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. 2016 Dec;48(12):1462-1472.
doi: 10.1038/ng.3698. Epub 2016 Oct 31.

Genome-wide Analysis Identifies 12 Loci Influencing Human Reproductive Behavior

Nicola Barban  1 Rick Jansen  2 Ronald de Vlaming  3   4   5 Ahmad Vaez  6   7 Jornt J Mandemakers  8 Felix C Tropf  1 Xia Shen  9   10   11 James F Wilson  10   11 Daniel I Chasman  12 Ilja M Nolte  6 Vinicius Tragante  13 Sander W van der Laan  14 John R B Perry  15 Augustine Kong  16   17 BIOS ConsortiumTarunveer S Ahluwalia  18   19   20 Eva Albrecht  21 Laura Yerges-Armstrong  22 Gil Atzmon  23   24   25 Kirsi Auro  26   27 Kristin Ayers  28 Andrew Bakshi  29 Danny Ben-Avraham  24 Klaus Berger  30 Aviv Bergman  31 Lars Bertram  32   33 Lawrence F Bielak  34 Gyda Bjornsdottir  17 Marc Jan Bonder  35 Linda Broer  36 Minh Bui  37 Caterina Barbieri  38 Alana Cavadino  39   40 Jorge E Chavarro  41   42   43 Constance Turman  43 Maria Pina Concas  44 Heather J Cordell  28 Gail Davies  45   46 Peter Eibich  47 Nicholas Eriksson  48 Tõnu Esko  49   50 Joel Eriksson  51 Fahimeh Falahi  6 Janine F Felix  4   52   53 Mark Alan Fontana  54 Lude Franke  35 Ilaria Gandin  55 Audrey J Gaskins  41 Christian Gieger  56   57 Erica P Gunderson  58 Xiuqing Guo  59 Caroline Hayward  10 Chunyan He  60 Edith Hofer  61   62 Hongyan Huang  43 Peter K Joshi  11 Stavroula Kanoni  63 Robert Karlsson  9 Stefan Kiechl  64 Annette Kifley  65 Alexander Kluttig  66 Peter Kraft  43   67 Vasiliki Lagou  68   69   70 Cecile Lecoeur  71 Jari Lahti  72   73   74 Ruifang Li-Gao  75 Penelope A Lind  76 Tian Liu  77 Enes Makalic  37 Crysovalanto Mamasoula  28 Lindsay Matteson  78 Hamdi Mbarek  79   80 Patrick F McArdle  22 George McMahon  81 S Fleur W Meddens  5   82 Evelin Mihailov  49 Mike Miller  83 Stacey A Missmer  43   84 Claire Monnereau  4   52   53 Peter J van der Most  6 Ronny Myhre  85 Mike A Nalls  86 Teresa Nutile  87 Ioanna Panagiota Kalafati  88 Eleonora Porcu  89   90 Inga Prokopenko  91   92   93 Kumar B Rajan  94 Janet Rich-Edwards  42   43   95 Cornelius A Rietveld  3   4   5 Antonietta Robino  96 Lynda M Rose  12 Rico Rueedi  97   98 Kathleen A Ryan  22 Yasaman Saba  99 Daniel Schmidt  37 Jennifer A Smith  34 Lisette Stolk  36 Elizabeth Streeten  22 Anke Tönjes  100 Gudmar Thorleifsson  17 Sheila Ulivi  96 Juho Wedenoja  101 Juergen Wellmann  30 Peter Willeit  64   102   103 Jie Yao  59 Loic Yengo  71   104 Jing Hua Zhao  15 Wei Zhao  34 Daria V Zhernakova  35 Najaf Amin  4 Howard Andrews  105 Beverley Balkau  71 Nir Barzilai  23 Sven Bergmann  97   98 Ginevra Biino  106 Hans Bisgaard  20 Klaus Bønnelykke  20 Dorret I Boomsma  79   80 Julie E Buring  12 Harry Campbell  11 Stefania Cappellani  96 Marina Ciullo  87   107 Simon R Cox  45   46 Francesco Cucca  89   90 Daniela Toniolo  38 George Davey-Smith  108 Ian J Deary  45   46 George Dedoussis  88 Panos Deloukas  63   109 Cornelia M van Duijn  4 Eco J C de Geus  79   80 Johan G Eriksson  74   110   111   112   113 Denis A Evans  94 Jessica D Faul  114 Cinzia Felicita Sala  38 Philippe Froguel  71 Paolo Gasparini  55   115 Giorgia Girotto  55   115 Hans-Jörgen Grabe  116 Karin Halina Greiser  117 Patrick J F Groenen  5   118 Hugoline G de Haan  75 Johannes Haerting  66 Tamara B Harris  119 Andrew C Heath  120 Kauko Heikkilä  27 Albert Hofman  4   5   43 Georg Homuth  121 Elizabeth G Holliday  122   123 John Hopper  37 Elina Hyppönen  39   124   125 Bo Jacobsson  85   126 Vincent W V Jaddoe  4   52   53 Magnus Johannesson  127 Astanand Jugessur  85 Mika Kähönen  128 Eero Kajantie  129   130   131 Sharon L R Kardia  34 Bernard Keavney  28   132 Ivana Kolcic  133 Päivikki Koponen  134 Peter Kovacs  135 Florian Kronenberg  136 Zoltan Kutalik  98   137 Martina La Bianca  96 Genevieve Lachance  138 William G Iacono  83 Sandra Lai  89 Terho Lehtimäki  139 David C Liewald  45 LifeLines Cohort StudyCecilia M Lindgren  92   93   140   141 Yongmei Liu  142 Robert Luben  141 Michael Lucht  110 Riitta Luoto  143 Per Magnus  85 Patrik K E Magnusson  9 Nicholas G Martin  76 Matt McGue  83   144 Ruth McQuillan  11 Sarah E Medland  76 Christa Meisinger  57   145 Dan Mellström  51 Andres Metspalu  49   146 Michela Traglia  38 Lili Milani  49 Paul Mitchell  65 Grant W Montgomery  120   147 Dennis Mook-Kanamori  75   148   149 Renée de Mutsert  75 Ellen A Nohr  150 Claes Ohlsson  51 Jørn Olsen  151 Ken K Ong  15 Lavinia Paternoster  108 Alison Pattie  46 Brenda W J H Penninx  2   80 Markus Perola  26   27   49 Patricia A Peyser  34 Mario Pirastu  44 Ozren Polasek  133 Chris Power  39 Jaakko Kaprio  26   27   101 Leslie J Raffel  152 Katri Räikkönen  72 Olli Raitakari  153 Paul M Ridker  12 Susan M Ring  108 Kathryn Roll  59 Igor Rudan  11 Daniela Ruggiero  87 Dan Rujescu  154 Veikko Salomaa  26 David Schlessinger  155 Helena Schmidt  99 Reinhold Schmidt  61 Nicole Schupf  156 Johannes Smit  2   80 Rossella Sorice  87   107 Tim D Spector  138 John M Starr  45   157 Doris Stöckl  156 Konstantin Strauch  21   158 Michael Stumvoll  100   135 Morris A Swertz  35 Unnur Thorsteinsdottir  17   159 A Roy Thurik  3   5   160 Nicholas J Timpson  108 Joyce Y Tung  48 André G Uitterlinden  3   5   36 Simona Vaccargiu  44 Jorma Viikari  161 Veronique Vitart  10 Henry Völzke  162 Peter Vollenweider  163 Dragana Vuckovic  55   115 Johannes Waage  20 Gert G Wagner  164 Jie Jin Wang  65 Nicholas J Wareham  15 David R Weir  114 Gonneke Willemsen  79   80 Johann Willeit  64 Alan F Wright  10 Krina T Zondervan  165   166 Kari Stefansson  17   159 Robert F Krueger  83 James J Lee  83 Daniel J Benjamin  54   167 David Cesarini  168   169 Philipp D Koellinger  3   5   82 Marcel den Hoed  170 Harold Snieder  6 Melinda C Mills  1
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Free PMC article

Genome-wide Analysis Identifies 12 Loci Influencing Human Reproductive Behavior

Nicola Barban et al. Nat Genet. .
Free PMC article

Abstract

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 a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals 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 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Manhattan plots of SNPs for AFB (age at first birth) and NEB (number of children ever born) in single genomic control meta-analysis
SNPs are plotted on the x-axis according to their position on each chromosome against association with AFB (panel a) and NEB (panel b). The solid blue line indicates the threshold for genome-wide significance (P<5x10−08) and the red line, the threshold for suggestive hits (P<5x10−06). Blue points indicate SNPs in a ±100 KB region around genome-wide significant hits. Gene labels are annotated as the nearby genes to the significant SNPs.
Figure 2
Figure 2. Quantile-quantile plots of SNPs for AFB (panel a) and NEB (panel b) in single genomic control, meta-analysis
The grey shaded areas in the Q-Q plots represent the 95% confidence bands around the P-values under the null hypothesis.
Figure 3
Figure 3. Genetic overlap between AFB and NEB and other related traits
Results from Linkage-Disequilibrium (LD) Score regressions: estimates of genetic correlation with developmental, reproductive, behavioral, neuropsychiatric and anthropometric phenotypes for which GWAS summary statistics were available in the public domain. The length of the bars indicates the estimates of genetic correlation. Grey error bars indicate 95% confidence intervals. The mark “*” indicates that the estimate of genetic correlation is statistically significant after controlling for multiple testing (P<0.05/27=1.85x10−3).

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