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Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.
van der Klaauw AA, Croizier S, Mendes de Oliveira E, Stadler LKJ, Park S, Kong Y, Banton MC, Tandon P, Hendricks AE, Keogh JM, Riley SE, Papadia S, Henning E, Bounds R, Bochukova EG, Mistry V, O'Rahilly S, Simerly RB, INTERVAL, UK10K Consortium, Minchin JEN, Barroso I, Jones EY, Bouret SG, Farooqi IS
(2019) Cell 176: 729-742.e18
MeSH Terms: Adolescent, Adult, Animals, Body Weight, Cell Line, Child, Child, Preschool, Disease Models, Animal, Eating, Energy Metabolism, Female, Genetic Variation, Homeostasis, Humans, Hypothalamus, Leptin, Male, Melanocortins, Mice, Mice, Inbred C57BL, Middle Aged, Nerve Tissue Proteins, Neurons, Obesity, Receptors, Cell Surface, Semaphorins, Young Adult, Zebrafish
Show Abstract · Added April 11, 2019
Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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28 MeSH Terms
Late onset obesity in mice with targeted deletion of potassium inward rectifier Kir7.1 from cells expressing the melanocortin-4 receptor.
Anderson EJP, Ghamari-Langroudi M, Cakir I, Litt MJ, Chen V, Reggiardo RE, Millhauser GL, Cone RD
(2019) J Neuroendocrinol 31: e12670
MeSH Terms: Animals, Feeding Behavior, Female, Hypothalamus, Male, Membrane Potentials, Mice, Inbred C57BL, Mice, Knockout, Neurons, Obesity, Potassium Channels, Inwardly Rectifying, Receptor, Melanocortin, Type 4
Show Abstract · Added January 8, 2019
Energy stores in fat tissue are determined in part by the activity of hypothalamic neurones expressing the melanocortin-4 receptor (MC4R). Even a partial reduction in MC4R expression levels in mice, rats or humans produces hyperphagia and morbid obesity. Thus, it is of great interest to understand the molecular basis of neuromodulation by the MC4R. The MC4R is a G protein-coupled receptor that signals efficiently through Gα , and this signalling pathway is essential for normal MC4R function in vivo. However, previous data from hypothalamic slice preparations indicated that activation of the MC4R depolarised neurones via G protein-independent regulation of the ion channel Kir7.1. In the present study, we show that deletion of Kcnj13 (ie, the gene encoding Kir7.1) specifically from MC4R neurones produced resistance to melanocortin peptide-induced depolarisation of MC4R paraventricular nucleus neurones in brain slices, resistance to the sustained anorexic effect of exogenously administered melanocortin peptides, late onset obesity, increased linear growth and glucose intolerance. Some MC4R-mediated phenotypes appeared intact, including Agouti-related peptide-induced stimulation of food intake and MC4R-mediated induction of peptide YY release from intestinal L cells. Thus, a subset of the consequences of MC4R signalling in vivo appears to be dependent on expression of the Kir7.1 channel in MC4R cells.
© 2018 British Society for Neuroendocrinology.
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12 MeSH Terms
Attenuation of diet-induced hypothalamic inflammation following bariatric surgery in female mice.
Herrick MK, Favela KM, Simerly RB, Abumrad NN, Bingham NC
(2018) Mol Med 24: 56
MeSH Terms: Animals, Bariatric Surgery, Diet, High-Fat, Female, Hypothalamus, Inflammation, Mice, Inbred C57BL, Obesity
Show Abstract · Added April 11, 2019
BACKGROUND - Exposure of rodents to chronic high-fat diet (HFD) results in upregulation of inflammatory markers and proliferation of microglia within the mediobasal hypothalamus. Such hypothalamic inflammation is associated with metabolic dysfunction, central leptin resistance, and maintenance of obesity. Bariatric surgeries result in long-term stable weight loss and improved metabolic function. However, the effects of such surgical procedures on HFD-induced hypothalamic inflammation are unknown. We sought to characterize the effects of two bariatric surgical procedures, Roux-en-Y gastric bypass (RYGB) and biliary diversion (BD-IL), in female mice with particular emphasis on HFD-induced hypothalamic inflammation and microgliosis.
METHODS - RYGB and BD-IL were performed on diet-induced obese (DIO) mice. Quantitative RT-PCR and fluorescent microscopy were used to evaluate hypothalamic inflammatory gene expression and microgliosis. Results were compared to lean (CD), DIO sham-surgerized mice (DIO-SHAM), and dietary weight loss (DIO-Rev) controls.
RESULTS - In female mice, RYGB and BD-IL result in normalization of hypothalamic inflammatory gene expression and microgliosis within 8 weeks of surgery, despite ongoing exposure to HFD. Paralleling these results, the hypothalamic expression levels of the orexigenic neuropeptide Agrp and the anorexic response of surgical mice to exogenous leptin were comparable to lean controls (CD). In contrast, results from DIO-Rev mice were comparable to DIO-SHAM mice, despite transition back to standard rodent show and normalization of weight.
CONCLUSION - Bariatric surgery attenuates HFD-induced hypothalamic inflammation and microgliosis and restores leptin sensitivity, despite ongoing exposure to HFD.
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MeSH Terms
Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain.
Fujiyama T, Miyashita S, Tsuneoka Y, Kanemaru K, Kakizaki M, Kanno S, Ishikawa Y, Yamashita M, Owa T, Nagaoka M, Kawaguchi Y, Yanagawa Y, Magnuson MA, Muratani M, Shibuya A, Nabeshima YI, Yanagisawa M, Funato H, Hoshino M
(2018) Cell Rep 24: 79-94
MeSH Terms: Animals, Cell Lineage, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Gonads, Hypothalamus, Male, Mice, Inbred C57BL, Mice, Knockout, Prosencephalon, Sex Differentiation, Sexual Behavior, Animal, Transcription Factors
Show Abstract · Added July 27, 2018
The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1, important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
3 Communities
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14 MeSH Terms
Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes.
Navarro G, Allard C, Morford JJ, Xu W, Liu S, Molinas AJ, Butcher SM, Fine NH, Blandino-Rosano M, Sure VN, Yu S, Zhang R, Münzberg H, Jacobson DA, Katakam PV, Hodson DJ, Bernal-Mizrachi E, Zsombok A, Mauvais-Jarvis F
(2018) JCI Insight 3:
MeSH Terms: Androgens, Animals, Diabetes Mellitus, Type 2, Diet, Western, Dihydrotestosterone, Female, Glucose, Humans, Hyperinsulinism, Hypothalamus, Insulin Resistance, Insulin-Secreting Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Neurons, Receptors, Androgen, Streptozocin
Show Abstract · Added June 28, 2018
Androgen excess predisposes women to type 2 diabetes (T2D), but the mechanism of this is poorly understood. We report that female mice fed a Western diet and exposed to chronic androgen excess using dihydrotestosterone (DHT) exhibit hyperinsulinemia and insulin resistance associated with secondary pancreatic β cell failure, leading to hyperglycemia. These abnormalities are not observed in mice lacking the androgen receptor (AR) in β cells and partially in neurons of the mediobasal hypothalamus (MBH) as well as in mice lacking AR selectively in neurons. Accordingly, i.c.v. infusion of DHT produces hyperinsulinemia and insulin resistance in female WT mice. We observe that acute DHT produces insulin hypersecretion in response to glucose in cultured female mouse and human pancreatic islets in an AR-dependent manner via a cAMP- and mTOR-dependent pathway. Acute DHT exposure increases mitochondrial respiration and oxygen consumption in female cultured islets. As a result, chronic DHT exposure in vivo promotes islet oxidative damage and susceptibility to additional stress induced by streptozotocin via AR in β cells. This study suggests that excess androgen predisposes female mice to T2D following AR activation in neurons, producing peripheral insulin resistance, and in pancreatic β cells, promoting insulin hypersecretion, oxidative injury, and secondary β cell failure.
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19 MeSH Terms
A critical period for the trophic actions of leptin on AgRP neurons in the arcuate nucleus of the hypothalamus.
Kamitakahara A, Bouyer K, Wang CH, Simerly R
(2018) J Comp Neurol 526: 133-145
MeSH Terms: Age Factors, Agouti-Related Protein, Analysis of Variance, Animals, Animals, Newborn, Arcuate Nucleus of Hypothalamus, Axons, ELAV-Like Protein 3, Estrogen Receptor alpha, Female, Green Fluorescent Proteins, Integrases, Leptin, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Neuropeptide Y, Receptors, Leptin, STAT3 Transcription Factor
Show Abstract · Added April 11, 2019
In the developing hypothalamus, the fat-derived hormone leptin stimulates the growth of axons from the arcuate nucleus of the hypothalamus (ARH) to other regions that control energy balance. These projections are significantly reduced in leptin deficient (Lep ) mice and this phenotype is largely rescued by neonatal leptin treatments. However, treatment of mature Lep mice is ineffective, suggesting that the trophic action of leptin is limited to a developmental critical period. To temporally delineate closure of this critical period for leptin-stimulated growth, we treated Lep mice with exogenous leptin during a variety of discrete time periods, and measured the density of Agouti-Related Peptide (AgRP) containing projections from the ARH to the ventral part of the dorsomedial nucleus of the hypothalamus (DMHv), and to the medial parvocellular part of the paraventricular nucleus (PVHmp). The results indicate that leptin loses its neurotrophic potential at or near postnatal day 28. The duration of leptin exposure appears to be important, with 9- or 11-day treatments found to be more effective than shorter (5-day) treatments. Furthermore, leptin treatment for 9 days or more was sufficient to restore AgRP innervation to both the PVHmp and DMHv in Lep females, but only to the DMHv in Lep males. Together, these findings reveal that the trophic actions of leptin are contingent upon timing and duration of leptin exposure, display both target and sex specificity, and that modulation of leptin-dependent circuit formation by each of these factors may carry enduring consequences for feeding behavior, metabolism, and obesity risk.
© 2017 Wiley Periodicals, Inc.
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MeSH Terms
Lef1-dependent hypothalamic neurogenesis inhibits anxiety.
Xie Y, Kaufmann D, Moulton MJ, Panahi S, Gaynes JA, Watters HN, Zhou D, Xue HH, Fung CM, Levine EM, Letsou A, Brennan KC, Dorsky RI
(2017) PLoS Biol 15: e2002257
MeSH Terms: Animals, Anxiety, Behavior, Animal, Biomarkers, Drosophila Proteins, Drosophila melanogaster, Female, Gene Expression Regulation, Genes, Reporter, Humans, Hypothalamus, Lymphoid Enhancer-Binding Factor 1, Male, Mice, Knockout, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Neurogenesis, Neurons, Species Specificity, Transcription Factors, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 14, 2018
While innate behaviors are conserved throughout the animal kingdom, it is unknown whether common signaling pathways regulate the development of neuronal populations mediating these behaviors in diverse organisms. Here, we demonstrate that the Wnt/ß-catenin effector Lef1 is required for the differentiation of anxiolytic hypothalamic neurons in zebrafish and mice, although the identity of Lef1-dependent genes and neurons differ between these 2 species. We further show that zebrafish and Drosophila have common Lef1-dependent gene expression in their respective neuroendocrine organs, consistent with a conserved pathway that has diverged in the mouse. Finally, orthologs of Lef1-dependent genes from both zebrafish and mouse show highly correlated hypothalamic expression in marmosets and humans, suggesting co-regulation of 2 parallel anxiolytic pathways in primates. These findings demonstrate that during evolution, a transcription factor can act through multiple mechanisms to generate a common behavioral output, and that Lef1 regulates circuit development that is fundamentally important for mediating anxiety in a wide variety of animal species.
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23 MeSH Terms
The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.
Burmeister MA, Ayala JE, Smouse H, Landivar-Rocha A, Brown JD, Drucker DJ, Stoffers DA, Sandoval DA, Seeley RJ, Ayala JE
(2017) Diabetes 66: 372-384
MeSH Terms: Animals, Body Composition, Diet, High-Fat, Eating, Energy Metabolism, Exenatide, Gene Knockdown Techniques, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucose, Glucose Tolerance Test, Homeostasis, Hypothalamus, Incretins, Liraglutide, Male, Mice, Neurons, Paraventricular Hypothalamic Nucleus, Peptides, Pro-Opiomelanocortin, Venoms, Weight Gain
Show Abstract · Added October 23, 2017
Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKD). We also generated mice lacking Glp1r expression specifically in two GLP-1RA-responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKD) and proopiomelanocortin neurons (GLP-1RKD). Chow-fed GLP-1RKD mice exhibited increased food intake and energy expenditure with no net effect on body weight. When fed a high-fat diet, these mice exhibited normal food intake but elevated energy expenditure, yielding reduced weight gain. None of these phenotypes were observed in GLP-1RKD and GLP-1RKD mice. The acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA exendin-4 and liraglutide were preserved in all mouse lines. Chronic liraglutide treatment reduced body weight in chow-fed GLP-1RKD mice, but this effect was attenuated with high-fat diet feeding. In sum, classic homeostatic control regions are sufficient but not individually necessary for the effects of GLP-1RA on nutrient homeostasis.
© 2017 by the American Diabetes Association.
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23 MeSH Terms
Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents.
Scarlett JM, Rojas JM, Matsen ME, Kaiyala KJ, Stefanovski D, Bergman RN, Nguyen HT, Dorfman MD, Lantier L, Wasserman DH, Mirzadeh Z, Unterman TG, Morton GJ, Schwartz MW
(2016) Nat Med 22: 800-6
MeSH Terms: Adipose Tissue, Animals, Blood Glucose, Blotting, Western, Body Composition, Brain, Carbon Radioisotopes, Deoxyglucose, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Diet, High-Fat, Disease Models, Animal, Ependymoglial Cells, Fibroblast Growth Factor 1, Forkhead Box Protein O1, Glucose Tolerance Test, Heart, Heat-Shock Proteins, Hyperglycemia, Hypothalamus, Injections, Intraventricular, Liver, Male, Mice, Mice, Knockout, Mice, Obese, Molecular Chaperones, Muscle, Skeletal, Myocardium, Neoplasm Proteins, Proto-Oncogene Proteins c-fos, Rats, Rats, Zucker, Real-Time Polymerase Chain Reaction, Receptor, Insulin, Remission Induction
Show Abstract · Added May 16, 2019
Type 2 diabetes (T2D) is among the most common and costly disorders worldwide. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors, we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes. We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.
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36 MeSH Terms
Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.
Day FR, Ruth KS, Thompson DJ, Lunetta KL, Pervjakova N, Chasman DI, Stolk L, Finucane HK, Sulem P, Bulik-Sullivan B, Esko T, Johnson AD, Elks CE, Franceschini N, He C, Altmaier E, Brody JA, Franke LL, Huffman JE, Keller MF, McArdle PF, Nutile T, Porcu E, Robino A, Rose LM, Schick UM, Smith JA, Teumer A, Traglia M, Vuckovic D, Yao J, Zhao W, Albrecht E, Amin N, Corre T, Hottenga JJ, Mangino M, Smith AV, Tanaka T, Abecasis G, Andrulis IL, Anton-Culver H, Antoniou AC, Arndt V, Arnold AM, Barbieri C, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bernstein L, Bielinski SJ, Blomqvist C, Boerwinkle E, Bogdanova NV, Bojesen SE, Bolla MK, Borresen-Dale AL, Boutin TS, Brauch H, Brenner H, Brüning T, Burwinkel B, Campbell A, Campbell H, Chanock SJ, Chapman JR, Chen YI, Chenevix-Trench G, Couch FJ, Coviello AD, Cox A, Czene K, Darabi H, De Vivo I, Demerath EW, Dennis J, Devilee P, Dörk T, Dos-Santos-Silva I, Dunning AM, Eicher JD, Fasching PA, Faul JD, Figueroa J, Flesch-Janys D, Gandin I, Garcia ME, García-Closas M, Giles GG, Girotto GG, Goldberg MS, González-Neira A, Goodarzi MO, Grove ML, Gudbjartsson DF, Guénel P, Guo X, Haiman CA, Hall P, Hamann U, Henderson BE, Hocking LJ, Hofman A, Homuth G, Hooning MJ, Hopper JL, Hu FB, Huang J, Humphreys K, Hunter DJ, Jakubowska A, Jones SE, Kabisch M, Karasik D, Knight JA, Kolcic I, Kooperberg C, Kosma VM, Kriebel J, Kristensen V, Lambrechts D, Langenberg C, Li J, Li X, Lindström S, Liu Y, Luan J, Lubinski J, Mägi R, Mannermaa A, Manz J, Margolin S, Marten J, Martin NG, Masciullo C, Meindl A, Michailidou K, Mihailov E, Milani L, Milne RL, Müller-Nurasyid M, Nalls M, Neale BM, Nevanlinna H, Neven P, Newman AB, Nordestgaard BG, Olson JE, Padmanabhan S, Peterlongo P, Peters U, Petersmann A, Peto J, Pharoah PDP, Pirastu NN, Pirie A, Pistis G, Polasek O, Porteous D, Psaty BM, Pylkäs K, Radice P, Raffel LJ, Rivadeneira F, Rudan I, Rudolph A, Ruggiero D, Sala CF, Sanna S, Sawyer EJ, Schlessinger D, Schmidt MK, Schmidt F, Schmutzler RK, Schoemaker MJ, Scott RA, Seynaeve CM, Simard J, Sorice R, Southey MC, Stöckl D, Strauch K, Swerdlow A, Taylor KD, Thorsteinsdottir U, Toland AE, Tomlinson I, Truong T, Tryggvadottir L, Turner ST, Vozzi D, Wang Q, Wellons M, Willemsen G, Wilson JF, Winqvist R, Wolffenbuttel BBHR, Wright AF, Yannoukakos D, Zemunik T, Zheng W, Zygmunt M, Bergmann S, Boomsma DI, Buring JE, Ferrucci L, Montgomery GW, Gudnason V, Spector TD, van Duijn CM, Alizadeh BZ, Ciullo M, Crisponi L, Easton DF, Gasparini PP, Gieger C, Harris TB, Hayward C, Kardia SLR, Kraft P, McKnight B, Metspalu A, Morrison AC, Reiner AP, Ridker PM, Rotter JI, Toniolo D, Uitterlinden AG, Ulivi S, Völzke H, Wareham NJ, Weir DR, Yerges-Armstrong LM, PRACTICAL consortium, kConFab Investigators, AOCS Investigators, Generation Scotland, EPIC-InterAct Consortium, LifeLines Cohort Study, Price AL, Stefansson K, Visser JA, Ong KK, Chang-Claude J, Murabito JM, Perry JRB, Murray A
(2015) Nat Genet 47: 1294-1303
MeSH Terms: Adult, Age Factors, Aging, BRCA1 Protein, Breast Neoplasms, DNA Repair, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genomics, Genotype, Humans, Hypothalamus, Menopause, Middle Aged, Models, Genetic, Phenotype, Reproduction, Signal Transduction
Show Abstract · Added February 22, 2016
Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
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21 MeSH Terms