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. 2017 Jun;49(6):834-841.
doi: 10.1038/ng.3841. Epub 2017 Apr 24.

Genomic Analyses Identify Hundreds of Variants Associated With Age at Menarche and Support a Role for Puberty Timing in Cancer Risk

Felix R Day  1 Deborah J Thompson  2 Hannes Helgason  3   4 Daniel I Chasman  5   6 Hilary Finucane  7   8 Patrick Sulem  3 Katherine S Ruth  9 Sean Whalen  10 Abhishek K Sarkar  11   12 Eva Albrecht  13 Elisabeth Altmaier  14   15 Marzyeh Amini  16 Caterina M Barbieri  17 Thibaud Boutin  18 Archie Campbell  19 Ellen Demerath  20 Ayush Giri  21   22 Chunyan He  23   24 Jouke J Hottenga  25 Robert Karlsson  26 Ivana Kolcic  27 Po-Ru Loh  7   28 Kathryn L Lunetta  29   30 Massimo Mangino  31   32 Brumat Marco  33 George McMahon  34 Sarah E Medland  35 Ilja M Nolte  16 Raymond Noordam  36 Teresa Nutile  37 Lavinia Paternoster  34   38 Natalia Perjakova  39 Eleonora Porcu  40 Lynda M Rose  5 Katharina E Schraut  41   42 Ayellet V Segrè  43 Albert V Smith  44   45 Lisette Stolk  46 Alexander Teumer  47 Irene L Andrulis  48   49 Stefania Bandinelli  50 Matthias W Beckmann  51 Javier Benitez  52   53 Sven Bergmann  54   55 Murielle Bochud  56 Eric Boerwinkle  57 Stig E Bojesen  58   59   60 Manjeet K Bolla  2 Judith S Brand  26 Hiltrud Brauch  61   62   63 Hermann Brenner  63   64   65 Linda Broer  46 Thomas Brüning  66 Julie E Buring  5   6 Harry Campbell  42 Eulalia Catamo  67 Stephen Chanock  68 Georgia Chenevix-Trench  69 Tanguy Corre  54   55   56 Fergus J Couch  70 Diana L Cousminer  71   72 Angela Cox  73 Laura Crisponi  40 Kamila Czene  26 George Davey Smith  34   38 Eco J C N de Geus  25 Renée de Mutsert  74 Immaculata De Vivo  7   75 Joe Dennis  2 Peter Devilee  76   77 Isabel Dos-Santos-Silva  78 Alison M Dunning  79 Johan G Eriksson  80 Peter A Fasching  51   81 Lindsay Fernández-Rhodes  82 Luigi Ferrucci  83 Dieter Flesch-Janys  84   85 Lude Franke  86 Marike Gabrielson  26 Ilaria Gandin  33 Graham G Giles  87   88 Harald Grallert  14   15   89 Daniel F Gudbjartsson  3   4 Pascal Guénel  90 Per Hall  26 Emily Hallberg  91 Ute Hamann  92 Tamara B Harris  93 Catharina A Hartman  94 Gerardo Heiss  82 Maartje J Hooning  95 John L Hopper  88 Frank Hu  75   96 David J Hunter  7   75   96 M Arfan Ikram  97 Hae Kyung Im  98 Marjo-Riitta Järvelin  99   100   101   102   103 Peter K Joshi  42 David Karasik  6   104 Manolis Kellis  11   12 Zoltan Kutalik  54   56 Genevieve LaChance  31 Diether Lambrechts  105   106 Claudia Langenberg  1 Lenore J Launer  93 Joop S E Laven  107 Stefania Lenarduzzi  67 Jingmei Li  26 Penelope A Lind  35 Sara Lindstrom  108 YongMei Liu  109 Jian'an Luan  1 Reedik Mägi  39 Arto Mannermaa  110   111   112 Hamdi Mbarek  25 Mark I McCarthy  113   114   115 Christa Meisinger  14   116 Thomas Meitinger  117 Cristina Menni  31 Andres Metspalu  39 Kyriaki Michailidou  2   118 Lili Milani  39 Roger L Milne  87   88 Grant W Montgomery  119 Anna M Mulligan  120   121 Mike A Nalls  122 Pau Navarro  18 Heli Nevanlinna  123 Dale R Nyholt  124 Albertine J Oldehinkel  125 Tracy A O'Mara  69 Sandosh Padmanabhan  126 Aarno Palotie  28   127   128   129   130   131 Nancy Pedersen  26 Annette Peters  14   89 Julian Peto  78 Paul D P Pharoah  2   79 Anneli Pouta  132 Paolo Radice  133 Iffat Rahman  134 Susan M Ring  34   38 Antonietta Robino  67 Frits R Rosendaal  74 Igor Rudan  42 Rico Rueedi  54   55 Daniela Ruggiero  37 Cinzia F Sala  17 Marjanka K Schmidt  135   136 Robert A Scott  1 Mitul Shah  79 Rossella Sorice  37 Melissa C Southey  137 Ulla Sovio  99   138 Meir Stampfer  7   75 Maristella Steri  40 Konstantin Strauch  13   139 Toshiko Tanaka  83 Emmi Tikkanen  131   140 Nicholas J Timpson  34   38 Michela Traglia  17 Thérèse Truong  90 Jonathan P Tyrer  79 André G Uitterlinden  46   97 Digna R Velez Edwards  22   141   142 Veronique Vitart  18 Uwe Völker  143 Peter Vollenweider  144 Qin Wang  2 Elisabeth Widen  131 Ko Willems van Dijk  77   145   146 Gonneke Willemsen  25 Robert Winqvist  147   148 Bruce H R Wolffenbuttel  149 Jing Hua Zhao  1 Magdalena Zoledziewska  40 Marek Zygmunt  150 Behrooz Z Alizadeh  16 Dorret I Boomsma  25 Marina Ciullo  37 Francesco Cucca  40   151 Tõnu Esko  28   39 Nora Franceschini  82 Christian Gieger  14   15   89 Vilmundur Gudnason  44   45 Caroline Hayward  18 Peter Kraft  7   152 Debbie A Lawlor  34   38 Patrik K E Magnusson  26 Nicholas G Martin  35 Dennis O Mook-Kanamori  74   153 Ellen A Nohr  154 Ozren Polasek  27 David Porteous  19 Alkes L Price  7   8   28 Paul M Ridker  5   6 Harold Snieder  16 Tim D Spector  31 Doris Stöckl  14   155 Daniela Toniolo  17 Sheila Ulivi  67 Jenny A Visser  46 Henry Völzke  47 Nicholas J Wareham  1 James F Wilson  18   42 LifeLines Cohort StudyInterAct ConsortiumkConFab/AOCS InvestigatorsEndometrial Cancer Association ConsortiumOvarian Cancer Association ConsortiumPRACTICAL consortiumAmanda B Spurdle  69 Unnur Thorsteindottir  3   44 Katherine S Pollard  10   156 Douglas F Easton  2   79 Joyce Y Tung  157 Jenny Chang-Claude  158   159 David Hinds  157 Anna Murray  9 Joanne M Murabito  30   160 Kari Stefansson  3   44 Ken K Ong  1   161 John R B Perry  1
Affiliations
Free PMC article

Genomic Analyses Identify Hundreds of Variants Associated With Age at Menarche and Support a Role for Puberty Timing in Cancer Risk

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

Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
GTEx tissue enrichment using LD score regression. Numbers on the x axis correspond to sample number for each tissue. The dashed line represents significance at FDR < 5%, and the solid horizontal line represents Bonferroni-corrected significance for the number of tissues tested.
Figure 2
Figure 2
Stronger effects of AAM-associated signals on early menarche than late menarche in women. The 377 index AAM-associated SNPs are ordered from smallest to largest P value for their continuous association with AAM. The y axis shows the log-transformed odds ratio for each SNP on early menarche (blue; ages 8–11 years, inclusive) or late menarche (red; ages 15–19 years, inclusive). The reference group comprises women with menarche at 13 years. Insert, −log10 P values for heterogeneity (based on Cochran’s Q) between the associations for early and late menarche plotted against the −log10 P value for the continuous AAM association.
Figure 3
Figure 3
Effects and 95% confidence intervals of genetically predicted AAM on risks for various sex-steroid-sensitive cancers, adjusted for the effects of the same AAM variants on BMI. AAM was predicted by all 375 autosomal AAM-associated SNPs, and models were adjusted for the genetic effects of the same AAM variants on BMI. Three further genetic score associations are shown as sensitivity analyses for each outcome: first, AAM predicted by the 314 AAM-associated SNPs that were not also associated with BMI in the BCAC iCOGS sample (at a nominal level of P < 0.05); second, AAM predicted by the 61 AAM-associated SNPs that were also associated with BMI in this sample; and, third, AAM predicted by all 375 autosomal AAM-associated SNPs (unadjusted for BMI).

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