Loci at chromosomes 13, 19 and 20 influence age at natural menopause

Nature Genetics 41, 645 - 647 (2009)
Published online: 17 May 2009 | doi:10.1038/ng.387

Lisette Stolk1,2,3,11, Guangju Zhai4,11, Joyce B J van Meurs1,3, Michael M P J Verbiest1, Jenny A Visser1, Karol Estrada1, Fernando Rivadeneira1,2, Frances M Williams4, Lynn Cherkas4, Panos Deloukas5, Nicole Soranzo5, Jules J de Keyzer6, Victor J M Pop7, Paul Lips8, Corinne E I Lebrun1,9, Yvonne T van der Schouw9, Diederick E Grobbee9, Jacqueline Witteman2,3, Albert Hofman2,3, Huibert A P Pols1, Joop S E Laven10, Tim D Spector4,11 & André G Uitterlinden1,2,3,11

Brief Communication abstract

We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; –0.4 year per T allele (39%); P = 6.3 times 10-11), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 times 10-11) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 times 10-8). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.

1. Departments of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
2. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
3. The Netherlands Genomics Initiative–sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Rotterdam, The Netherlands.
4. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
5. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
6. Research Unit, Diagnostic Center Eindhoven, Eindhoven, The Netherlands.
7. Department of Clinical Health Psychology, University of Tilburg, Tilburg, The Netherlands.
8. Department of Internal Medicine, Endocrine Section, and EMGO Institute, VU University Medical Center, Amsterdam, The Netherlands.
9. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands.
10. Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, The Netherlands.
11. These authors contributed equally to this work.

Correspondence to: André G Uitterlinden1,2,3,11 e-mail: a.g.uitterlinden@erasmusmc.nl

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Meta-analysis of genome-wide association data identifies two loci influencing age at menarche

Nature Genetics 41, 648 - 650 (2009)
Published online: 17 May 2009 | doi:10.1038/ng.386

John R B Perry1,23, Lisette Stolk2,3,4,23, Nora Franceschini5,23, Kathryn L Lunetta6,7,23, Guangju Zhai8,23, Patrick F McArdle9,23, Albert V Smith10,23, Thor Aspelund10,11, Stefania Bandinelli12, Eric Boerwinkle13, Lynn Cherkas8, Gudny Eiriksdottir10, Karol Estrada2, Luigi Ferrucci14, Aaron R Folsom15, Melissa Garcia16, Vilmundur Gudnason10,11, Albert Hofman3,4, David Karasik6,17, Douglas P Kiel6,17, Lenore J Launer16, Joyce van Meurs2,4, Michael A Nalls18, Fernando Rivadeneira2,3,4, Alan R Shuldiner9, Andrew Singleton18, Nicole Soranzo8,19, Toshiko Tanaka20, Jenny A Visser2, Michael N Weedon1, Scott G Wilson8,21, Vivian Zhuang7, Elizabeth A Streeten9,23, Tamara B Harris16,23, Anna Murray1,23, Tim D Spector8,23, Ellen W Demerath15,23, André G Uitterlinden2,3,4,23 & Joanne M Murabito6,22,23

We conducted a meta-analysis of genome-wide association data to detect genes influencing age at menarche in 17,510 women. The strongest signal was at 9q31.2 (P = 1.7 times 10-9), where the nearest genes include TMEM38B, FKTN, FSD1L, TAL2 and ZNF462. The next best signal was near the LIN28B gene (rs7759938; P = 7.0 times 10-9), which also influences adult height. We provide the first evidence for common genetic variants influencing female sexual maturation.

Brief Communication abstract

1. Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK.
2. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
3. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
4. Netherlands Genomics Initiative–sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Chapel Hill, North Carolina, USA.
5. Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina, USA.
6. The National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
7. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
8. Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
9. Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA.
10. Icelandic Heart Association, Kopavogur, Iceland.
11. University of Iceland, Reykjavik, Iceland.
12. Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy.
13. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
14. Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.
15. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
16. Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.
17. Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, Massachusetts, USA.
18. Laboratory of Neurogenetics, National Institute of Aging, Bethesda, Maryland, USA.
19. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
20. Medstar Research Institute, National Institute on Aging, Baltimore, Maryland, USA.
21. School of Medicine & Pharmacology, University of Western Australia and Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
22. Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
23. These authors contributed equally to this work.

Correspondence to: André G Uitterlinden2,3,4,23 e-mail: a.g.uitterlinden@erasmusmc.nl

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Genetic variation in LIN28B is associated with the timing of puberty

Nature Genetics 41, 729 - 733 (2009)
Published online: 17 May 2009 | doi:10.1038/ng.382

Ken K Ong1,2,3, Cathy E Elks1,2, Shengxu Li1,2, Jing Hua Zhao1,2, Jian'an Luan1,2, Lars B Andersen4, Sheila A Bingham5,6, Soren Brage1,2, George Davey Smith7, Ulf Ekelund1,2,8, Christopher J Gillson1,2, Beate Glaser7, Jean Golding9, Rebecca Hardy10, Kay-Tee Khaw11, Diana Kuh10, Robert Luben11, Michele Marcus12,13,14, Michael A McGeehin12, Andrew R Ness15, Kate Northstone16, Susan M Ring16, Carol Rubin12, Matthew A Sims1,2, Kijoung Song17, David P Strachan18, Peter Vollenweider19, Gerard Waeber19, Dawn M Waterworth17, Andrew Wong10, Panagiotis Deloukas20, Inês Barroso20, Vincent Mooser17, Ruth J Loos1,2 & Nicholas J Wareham1,2

Letter abstract

The timing of puberty is highly variable1. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 times 10-8). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08–0.16; P = 2.8 times 10-10; combined P = 3.6 times 10-16). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 times 10-7; N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing2, as the first genetic determinant regulating the timing of human pubertal growth and development.

1. Medical Research Council (MRC) Epidemiology Unit, Addenbrooke's Hospital, Cambridge, UK.
2. Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
3. Department of Paediatrics, University of Cambridge, Cambridge, UK.
4. Institute of Sport Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark.
5. MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge, UK.
6. MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Cambridge, UK.
7. MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, UK.
8. School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
9. Avon Longitudinal Study of Parents and Children (ALSPAC), Department of Community Based Medicine, University of Bristol, Bristol, UK.
10. MRC Unit for Lifelong Health and Ageing, London, UK.
11. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.
12. National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
13. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
14. Departments of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
15. Department of Oral and Dental Science, University of Bristol, Bristol, UK.
16. ALSPAC, Department of Social Medicine, University of Bristol, Bristol, UK.
17. Genetics Division, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
18. Division of Community Health Sciences, St. George's, University of London, London, UK.
19. Department of Internal Medicine, BH-10 Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
20. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

Correspondence to: Ken K Ong1,2,3 e-mail: ken.ong@mrc-epid.cam.ac.uk

Correspondence to: Ruth J Loos1,2 e-mail: ruth.loos@mrc-epid.cam.ac.uk

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Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche

Nature Genetics 41, 734 - 738 (2009)
Published online: 17 May 2009 | doi:10.1038/ng.383

Patrick Sulem1,12, Daniel F Gudbjartsson1,12, Thorunn Rafnar1, Hilma Holm1,2, Elinborg J Olafsdottir3, Gudridur H Olafsdottir3, Thorvaldur Jonsson4, Peter Alexandersen5, Bjarke Feenstra6, Heather A Boyd6, Katja K Aben7, Andre L M Verbeek8, Nel Roeleveld8, Aslaug Jonasdottir1, Unnur Styrkarsdottir1, Valgerdur Steinthorsdottir1, Ari Karason1, Simon N Stacey1, Julius Gudmundsson1, Margret Jakobsdottir1, Gudmar Thorleifsson1, Gudmundur Hardarson1, Jeffrey Gulcher1, Augustine Kong1, Lambertus A Kiemeney7,8,9, Mads Melbye6, Claus Christiansen10, Laufey Tryggvadottir3, Unnur Thorsteinsdottir1,11 & Kari Stefansson1,11

Letter abstract

Earlier menarche correlates with shorter adult height1 and higher childhood body fat2. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 times 10-14). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height3, 4. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height3, 4, 5, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI)6, 7, 8, 9, 10, 11 and 5 of those associated with earlier AAM.

1. deCODE Genetics, Reykjavik, Iceland.
2. Department of Internal Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
3. Icelandic Cancer Registry, Reykjavik, Iceland.
4. Department of Surgery, University Hospital, Reykjavik, Iceland.
5. Center for Clinical and Basic Research A/S, Ballerup, Denmark.
6. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
7. Comprehensive Cancer Centre East, Nijmegen, The Netherlands.
8. Radboud University Nijmegen Medical Center Department of Epidemiology & Biostatistics, Nijmegen, The Netherlands.
9. Radboud University Nijmegen Department of Urology, Nijmegen, The Netherlands.
10. Nordic bioscience A/S, Herlev, Denmark.
11. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
12. These authors contributed equally to this work.

Correspondence to: Patrick Sulem1,12 e-mail: patrick.sulem@decode.is

Correspondence to: Kari Stefansson1,11 e-mail: kstefans@decode.is