Lessons from Genome-Wide Association Studies in Reproductive Medicine: Menopause.

2.50
Hdl Handle:
http://hdl.handle.net/11287/619995
Title:
Lessons from Genome-Wide Association Studies in Reproductive Medicine: Menopause.
Authors:
Ruth, K S; Murray, Anna
Abstract:
In recent years, common genetic variants have been identified by genome-wide association studies (GWASs) that have led to the detection of 44 genetic loci associated with approximately 6% of common variation in age at natural menopause. In the latest GWAS, doubling the sample size to approximately 70,000 women more than doubled the number of signals identified, from 17 to 56. In addition, low-frequency coding variants (< 5% minor allele frequency), with relatively large effect sizes, have been identified in two genes, by analyzing genome-wide exome data. GWAS has been very successful in identifying novel biological pathways involved in reproductive aging. Approximately two-thirds of the loci reported so far include genes involved in DNA damage response (DDR), highlighting the importance of this pathway in determining oocyte reserve. In addition, GWAS demonstrates that the hypothalamic-pituitary axis is involved in menopause timing as well as puberty timing, showing the first genetic link between timing of the start and end of reproductive life. Genetic variants have been used to explore the causal relationships between menopause timing and breast cancer. These studies demonstrate that for a 1 year increase in menopause age, there is a 6% increase in breast cancer risk, a value approximately double the estimate from epidemiological studies. Prolonged exposure to estrogen during reproductive life is the likely mechanism, rather than a direct effect of DDR variants on cancer risk. Further work is needed to determine the mechanism for the effect of each variant identified by GWAS and more variants will undoubtedly be discovered as sample sizes increase, denser single nucleotide polymorphism arrays and reference genomes are used, and populations from diverse ethnic groups are studied.
Citation:
Lessons from Genome-Wide Association Studies in Reproductive Medicine: Menopause. 2016, 34 (4):215-23 Semin. Reprod. Med.
Publisher:
Thieme
Journal:
Seminars in Reproductive Medicine
Issue Date:
Jul-2016
URI:
http://hdl.handle.net/11287/619995
DOI:
10.1055/s-0036-1585404
PubMed ID:
27513022
Type:
Journal Article
Language:
en
ISSN:
1526-4564
Appears in Collections:
Honorary contracts publications; 2016 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorRuth, K Sen
dc.contributor.authorMurray, Annaen
dc.date.accessioned2016-09-08T11:06:06Z-
dc.date.available2016-09-08T11:06:06Z-
dc.date.issued2016-07-
dc.identifier.citationLessons from Genome-Wide Association Studies in Reproductive Medicine: Menopause. 2016, 34 (4):215-23 Semin. Reprod. Med.en
dc.identifier.issn1526-4564-
dc.identifier.pmid27513022-
dc.identifier.doi10.1055/s-0036-1585404-
dc.identifier.urihttp://hdl.handle.net/11287/619995-
dc.description.abstractIn recent years, common genetic variants have been identified by genome-wide association studies (GWASs) that have led to the detection of 44 genetic loci associated with approximately 6% of common variation in age at natural menopause. In the latest GWAS, doubling the sample size to approximately 70,000 women more than doubled the number of signals identified, from 17 to 56. In addition, low-frequency coding variants (< 5% minor allele frequency), with relatively large effect sizes, have been identified in two genes, by analyzing genome-wide exome data. GWAS has been very successful in identifying novel biological pathways involved in reproductive aging. Approximately two-thirds of the loci reported so far include genes involved in DNA damage response (DDR), highlighting the importance of this pathway in determining oocyte reserve. In addition, GWAS demonstrates that the hypothalamic-pituitary axis is involved in menopause timing as well as puberty timing, showing the first genetic link between timing of the start and end of reproductive life. Genetic variants have been used to explore the causal relationships between menopause timing and breast cancer. These studies demonstrate that for a 1 year increase in menopause age, there is a 6% increase in breast cancer risk, a value approximately double the estimate from epidemiological studies. Prolonged exposure to estrogen during reproductive life is the likely mechanism, rather than a direct effect of DDR variants on cancer risk. Further work is needed to determine the mechanism for the effect of each variant identified by GWAS and more variants will undoubtedly be discovered as sample sizes increase, denser single nucleotide polymorphism arrays and reference genomes are used, and populations from diverse ethnic groups are studied.en
dc.language.isoenen
dc.publisherThiemeen
dc.rightsArchived with thanks to Seminars in reproductive medicineen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleLessons from Genome-Wide Association Studies in Reproductive Medicine: Menopause.en
dc.typeJournal Articleen
dc.identifier.journalSeminars in Reproductive Medicineen
dc.type.versionPublisheden

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