Abstract
To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10 -60) and 9q31.2 (P = 2.2 × 10 -33), we identified 30 new menarche loci (all P < 5 × 10 -8) and found suggestive evidence for a further 10 loci (P < 1.9 × 10 -6). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
Original language | English |
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Pages (from-to) | 1077-1085 |
Number of pages | 9 |
Journal | Nature Genetics |
Volume | 42 |
Issue number | 12 |
DOIs | |
State | Published - 1 Dec 2010 |
Externally published | Yes |
Bibliographical note
Funding Information:Drug Abuse (NIDA); National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, HHSN268200782096C, M01 RR-00750, MH66206, N01-AG-12100, N01-AG-1-2109, P01-AG-18397, R01-088119, R01-DA013423, RFAHG006033, U01DE018993, U01DE018903, U01HG004422, U01HG004446, U01HL72515, U01 HL84756, U01HG004399, U01HG004402, U01HG004415, U01HG004423, U01HG004436, U01HG004438, U01HG004402, U01HG004446, U01HG004726, U01HG004728, U01HG004729, U01HG004735, U01HG004738, U01HG04424, U10AA008401, U54RR025204-01, UL1RR025005, UL1 RR025774, Z01CP010200, HHSN268200625226C); the National Institute for Health Research Cambridge Biomedical Research Centre; Netherlands Organization for Scientific Research (904-61-193, 575-25-006, 480-04-004, 56-464-14192, NWO 480-05-003, 175.010.2005.011, 911-03-012, 014-93-015); Netherlands Genomic Initiative (NGI, 050-060-810), National Institute on Aging (NIA) Intramural Research Program; and Laboratory of Neurogenetics; US National Institutes of Health Genes, Environment and Health Initiative; Republic of Croatia Ministry of Science, Education and Sports (108-1080315-0302); Robert Dawson Evans Endowment; the Royal Society, Royal Swedish Academy of Science; State of Bavaria, Germany; Susan G. Komen Breast Cancer Foundation; Swedish Foundation for Strategic Research (SSF); Swedish Heart-Lung Foundation; Swedish Ministry of Higher Education and Research; Swedish Research Council; Swedish Society of Medicine; Swiss National Science Foundation (Ref: 33CSCO-122661, 3100AO-116323/1); the University of Bristol, University of Maryland General Clinical Research Center (M01 RR 16500); the Wellcome Trust (068545/Z/02, 076467/Z/05/Z, 077016/Z/05/Z, 89061/Z/09/Z, strategic award 079895); Western Australian DNA Bank; Western Australian Genetic Epidemiology Resource (see Supplementary Note for extended acknowledgments).
Funding Information:
Academy of Finland (Finnish Centre of Excellence in Complex Disease Genetics 129680, 120315, 129287, 129494); Affymetrix (N02-HL-6-4278); Agency of Science, Technology and Research of Singapore (A*STAR); Althingi (the Icelandic Parliament); American Heart Association (0855082E); Amgen; Augustinus Foundation; Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498, 619667); Australian Research Council (A7960034, A79801419, A79906588, DP0212016, DP0343921, DP0770096); Baltimore Veterans Administration Medical Center Geriatrics Research; Canadian Institutes of Health Research (grant ID 166067); Cancer Research United Kingdom; the Cariplo Foundation; Center for Disease Control and Prevention (USA), Centre for Medical Systems Biology (CMSB); the Chief Scientist Office of the Scottish Government; Clinical Nutrition Research Unit of Maryland (P30 DK072488); Danish National Research Foundation; Danish Pharmacists’ Fund; the Egmont Foundation; Erasmus Medical Center; Erasmus University; Estonian Government (SF0180142s08); the European Commision (212111 BBMRI, 205419 ECOGENE, 201413 ENGAGE, HEALTH-F2-2008-201865 - GEFOS, HEALTH-F2-2008-35627, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550 HYPERGENES, 245536 OPENGENE, TREAT-OA, GenomEUtwin Project QLG2-CT-2002-01254, EU/QLRT-2001-01254; ERC-230374); European Union framework program 6 EUROSPAN project (LSHG-CT-2006-018947, LSHM-CT-2003-503041); European Regional Development Fund; Faculty of Biology and Medicine of Lausanne, Switzerland; Fondazione Compagnia di San Paolo Health Ministry, Framingham Heart Study (N01-HC-25195); GENEVA Coordinating Center (U01HG004446); German Federal Ministry of Education and Research; German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823); Giorgi-Cavaglieri Foundation; GlaxoSmithKline; Health Fund of the Danish Health Insurance Societies; Helmholtz Zentrum München-German Research Center for Environmental Health; Hjartavernd (the Icelandic Heart Association); Italian Ministry of Health (ICS110.1/RF97.71, RF-FSR-2007-647201); Juvenile Diabetes Research Foundation International (JDRF); Leenaards Foundation; March of Dimes Birth Defects Foundation; the Medical Research Council (G0000934, G0500539, G0701863); National Cancer Institute (CA40356, CA98233, P01CA087969, P01CA055075, CA047988, CA63464, CA54281, CA136792, CA089392, CA104021); Munich Center of Health Sciences (MC Health, LMUinnovativ); National Health and Medical Research Council of Australia (572613 and 003209); National Heart, Lung, and Blood Institute (HL 043851, HL087679, HL69757, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, RC2 HL102419); National Human Genome Research Institute (NHGRI); National Institute of Aging (263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002, AG-16592, Genetics of Reproductive Life Period and Health Outcomes - R21AG032598); National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute on Aging ((NIAMS/NIA) R01 AR/AG 41398); National Institute of Child Health and Human Development (HD-061437); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, R01DK058845, U01 DK062418); National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute of Allergy and Infectious Diseases (NIAID); National Institute on
Funding
Drug Abuse (NIDA); National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, HHSN268200782096C, M01 RR-00750, MH66206, N01-AG-12100, N01-AG-1-2109, P01-AG-18397, R01-088119, R01-DA013423, RFAHG006033, U01DE018993, U01DE018903, U01HG004422, U01HG004446, U01HL72515, U01 HL84756, U01HG004399, U01HG004402, U01HG004415, U01HG004423, U01HG004436, U01HG004438, U01HG004402, U01HG004446, U01HG004726, U01HG004728, U01HG004729, U01HG004735, U01HG004738, U01HG04424, U10AA008401, U54RR025204-01, UL1RR025005, UL1 RR025774, Z01CP010200, HHSN268200625226C); the National Institute for Health Research Cambridge Biomedical Research Centre; Netherlands Organization for Scientific Research (904-61-193, 575-25-006, 480-04-004, 56-464-14192, NWO 480-05-003, 175.010.2005.011, 911-03-012, 014-93-015); Netherlands Genomic Initiative (NGI, 050-060-810), National Institute on Aging (NIA) Intramural Research Program; and Laboratory of Neurogenetics; US National Institutes of Health Genes, Environment and Health Initiative; Republic of Croatia Ministry of Science, Education and Sports (108-1080315-0302); Robert Dawson Evans Endowment; the Royal Society, Royal Swedish Academy of Science; State of Bavaria, Germany; Susan G. Komen Breast Cancer Foundation; Swedish Foundation for Strategic Research (SSF); Swedish Heart-Lung Foundation; Swedish Ministry of Higher Education and Research; Swedish Research Council; Swedish Society of Medicine; Swiss National Science Foundation (Ref: 33CSCO-122661, 3100AO-116323/1); the University of Bristol, University of Maryland General Clinical Research Center (M01 RR 16500); the Wellcome Trust (068545/Z/02, 076467/Z/05/Z, 077016/Z/05/Z, 89061/Z/09/Z, strategic award 079895); Western Australian DNA Bank; Western Australian Genetic Epidemiology Resource (see Supplementary Note for extended acknowledgments). Academy of Finland (Finnish Centre of Excellence in Complex Disease Genetics 129680, 120315, 129287, 129494); Affymetrix (N02-HL-6-4278); Agency of Science, Technology and Research of Singapore (A*STAR); Althingi (the Icelandic Parliament); American Heart Association (0855082E); Amgen; Augustinus Foundation; Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498, 619667); Australian Research Council (A7960034, A79801419, A79906588, DP0212016, DP0343921, DP0770096); Baltimore Veterans Administration Medical Center Geriatrics Research; Canadian Institutes of Health Research (grant ID 166067); Cancer Research United Kingdom; the Cariplo Foundation; Center for Disease Control and Prevention (USA), Centre for Medical Systems Biology (CMSB); the Chief Scientist Office of the Scottish Government; Clinical Nutrition Research Unit of Maryland (P30 DK072488); Danish National Research Foundation; Danish Pharmacists’ Fund; the Egmont Foundation; Erasmus Medical Center; Erasmus University; Estonian Government (SF0180142s08); the European Commision (212111 BBMRI, 205419 ECOGENE, 201413 ENGAGE, HEALTH-F2-2008-201865 - GEFOS, HEALTH-F2-2008-35627, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550 HYPERGENES, 245536 OPENGENE, TREAT-OA, GenomEUtwin Project QLG2-CT-2002-01254, EU/QLRT-2001-01254; ERC-230374); European Union framework program 6 EUROSPAN project (LSHG-CT-2006-018947, LSHM-CT-2003-503041); European Regional Development Fund; Faculty of Biology and Medicine of Lausanne, Switzerland; Fondazione Compagnia di San Paolo Health Ministry, Framingham Heart Study (N01-HC-25195); GENEVA Coordinating Center (U01HG004446); German Federal Ministry of Education and Research; German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823); Giorgi-Cavaglieri Foundation; GlaxoSmithKline; Health Fund of the Danish Health Insurance Societies; Helmholtz Zentrum München-German Research Center for Environmental Health; Hjartavernd (the Icelandic Heart Association); Italian Ministry of Health (ICS110.1/RF97.71, RF-FSR-2007-647201); Juvenile Diabetes Research Foundation International (JDRF); Leenaards Foundation; March of Dimes Birth Defects Foundation; the Medical Research Council (G0000934, G0500539, G0701863); National Cancer Institute (CA40356, CA98233, P01CA087969, P01CA055075, CA047988, CA63464, CA54281, CA136792, CA089392, CA104021); Munich Center of Health Sciences (MC Health, LMUinnovativ); National Health and Medical Research Council of Australia (572613 and 003209); National Heart, Lung, and Blood Institute (HL 043851, HL087679, HL69757, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, RC2 HL102419); National Human Genome Research Institute (NHGRI); National Institute of Aging (263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002, AG-16592, Genetics of Reproductive Life Period and Health Outcomes - R21AG032598); National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute on Aging ((NIAMS/NIA) R01 AR/AG 41398); National Institute of Child Health and Human Development (HD-061437); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, R01DK058845, U01 DK062418); National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute of Allergy and Infectious Diseases (NIAID); National Institute on
Funders | Funder number |
---|---|
Agency of Science, Technology and Research of Singapore | |
Australian National Health and Medical Research Council | 339462, 389892, 389891, 619667, 241944, 552485, 442981, 552498, 496739, 389875, 442915, 389927, 389938 |
Baltimore Veterans Administration Medical Center Geriatrics Research | |
Cancer Research United Kingdom | |
Clinical Nutrition Research Unit of Maryland | P30 DK072488 |
Danish Health Insurance Societies | |
Environment and Health Initiative | |
Erasmus University | |
Estonian Government | SF0180142s08 |
European Commision | 212111, 245536, HEALTH-F4-2007-201550, QLG2-CT-2002-01254, EU/QLRT-2001-01254, HEALTH-F2-2008-201865, HEALTH-F2-2008-35627, 205419, ERC-230374, 201413, HEALTH-F4-2007-201413 |
European Union framework program | LSHM-CT-2003-503041, LSHG-CT-2006-018947 |
German Federal Ministry of Education and Research | |
German National Genome Research Network | 01GS0823 |
Giorgi-Cavaglieri Foundation | |
Helmholtz Zentrum München-German Research Center for Environmental Health | |
Italian Ministry of Health | ICS110.1/RF97.71, RF-FSR-2007-647201 |
Laboratory of Neurogenetics | |
NIAMS/NIA | R01 AR/AG 41398 |
National Health and Medical Research Council of Australia | 572613, 003209 |
National Institute on | |
National Institutes of Health Genes | |
Netherlands Genomic Initiative | 050-060-810 |
Netherlands Organization for Scientific Research | 480-04-004, 575-25-006, 904-61-193, 56-464-14192 |
Robert Dawson Evans Endowment | |
Swedish Ministry of Higher Education and Research | |
University of Maryland General Clinical Research Center | M01 RR 16500 |
National Institutes of Health | AA14041, U01HL72515, AA13320, M01 RR-00750, R01-088119, P01-AG-18397, HHSN268200625226C, N01-AG-1-2109, U01HG04424, UL1RR025005, R01-DA013423, RFAHG006033, AA07535, MH66206, U01DE018993, N01-AG-12100, UL1 RR025774, AA13321, U01 HL84756, U01DE018903, U54RR025204-01, AA10248, AA13326 |
National Institute on Drug Abuse | |
National Institute on Alcohol Abuse and Alcoholism | U10AA008401 |
Centers for Disease Control and Prevention | |
National Institute on Aging | N01-AG-5-0002, R21AG032598, 263 MD 821336, 263 MD 9164, AG-16592 |
National Heart, Lung, and Blood Institute | N01-HC-55021, N01-HC-55020, RC2 HL102419, N01-HC-55022, HL087679, R01HL59367, HL69757, N01-HC-55018, N01-HC-55016, N01-HC-55015, HL 043851, R01HL087641, N01-HC-55019, R01HL086694 |
National Human Genome Research Institute | U01HG004423, U01HG004402, U01HG004446, U01HG004399, U01HG004422, U01HG004438, U01HG004735, U01HG004436, U01HG004415, U01HG004728, U01HG004729, U01HG004726, U01HG004738 |
National Cancer Institute | CA54281, CA136792, Z01CP010200, CA089392, CA40356, CA104021, CA047988, CA63464, P01CA055075, CA98233, P01CA087969 |
National Institute of Allergy and Infectious Diseases | |
National Institute of Diabetes and Digestive and Kidney Diseases | R01DK058845, U01 DK062418 |
National Institute of Arthritis and Musculoskeletal and Skin Diseases | |
National Institute of Child Health and Human Development | HD-061437 |
Juvenile Diabetes Research Foundation International | |
March of Dimes Foundation | |
American Heart Association | 0855082E |
Amgen | |
GlaxoSmithKline | |
Compagnia di San Paolo | N01-HC-25195 |
Susan G. Komen | |
Wellcome Trust | 89061/Z/09/Z, 076467/Z/05/Z, 068545/Z/02, 079895, 077016/Z/05/Z |
Chief Scientist Office, Scottish Government Health and Social Care Directorate | |
Canadian Institutes of Health Research | ID 166067 |
Medical Research Council | G0000934, G0701863, G0500539 |
Royal Society | |
University of Bristol | |
Australian Research Council | A7960034, DP0212016, A79801419, DP0343921, A79906588, DP0770096 |
Agency for Science, Technology and Research | |
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung | 3100AO-116323/1, 33CSCO-122661 |
Royal Swedish Academy of Sciences | |
Stiftelsen för Strategisk Forskning | |
Danmarks Grundforskningsfond | |
Academy of Finland | 129287, N02-HL-6-4278, 120315, 129680, 129494 |
Fondazione Cariplo | |
Erasmus Medisch Centrum | |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 480-05-003, 014-93-015, 175.010.2005.011, 911-03-012 |
Ministarstvo Obrazovanja, Znanosti i Sporta | 108-1080315-0302 |
Hjärt-Lungfonden | |
Vetenskapsrådet | |
Augustinus Fonden | |
Fondation Leenaards | |
Svenska Läkaresällskapet | |
European Regional Development Fund | |
Egmont Fonden | |
Hjartavernd | |
Centre for Medical Systems Biology | |
Münchner Zentrum für Gesundheitswissenschaften, Ludwig-Maximilians-Universität München | |
NIHR Cambridge Biomedical Research Centre |