Common variants at 12q15 and 12q24 are associated with infant head circumference

H. Rob Taal, Beate St Pourcain, Elisabeth Thiering, Shikta Das, Dennis O. Mook-Kanamori, Nicole M. Warrington, Marika Kaakinen, Eskil Kreiner-Møller, Jonathan P. Bradfield, Rachel M. Freathy, Frank Geller, Mònica Guxens, Diana L. Cousminer, Marjan Kerkhof, Nicholas J. Timpson, M. Arfan Ikram, Lawrence J. Beilin, Klaus Bønnelykke, Jessica L. Buxton, Pimphen CharoenBo Lund Krogsgaard Chawes, Johan Eriksson, David M. Evans, Albert Hofman, John P. Kemp, Cecilia E. Kim, Norman Klopp, Jari Lahti, Stephen J. Lye, George Mcmahon, Frank D. Mentch, Martina Müller-Nurasyid, Paul F. O'reilly, Inga Prokopenko, Fernando Rivadeneira, Eric A.P. Steegers, Jordi Sunyer, Carla Tiesler, Hanieh Yaghootkar, Myriam Fornage, Albert V. Smith, Sudha Seshadri, Reinhold Schmidt, Stéphanie Debette, Henri A. Vrooman, Sigurdur Sigurdsson, Stefan Ropele, Laura H. Coker, W. T. Longstreth, Wiro J. Niessen, Anita L. Destefano, Alexa Beiser, Alex P. Zijdenbos, Maksim Struchalin, Clifford R. Jack, Mike A. Nalls, Rhoda Au, Haukur Gudnason, Aad Van Der Lugt, Tamara B. Harris, William M. Meeks, Meike W. Vernooij, Mark A. Van Buchem, Diane Catellier, Vilmundur G. Guðnason, B. Gwen Windham, Philip A. Wolf, Cornelia M. Van Duijn, Thomas H. Mosley, Helena Schmidt, Lenore J. Launer, Monique M.B. Breteler, Wei Ang, Toos Van Beijsterveldt, Nienke Bergen, Kelly Benke, Diane Berry, Lachlan Coin, Paul Elliott, Tim Frayling, Romy Gaillard, Maria Groen-Blokhuis, Dexter Hadley, Jouke Jan Hottenga, Ville Huikari, Elina Hypponen, Matthew Kowgier, Debbie A. Lawlor, Alex Lewin, Cecilia Lindgren, Julie Marsh, Christel Middeldorp, Iona Millwood, Michel Nivard, Lyle J. Palmer, Alina Rodriguez, Sylvain Sebert, Ulla Sovio, Marie Standl, David P. Strachan, H. Rob Taal, Andre G. Uitterlinden, Beatriz Valcárcel, Scott White, Gonneke Willemsen, Dorret I. Boomsma, Xavier Estivill, Struan F.A. Grant, Andrew T. Hattersley, Joachim Heinrich, Vincent W.V. Jaddoe, Marjo Riitta Jarvelin, Mark I. Mccarthy, Craig E. Pennell, Chris Power, Elisabeth Widen, Alexandra I.F. Blakemore, Rosetta M. Chiavacci, Bjarke Feenstra, Julio Fernandez-Banet, Anna Liisa Hartikainen, Albert J. Van Der Heijden, Carmen Iñiguez, Mark Lathrop, Wendy L. Mcardle, Anne Mølgaard, John P. Newnham, Aarno Palotie, Annneli Pouta, Susan M. Ring, H. Erich Wichmann, Nadja Hawwa Vissing, Charles Decarli, Gerard H. Koppelman, Mads Melbye, Hans Bisgaard, Hakon Hakonarson, George Davey Smith*, Linda S. Adair, Mustafa Atalay, Oliver S.P. Davis, Claudia Flexeder, Liang Kee Goh, Claire M.A. Haworth, Johannes Hedebrand, Anke Hinney, Joel N. Hirschhorn, John W. Holloway, Claus Holst, Momoko Horikoshi, Tuomas O. Kilpeläinen, Mirna Kirin, Hanna Maaria Lakka, Leslie A. Lange, Terho Lehtimäki, Virpi Lindi, Reedik Maggi, Jeffrey C. Murray, Ellen Aagaard Nohr, Ioanna Ntalla, Emily Oken, Kalliope Panoutsopoulou, Jennifer Pararajasingham, Rany M. Salem, Niina Siitonen, H. Rob Taal, Yik Ying Teo, Eleftheria Zeggini, Cyrus Cooper, Matthew Gillman, Berthold Hocher, Timo A. Lakka, Karen L. Mohlke, George V. Dedoussis, Ken K. Ong, Ewan R. Pearson, Thomas S. Price, Olli T. Raitakari, Seang Mei Saw, Andre Scherag, Olli Simell, Thorkild I.A. Sørensen, James F. Wilson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10-9) and rs1042725 on chromosome 12q15 (P = 2.8 × 10-10) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10 -7 for rs7980687 and P = 1.3 × 10-7 for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10-6). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

Original languageEnglish
Pages (from-to)532-538
Number of pages7
JournalNature Genetics
Volume44
Issue number5
DOIs
Publication statusPublished - 15 Apr 2012

Bibliographical note

Funding text
We thank A. Sayers for helpful discussions with respect to the conducted mediation analysis. Major funding for the research in this paper is from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 134839, 129287 and Center of Excellence in Complex Disease Genetics); Biocentrum Helsinki; Biocenter, University of Oulu, Finland; the British Heart Foundation; the Canadian Institutes of Health Research (grant MOP 82893); The Children’s Hospital of Philadelphia (Institute Development Award); the Cotswold Foundation (Research Development Award); the Darlington Trust; the Dutch Asthma Foundation; the Dutch Ministry of the Environment; Erasmus Medical Center Rotterdam; Erasmus University Rotterdam; The European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE project and grant agreement HEALTH-F4-2007-201413; Exeter National Health Service (NHS) Research and Development; Fundació La Marató de TV3 (Televisió de Catalunya); Helmholtz Zentrum Muenchen, the German Research Center for Environment and Health, Institute of Epidemiology I, Neuherberg; Instituto de Salud Carlos III (FIS PI081151 and PS09/00432); Institut für Umweltmedizinische Forschung (IUF) Düsseldorf; Marien-Hospital Wesel; the UK MRC (G0500539, G0600331, PrevMetSyn/Salve/MRC and G0600705); the Municipal Health Service Rotterdam; the National Health and Medical Research Council of Australia (403981 and 003209); the National Public Health Institute, Helsinki, Finland; the Netherlands Organisation for Scientific Research (NWO) and the Netherlands Organisation for Health Research and Development (ZonMw) (grants SPI 56-464-14192, 904-61-090, 904-61-193, 912-03-031, 480-04-004 and 400-05-717); the US NHLBI (grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01)); the US NIH (grant 1R01HD056465-01A1); the Peninsula NIHR Clinical Research Facility; the RAINE Medical Research Foundation; the Rotterdam Homecare Foundation; South West NHS Research and Development; Stichting Astmabestrijding; Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR) Rotterdam; Technical University Munich; the Telethon Institute for Child Health Research; UFZ–Centre for Environmental Research Leipzig–Halle; University Hospital Oulu, Finland; University of Bristol; University of Leipzig; the Wellcome Trust (project grant GR069224); the Western Australian DNA Bank; the Western Australian Genetic Epidemiology Resource and ZonMW (grant 21000074). Data exchange and deposition has been facilitated by the SIMBioMS platform. Personal funding was provided by the Dutch Kidney Foundation (C08.2251 to H.R.T.), the MRC UK (G0500539, PrevMetSyn and PS0476 to S. Das), a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust grant 085541/Z/08/Z to R.M.F.), a MRC New Investigator Award (MRC G0800582 to D.M.E.) and Wellcome Trust 4-year PhD studentships (WT083431MA to J.P.K. and WT088431MA to J.L.B.). I.P. and J.F.-B. are in part supported by the European Community’s ENGAGE grant HEALTH-F4-2007-201413, A.T.H. is employed as a core member of the Peninsula NIHR Clinical Research Facility and V.W.V.J. is funded by the Netherlands Organisation for Health Research (ZonMw 90700303 and 916.10159). Detailed acknowledgments by study are given in the Supplementary Note.

Other keywords

  • Chromosomes, Human, Pair 12/genetics
  • Female
  • Genetic Loci
  • Genetic Markers
  • Genome-Wide Association Study
  • Head/growth & development
  • Humans
  • Infant
  • Male
  • Meta-Analysis as Topic
  • Polymorphism, Single Nucleotide/genetics
  • Pregnancy
  • Pregnancy Complications/etiology
  • Whites/genetics

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