Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Day, Felix R.; Ruth, Katherine S.; Thompson, Deborah J.; Lunetta, Kathryn L.; Pervjakova, Natalia; Chasman, Daniel I.; Stolk, Lisette; Finucane, Hilary; Sulem, Patrick; Bulik-Sullivan, Brendan; Esko, Tõnu; Johnson, Andrew D.; Elks, Cathy E.; Franceschini, Nora; He, Chunyan; Altmaier, Elisabeth; Brody, Jennifer A.; Franke, Lude; Huffman, Jennifer E.; Keller, Margaux F.; McArdle, Patrick F.; Nutile, Teresa; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M.; Schick, Ursula M.; Smith, Jennifer A.; Teumer, Alexander; Traglia, Michela; Vuckovic, Dragana; Yao, Jie; Zhao, Wei; Albrecht, Eva; Amin, Najaf; Corre, Tanguy; Hottenga, Jouke Jan; Mangino, Massimo; Smith, Albert V.; Tanaka, Toshiko; Abecasis, Gonçalo R.; Andrulis, Irene L.; Anton‐Culver, Hoda; Antoniou, Antonis C.; Arndt, Volker; Arnold, Alice M.; Barbieri, Caterina; Beckmann, Matthias W.; Beeghly–Fadiel, Alicia; Benı́tez, Javier; Bernstein, Leslie; Bielinski, Suzette J.; Blomqvist, Carl; Boerwinkle, Eric; Bogdanova, Natalia; Bojesen, Stig E.; Bolla, Manjeet K.; Børresen‐Dale, Anne‐Lise; Boutin, Thibaud; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Campbell, Archie; Campbell, Harry; Chanock, Stephen J.; Chapman, J. Ross; Chen, Yii Der Ida; Chenevix-Trench, Georgia; Couch, Fergus J.; Coviello, Andrea D.; Cox, Angela; Czene, Kamila; Darabi, Hatef; Vivo, Immaculata De; Demerath, Ellen W.; Dennis, Joe; Devilee, Peter; Dörk, Thilo; dos‐Santos‐Silva, Isabel; Dunning, Alison M.; Eicher, John D.; Fasching, Peter A.; Faul, Jessica D.; Figueroa, Jonine D.; Flesch-Janys, Dieter; Gandin, Ilaria; García, Melissa; García‐Closas, Montserrat; Giles, Graham G.; Girotto, Giorgia; Goldberg, Mark S.; González‐Neira, Anna; Goodarzi, Mark O.; Grove, Megan L.; Guðbjartsson, Daníel F.; Guénel, Pascal; Guo, Xiuqing; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Henderson, Brian E.; Hocking, Lynne J.; Hofman, Albert; Homuth, Georg; Hooning, Maartje J.; Hopper, John L.; Hu, Frank B.; Huang, Jinyan; Humphreys, Keith; Hunter, David J.; Jakubowska, Anna; Jones, Samuel E.; Kabisch, Maria; Karasik, David; Knight, Julia A.; Kolčić, Ivana; Kooperberg, Charles; Kosma, Veli‐Matti; Kriebel, Jennifer; Kristensen, Vessela N.; Lambrechts, Diether; Langenberg, Claudia; Li, Jingmei; Li, Xin; Lindström, Sara; Liu, Yongmei; Luan, Jian’an; Lubiński, Jan; Mägi, Reedik; Mannermaa, Arto; Manz, Judith; Margolin, Sara; Marten, Jonathan; Martin, Nicholas G.; Masciullo, Corrado; Meindl, Alfons; Michailidou, Kyriaki; Mihailov, Evelin; Milani, Lili; Milne, Roger L.; Müller‐Nurasyid, Martina; Nalls, Michael A.; Neale, Benjamin M.; Nevanlinna, Heli; Neven, Patrick; Newman, Anne B.; Nordestgaard, Børge G.; Olson, Janet E.; Padmanabhan, Sandosh; Peterlongo, Paolo; Peters, Ulrike; Petersmann, Astrid; Peto, Julian; Pharoah, Paul D.P.; Pirastu, Nicola; Pirie, Ailith; Pistis, Giorgio; Polašek, Ozren; Porteous, David J.; Psaty, Bruce M.; Pylkäs, Katri; Radice, Paolo; Raffel, Leslie J.; Rivadeneira, Fernando; Rudan, Igor; Rudolph, Anja; Ruggiero, Daniela; Sala, Cinzia; Sanna, Serena; Sawyer, Elinor J.; Schlessinger, David; Schmidt, Marjanka K.; Schmidt, Frank; Schmutzler, Rita K.; Schoemaker, Minouk J.; Scott, Robert A.; Seynaeve, Caroline; Simard, Jacques; Sorice, Rossella; Southey, Melissa C.; Stöckl, Doris; Strauch, Konstantin; Swerdlow, Anthony; Taylor, Kent D.; Þorsteinsdóttir, Unnur; Toland, Amanda E.; Tomlinson, Ian; Truong, Thérèse; Tryggvadóttír, Laufey; Turner, Stephen T.; Vozzi, Diego; Wang, Qin; Wellons, Melissa; Willemsen, Gonneke; Wilson, James F.; Winqvist, Robert; Wolffenbuttel, Bruce H. R.; Wright, Alan F.; Yannoukakos, Drakoulis; Zemunik, Tatijana; Zheng, Wei; Zygmunt, Marek; Bergmann, Sven; Boomsma, Dorret I.; Buring, Julie E.; Ferrucci, Luigi; Montgomery, Grant W.; Gudnason, Vilmundur; Spector, Tim D.; Duijn, Cornelia M. van; Alizadeh, Behrooz Z.; Ciullo, Marina; Crisponi, Laura; Easton, Douglas F.; Gasparini, Paolo; Gieger, Christian; Harris, Tamara B.; Hayward, Caroline; Kardia, Sharon L.R.; Kraft, Peter; McKnight, Barbara; Metspalu, Andres; Morrison, Alanna C.; Reiner, Alex P.; Ridker, Paul M.; Rotter, Jerome I.; Toniolo, Daniela; Uitterlinden, André G.; Ulivi, Sheila; Völzke, Henry; Wareham, Nicholas J.; Weir, David R.; Yerges‐Armstrong, Laura M.; Price, Alkes L.; Stefánsson, Kári; Visser, Jenny A.; Ong, Ken K.; Chang‐Claude, Jenny; Murabito, Joanne M.; Perry, John; Murray, Anna

doi:10.1038/ng.3412

Cited by 377 publications

(293 citation statements)

References 63 publications

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“…A recent large scale genomic analysis by Day et al (Day et al, 2015) extended the findings of a prior genome-wide association study (Stolk et al, 2012) and showed that genetic variants in several DNA repair enzymes, including BRCA1, are associated with age at menopause in large populations, providing further evidence for the importance of DNA repair processes in determining reproductive lifespan. Oocyte meiosis is characterized by very prolonged arrest at meiosis I, from fetal life until ovulation which might be decades later.…”

Section: Discussionmentioning

confidence: 80%

Anti-Müllerian Hormone Serum Concentrations of Women With Germline BRCA1 or BRCA2 Mutations

Phillips

Collins

Milne

et al. 2016

Obstetrical &Amp; Gynecological Survey

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participants/materials, setting, methods: Eligible women were from families segregating BRCA1 or BRCA2 mutations and had known mutation status. Participants were aged 25 -45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking.main results and the role of chance: Mean AMH concentration was negatively associated with age (P , 0.001). Mutation carriers were younger at blood draw than non-carriers (P ≤ 0.031). BRCA1 mutation carriers had, on average, 25% (95% CI: 5% -41%, P ¼ 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11 -303, P ¼ 0.02). There was no evidence of an association between AMH concentration and BRCA2 mutation status (P ¼ 0.94). wider implications of the findings: Women with a germline mutation in BRCA1 may have reduced ovarian reserve. This is consistent with other smaller studies in the literature and has potential implications for fertility and reproductive lifespan.

show abstract

Section: Discussionmentioning

confidence: 80%

Anti-Müllerian Hormone Serum Concentrations of Women With Germline BRCA1 or BRCA2 Mutations

Phillips

Collins

Milne

et al. 2016

Obstetrical &Amp; Gynecological Survey

View full text Add to dashboard Cite

show abstract

“…Related studies previously focussed on reproductive life span 42,43 , age at first sexual intercourse 11 and more proximal infertility phenotypes, 2–4 largely overlooking AFB and NEB. The rapid postponement of AFB and increased infertility and involuntary childlessness in many societies 7 makes it important to uncover the genetic and biological architecture of reproduction.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Barban¹,

Jansen²,

Vlaming³

et al. 2016

Nat Genet

Self Cite

315

265

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The genetic architecture of human reproductive behavior – age at first birth (AFB) and number of children ever born (NEB) – has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified and the underlying mechanisms of AFB and NEB are poorly understood. We report the largest genome-wide association study to date of both sexes including 251,151 individuals for AFB and 343,072 for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study, and four additional loci in a gene-based effort. These loci harbor genes that are likely to play a role – either directly or by affecting non-local gene expression – in human reproduction and infertility, thereby increasing our understanding of these complex traits.

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“…Early age at natural menopause was highly correlated with four common BRCA1 variants; however, all four are considered “not clinically important” for hereditary breast and ovarian cancer risk. (47) These findings could suggest a potential for misclassification bias since most studies include only women with deleterious mutations in the affected group. Additionally, the authors identified 15 signals involving various DNA repair mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Antimüllerian hormone levels are lower in BRCA2 mutation carriers

Johnson

Sammel

Domchek

et al. 2017

Fertility and Sterility

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Objective To compare Anti-Mullerian Hormone (AMH) levels in women at high risk for hereditary breast and ovarian cancer compared to healthy, low-risk controls. Design Prospective cohort Setting Ambulatory Patient(s) Reproductive age women with a uterus and both ovaries were analyzed in four groups: BRCA1 carriers, BRCA2 carriers, BRCA negative, and low-risk controls Intervention(s) Self-collected dried blood spot (DBS) Main Outcome Measure(s) AMH levels Result(s) One hundred ninety-five women were included: 55 BRCA1 carriers, 50 BRCA2 carriers, 26 BRCA negative, and 64 low-risk controls. After adjusting for confounders, BRCA2 carriers had AMH levels that were 33% lower than controls (Geometric Mean Ratio(GMR)=0.67, 95% CI 0.47–0.94) and an increased odds of having AMH<1 ng/mL (OR 3.69, 95% CI 1.34–10.19). BRCA1 carriers and BRCA negative women had similar AMH levels to controls. When analysis was restricted to regularly menstruating women younger than 40, BRCA2 carriers continued to demonstrate significantly lower AMH levels and increased likelihood of low AMH. Also, in this restricted group, BRCA negative women demonstrated AMH levels that were 42% lower than controls (GMR=0.58; 95%CI 0.35–0.95). No difference in AMH was observed among BRCA1 carriers. Conclusion(s) We observed significantly lower AMH levels among BRCA2 carriers compared to low-risk controls. These results were stable across all models. BRCA negative women also had lower AMH values, but only in models restricted to young, regularly menstruating women. In contrast to previous analyses, BRCA1 carriers had AMH values that were similar to low-risk controls, but this may be due to differences in the population studied.

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Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Cited by 377 publications

References 63 publications

Anti-Müllerian Hormone Serum Concentrations of Women With Germline BRCA1 or BRCA2 Mutations

Anti-Müllerian Hormone Serum Concentrations of Women With Germline BRCA1 or BRCA2 Mutations

Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Antimüllerian hormone levels are lower in BRCA2 mutation carriers

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