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. 2015 Nov;47(11):1294-1303.
doi: 10.1038/ng.3412. Epub 2015 Sep 28.

Large-scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility and BRCA1-mediated DNA Repair

Felix R Day #  1 Katherine S Ruth #  2 Deborah J Thompson #  3 Kathryn L Lunetta  4   5 Natalia Pervjakova  6   7 Daniel I Chasman  8   9 Lisette Stolk  10   11 Hilary K Finucane  12   13 Patrick Sulem  14 Brendan Bulik-Sullivan  15   16   17 Tõnu Esko  6   18   19   20 Andrew D Johnson  5 Cathy E Elks  1 Nora Franceschini  21 Chunyan He  22   23 Elisabeth Altmaier  24   25   26 Jennifer A Brody  27 Lude L Franke  28 Jennifer E Huffman  5   29 Margaux F Keller  30 Patrick F McArdle  31 Teresa Nutile  32 Eleonora Porcu  33   34   35 Antonietta Robino  36 Lynda M Rose  8 Ursula M Schick  37 Jennifer A Smith  38 Alexander Teumer  39 Michela Traglia  40 Dragana Vuckovic  36   41 Jie Yao  42 Wei Zhao  38 Eva Albrecht  25 Najaf Amin  43 Tanguy Corre  44   45 Jouke-Jan Hottenga  46 Massimo Mangino  47   48 Albert V Smith  49   50 Toshiko Tanaka  51 Goncalo Abecasis  35 Irene L Andrulis  52   53 Hoda Anton-Culver  54 Antonis C Antoniou  3 Volker Arndt  55 Alice M Arnold  56 Caterina Barbieri  36   40 Matthias W Beckmann  57 Alicia Beeghly-Fadiel  58 Javier Benitez  59   60 Leslie Bernstein  61 Suzette J Bielinski  62 Carl Blomqvist  63 Eric Boerwinkle  64   65 Natalia V Bogdanova  66 Stig E Bojesen  67   68 Manjeet K Bolla  3 Anne-Lise Borresen-Dale  69   70 Thibaud S Boutin  29 Hiltrud Brauch  71   72   73 Hermann Brenner  55   73   74 Thomas Brüning  75 Barbara Burwinkel  76   77 Archie Campbell  78 Harry Campbell  79 Stephen J Chanock  80 J Ross Chapman  81 Yii-Der Ida Chen  42 Georgia Chenevix-Trench  82 Fergus J Couch  83 Andrea D Coviello  84 Angela Cox  85 Kamila Czene  86 Hatef Darabi  86 Immaculata De Vivo  12   87 Ellen W Demerath  88 Joe Dennis  3 Peter Devilee  89   90 Thilo Dörk  91 Isabel Dos-Santos-Silva  92 Alison M Dunning  93 John D Eicher  5 Peter A Fasching  57   94 Jessica D Faul  95 Jonine Figueroa  96 Dieter Flesch-Janys  97   98 Ilaria Gandin  36   41 Melissa E Garcia  99 Montserrat García-Closas  100   101 Graham G Giles  102   103 Giorgia G Girotto  41 Mark S Goldberg  104   105 Anna González-Neira  59 Mark O Goodarzi  106 Megan L Grove  64 Daniel F Gudbjartsson  14   107 Pascal Guénel  108   109 Xiuqing Guo  42 Christopher A Haiman  110 Per Hall  86 Ute Hamann  111 Brian E Henderson  110 Lynne J Hocking  112 Albert Hofman  43 Georg Homuth  113 Maartje J Hooning  114 John L Hopper  102 Frank B Hu  12   87   115 Jinyan Huang  116 Keith Humphreys  86 David J Hunter  12   20   87   115 Anna Jakubowska  117 Samuel E Jones  2 Maria Kabisch  111 David Karasik  9   118 Julia A Knight  119   120 Ivana Kolcic  121 Charles Kooperberg  37 Veli-Matti Kosma  122   123   124 Jennifer Kriebel  24   26   125 Vessela Kristensen  69   70   126 Diether Lambrechts  127   128 Claudia Langenberg  1 Jingmei Li  86 Xin Li  12 Sara Lindström  12 Yongmei Liu  129 Jian'an Luan  1 Jan Lubinski  117 Reedik Mägi  6 Arto Mannermaa  122   123   124 Judith Manz  24   26 Sara Margolin  130 Jonathan Marten  29 Nicholas G Martin  131 Corrado Masciullo  40 Alfons Meindl  132 Kyriaki Michailidou  3 Evelin Mihailov  6 Lili Milani  6 Roger L Milne  102   103 Martina Müller-Nurasyid  25   133   134 Michael Nalls  135 Ben M Neale  15   16   17 Heli Nevanlinna  136 Patrick Neven  137 Anne B Newman  138   139   140 Børge G Nordestgaard  67   68 Janet E Olson  62 Sandosh Padmanabhan  141 Paolo Peterlongo  142 Ulrike Peters  37 Astrid Petersmann  143 Julian Peto  92 Paul D P Pharoah  3   93 Nicola N Pirastu  36   41 Ailith Pirie  3 Giorgio Pistis  33   34   35 Ozren Polasek  121 David Porteous  78 Bruce M Psaty  27   144   145   146 Katri Pylkäs  147   148 Paolo Radice  149 Leslie J Raffel  150   151 Fernando Rivadeneira  10   11   43 Igor Rudan  79 Anja Rudolph  152 Daniela Ruggiero  32 Cinzia F Sala  40 Serena Sanna  33 Elinor J Sawyer  153 David Schlessinger  154 Marjanka K Schmidt  155 Frank Schmidt  113 Rita K Schmutzler  156   157   158 Minouk J Schoemaker  100 Robert A Scott  1 Caroline M Seynaeve  114 Jacques Simard  159 Rossella Sorice  32 Melissa C Southey  160 Doris Stöckl  26 Konstantin Strauch  25   161 Anthony Swerdlow  100   162 Kent D Taylor  42 Unnur Thorsteinsdottir  14   50 Amanda E Toland  163 Ian Tomlinson  81   164 Thérèse Truong  108   109 Laufey Tryggvadottir  165 Stephen T Turner  166 Diego Vozzi  36 Qin Wang  3 Melissa Wellons  167 Gonneke Willemsen  46 James F Wilson  29   79 Robert Winqvist  147   148 Bruce B H R Wolffenbuttel  168   169 Alan F Wright  29 Drakoulis Yannoukakos  170 Tatijana Zemunik  121 Wei Zheng  58 Marek Zygmunt  171 Sven Bergmann  44   45 Dorret I Boomsma  46 Julie E Buring  8   9 Luigi Ferrucci  51 Grant W Montgomery  131 Vilmundur Gudnason  49   50 Tim D Spector  47 Cornelia M van Duijn  43 Behrooz Z Alizadeh  172 Marina Ciullo  32 Laura Crisponi  33 Douglas F Easton  3   93 Paolo P Gasparini  36   41 Christian Gieger  24   25   26 Tamara B Harris  99 Caroline Hayward  29 Sharon L R Kardia  38 Peter Kraft  12   173 Barbara McKnight  56 Andres Metspalu  6 Alanna C Morrison  64 Alex P Reiner  37   144 Paul M Ridker  8   9 Jerome I Rotter  42 Daniela Toniolo  40 André G Uitterlinden  10   11   43 Sheila Ulivi  36 Henry Völzke  39 Nicholas J Wareham  1 David R Weir  95 Laura M Yerges-Armstrong  31 PRACTICAL consortiumkConFab InvestigatorsAOCS InvestigatorsGeneration ScotlandEPIC-InterAct ConsortiumLifeLines Cohort StudyAlkes L Price  12 Kari Stefansson  14   50 Jenny A Visser  10 Ken K Ong  1   174 Jenny Chang-Claude  152 Joanne M Murabito  5   175 John R B Perry  1 Anna Murray  2
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Free PMC article

Large-scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility and BRCA1-mediated DNA Repair

Felix R Day et al. Nat Genet. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1
Miami plot of HapMap and exome SNP associations. Log-transformed P values are shown for association with ANM for SNPs from HapMap 2 (top; pink) and SNPs from the meta-analysis of exome chip data (bottom; blue). Previously known signals are shown in gray, and newly discovered signals are shown in red (HapMap 2) or purple (exome chip and HapMap 2). The yellow lines correspond to genome-wide significant levels in each direction; the gray lines indicate where the y axis has been truncated.
Figure 2
Figure 2
Multiple signals at HELB and relationship to DNA helicase B protein sequence. Positions are given in Build 37 coordinates of the reference genome. The top signal from the exome chip analysis maps to an acidic motif of DNA helicase B and results in the replacement of an acidic aspartate residue by a nonpolar glycine residue. Concurrent alteration of three acidic amino acids, (including the aspartate residue identified by the exome chip analysis) to nonpolar residues has been shown to reduce RPA binding (8)
Figure 3
Figure 3
Classification of genes identified as being involved in the DNA damage response, at genetic loci associated with ANM.

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