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 height1, 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 volume2, Parkinson's disease and other neurodegenerative diseases3,4,5, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
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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.