AA women, and further, may have an impact on breast cancer risk. Specific Aim 1: To evaluate rare and low-frequency coding variants in the regions identified by previous GWAS for AM and ANM. We will perform conditional analysis to test whether the signals are independent from the known common GWAS variants. Specific Aim 2: To identify rare and low-frequency coding variants across the exome associated with reproductive aging phenotypes. We will perform single variant analysis, gene-based analysis, and gene-set analysis using a novel analytical framework for rare variants. Specific Aim 3: To examine whether the identified variants are associated with breast cancer risk, and whether the associations are mediated by reproductive aging phenotypes. Study population and methods. The study population consists of 8,477 AA women, 3,731 of whom are breast cancer cases, from the African American Breast Cancer Epidemiology and Risk Consortium (AMBER). Firstly, a candidate approach was used to identify low frequency and rare variants in the GWAS loci from previous studies. All single nucleotide polymorphisms (SNPs) within a 500kb window of previously discovered GWAS SNPs for AM and ANM were extracted from the Illumina Exome array and single SNP association tests were run using linear regressions for the continuous trend test for AM/ANM and logistic regression for the extreme AM phenotype (<11 v. 15 years). The SKAT-O test for the gene-based analyses was performed using the SKAT R package to aggregate variants with an MAF upper bound of 5%. Secondly, a similar analytical framework was conducted on the whole exome chip analysis, with the addition of the use of MAGMA to aggregate genes into gene-sets and pathways from the KEGG Pathway Database. Thirdly, the same analytical framework was used to examine whether identified variants, genes, or gene-sets were related to breast cancer risk. Results. In the replication study, while most of the GWAS index SNPs associated with AM or ANM were not significant in our analysis of AA women, we were able to replicate three variants located in LIN28B (including rs314277, p=6.24x10-5) and identified two additional variants within that locus. We also replicated the association of rs16991615 in MCM8 with ANM (p=0.0005). In exploratory analysis of the surrounding regions, we identified a few loci harboring more significant variants additional to the index SNPs. In the second exome array-wide study, the most significant variant found associated with AM was rs199994540 (p=1.04e-06). The top variant in the TRLS analysis, rs4946672 (p=1.68e-07), was significantly associated with shorter TRLS (<45 years v. 45-49 years), located in an intergenic region between the genes PREP and PRDM1 of chromosome 6. In addition, one gene was associated with longer TRLS, IGF2 (#SNPs/gene=3, p=8.53e-06). The top pathway associated with a shorter TRLS was the TGF Beta Signaling Pathway containing 67 genes (p=0.0002, pcorr=0.042). Nevertheless, none of the identified variants, genes and gene-sets were associated with breast cancer risk in our study.Conclusion. We were able to systematically interrogate rare and low-frequency variants in association with reproductive aging phenotypes in a large population of AA women. The replication study of previous GWAS variants and the surrounding region was not entirely successful in our sample of AA women, except for the LIN28B region in association with AM. This lends support to the hypothesis of uncertain portability of the previously discovered common variants, as the majority of genetic studies examining reproductive aging have been conducted in EA women. The findings of new variants and genes associated with the reproductive aging analyses may explain, in part, the missing heritability for the reproductive aging phenotypes in AA, but evidently these do not mediate breast cancer risk in our study. Our findings suggest that even larger sample sizes are necessary to unravel the genetic underpinning of reproductive aging phenotypes in AA women, and highlight the need to engage minority populations to participate in research studies."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Analysis of reproductive aging in African American women: A replication study and exome array analysis in the AMBER Consortium."]}]}],"canonical_facts":{"dc:contributor":["Yao, Song","Pathology and Anatomical Sciences"],"dc:creator":["Coignet, Marie; 0000-0002-1236-1722"],"dc:date":["2018-10-26T02:54:42Z","2018","2018-07-23 16:28:35"],"dc:description":["Ph.D.","Background. The two main hormonal events of a woman’s life, menarche and menopause, have a paramount impact on the duration of exposure to estrogen. Reproductive aging phenotypes, including age at menarche (AM) and age at natural menopause (ANM) have been consistently associated with breast cancer risk. Despite an estimated strong genetic component, genome-wide association studies (GWAS) for AM and ANM found that common variants identified to date account for only a small fraction of the variation of the two phenotypes. As those GWAS were conducted mostly in women of European ancestry (EA), studies are warranted to examine the genetic components of reproductive aging in African-American (AA) women, who have earlier AM and ANM than EA women. Hypothesis and specific aims. We hypothesize that rare and low-frequency coding variants explain a substantial proportion of the heritability for reproductive aging phenotypes (AM, ANM, and total reproductive lifespan (TRLS)) in AA women, and further, may have an impact on breast cancer risk. Specific Aim 1: To evaluate rare and low-frequency coding variants in the regions identified by previous GWAS for AM and ANM. We will perform conditional analysis to test whether the signals are independent from the known common GWAS variants. Specific Aim 2: To identify rare and low-frequency coding variants across the exome associated with reproductive aging phenotypes. We will perform single variant analysis, gene-based analysis, and gene-set analysis using a novel analytical framework for rare variants. Specific Aim 3: To examine whether the identified variants are associated with breast cancer risk, and whether the associations are mediated by reproductive aging phenotypes. Study population and methods. The study population consists of 8,477 AA women, 3,731 of whom are breast cancer cases, from the African American Breast Cancer Epidemiology and Risk Consortium (AMBER). Firstly, a candidate approach was used to identify low frequency and rare variants in the GWAS loci from previous studies. All single nucleotide polymorphisms (SNPs) within a 500kb window of previously discovered GWAS SNPs for AM and ANM were extracted from the Illumina Exome array and single SNP association tests were run using linear regressions for the continuous trend test for AM/ANM and logistic regression for the extreme AM phenotype (<11 v. 15 years). The SKAT-O test for the gene-based analyses was performed using the SKAT R package to aggregate variants with an MAF upper bound of 5%. Secondly, a similar analytical framework was conducted on the whole exome chip analysis, with the addition of the use of MAGMA to aggregate genes into gene-sets and pathways from the KEGG Pathway Database. Thirdly, the same analytical framework was used to examine whether identified variants, genes, or gene-sets were related to breast cancer risk. Results. In the replication study, while most of the GWAS index SNPs associated with AM or ANM were not significant in our analysis of AA women, we were able to replicate three variants located in LIN28B (including rs314277, p=6.24x10-5) and identified two additional variants within that locus. We also replicated the association of rs16991615 in MCM8 with ANM (p=0.0005). In exploratory analysis of the surrounding regions, we identified a few loci harboring more significant variants additional to the index SNPs. In the second exome array-wide study, the most significant variant found associated with AM was rs199994540 (p=1.04e-06). The top variant in the TRLS analysis, rs4946672 (p=1.68e-07), was significantly associated with shorter TRLS (<45 years v. 45-49 years), located in an intergenic region between the genes PREP and PRDM1 of chromosome 6. In addition, one gene was associated with longer TRLS, IGF2 (#SNPs/gene=3, p=8.53e-06). The top pathway associated with a shorter TRLS was the TGF Beta Signaling Pathway containing 67 genes (p=0.0002, pcorr=0.042). Nevertheless, none of the identified variants, genes and gene-sets were associated with breast cancer risk in our study.Conclusion. We were able to systematically interrogate rare and low-frequency variants in association with reproductive aging phenotypes in a large population of AA women. The replication study of previous GWAS variants and the surrounding region was not entirely successful in our sample of AA women, except for the LIN28B region in association with AM. This lends support to the hypothesis of uncertain portability of the previously discovered common variants, as the majority of genetic studies examining reproductive aging have been conducted in EA women. The findings of new variants and genes associated with the reproductive aging analyses may explain, in part, the missing heritability for the reproductive aging phenotypes in AA, but evidently these do not mediate breast cancer risk in our study. Our findings suggest that even larger sample sizes are necessary to unravel the genetic underpinning of reproductive aging phenotypes in AA women, and highlight the need to engage minority populations to participate in research studies."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/78517"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["epidemiology","genetics"],"dc:title":["Analysis of reproductive aging in African American women: A replication study and exome array analysis in the AMBER Consortium."],"dc:type":["Text","Dissertation"]},"updated_at":"2026-07-27T19:05:12Z"}