Common variants at 6q22 and 17q21 are associated with intracranial volume

M. Arfan Ikram*, Myriam Fornage, Albert V. Smith, Sudha Seshadri, Reinhold Schmidt, Stéphanie Debette, Henri A. Vrooman, Sigurdur Sigurdsson, Stefan Ropele, H. Rob Taal, Dennis O. Mook-Kanamori, Laura H. Coker, W. T. Longstreth, Wiro J. Niessen, Anita L. Destefano, Alexa Beiser, Alex P. Zijdenbos, Maksim Struchalin, Clifford R. Jack, Fernando RivadeneiraAndre G. Uitterlinden, David S. Knopman, Anna Liisa Hartikainen, Craig E. Pennell, Elisabeth Thiering, Eric A.P. Steegers, Hakon Hakonarson, Joachim Heinrich, Lyle J. Palmer, Marjo Riitta Jarvelin, Mark I. Mccarthy, Struan F.A. Grant, Beate St Pourcain, Nicholas J. Timpson, George Davey Smith, Ulla Sovio, Mike A. Nalls, Rhoda Au, Albert Hofman, Haukur Gudnason, Aad Van Der Lugt, Tamara B. Harris, William M. Meeks, Meike W. Vernooij, Mark A. Van Buchem, Diane Catellier, Vincent W.V. Jaddoe, Vilmundur Gudnason, B. Gwen Windham, Philip A. Wolf, Cornelia M. Van Duijn, Thomas H. Mosley, Helena Schmidt, Lenore J. Launer, Monique M.B. Breteler, Charles Decarli, Linda S. Adair, Wei Ang, Mustafa Atalay, Toos Van Beijsterveldt, Nienke Bergen, Kelly Benke, Diane Berry, Lachlan Coin, Oliver S.P. Davis, Paul Elliott, Claudia Flexeder, Tim Frayling, Romy Gaillard, Maria Groen-Blokhuis, Liang Kee Goh, Claire M.A. Haworth, Dexter Hadley, Johannes Hedebrand, Anke Hinney, Joel N. Hirschhorn, John W. Holloway, Claus Holst, Jouke Jan Hottenga, Momoko Horikoshi, Ville Huikari, Elina Hypponen, Tuomas O. Kilpeläinen, Mirna Kirin, Matthew Kowgier, Hanna Maaria Lakka, Leslie A. Lange, Debbie A. Lawlor, Terho Lehtimäki, Alex Lewin, Cecilia Lindgren, Virpi Lindi, Reedik Maggi, Julie Marsh, Christel Middeldorp, Iona Millwood, Jeffrey C. Murray, Michel Nivard, Ellen Aagaard Nohr, Ioanna Ntalla, Emily Oken, Kalliope Panoutsopoulou, Jennifer Pararajasingham, Alina Rodriguez, Rany M. Salem, Sylvain Sebert, Niina Siitonen, David P. Strachan, Yik Ying Teo, Beatriz Valcárcel, Gonneke Willemsen, Eleftheria Zeggini, Dorret I. Boomsma, Cyrus Cooper, Matthew Gillman, Berthold Hocher, Timo A. Lakka, Karen L. Mohlke, George V. Dedoussis, Ken K. Ong, Ewan R. Pearson, Thomas S. Price, Chris Power, 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

86 Citations (Scopus)


During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10 -8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10 -11), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10 -12), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10 -3 for 6q22 and 1.2 × 10 -3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.

Original languageEnglish
Pages (from-to)539-544
Number of pages6
JournalNature Genetics
Issue number5
Publication statusPublished - May 2012

Bibliographical note

Funding Information:
Framingham Heart Study (FHS): This study is carried out by the US NHLBI of the NIH and Boston University School of Medicine. This work was supported by the Framingham Heart Study of the NHLBI (N01-HC-25195) and its contract with Affymetrix, Inc, for genotyping services (N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950), the NHLBI (HL093029) and the NIA (AG08122, AG16495, AG033193, AG033040, AG031287 and P30AG013846).

Funding Information:
participants of the ASPS for their valuable contributions. We thank B. Reinhart for her long-term administrative commitment and I.J. Semmler for technical assistance in creating the DNA bank. The research reported here was funded by the Austrian Science Fond (FWF) (P20545-P05 and P13180). The Medical University of Graz supports the databank of the ASPS.

Funding Information:
The authors would like to thank all participating subjects and families from the Children’s Hospital in Philadelphia. The research was financially supported by an Institute Development Award from the Children’s Hospital of Philadelphia, a Research Development Award from the Cotswold Foundation and by the US NIH (1R01HD056465-01A1). The authors are grateful to the Raine Foundation, the RAINE Study families and the RAINE Study research staff. We gratefully acknowledge the assistance of the Western Australian Genetic Epidemiology Resource and the Western Australian DNA Bank (both National Health and Medical Research Council of Australia National Enabling Facilities). The authors also acknowledge the support of Healthway Western Australia, the National Health and Medical Research Council of Australia (572613) and the Canadian Institutes of Health Research (MOP 82893). We gratefully acknowledge the assistance of the Wind Over Water Foundation, the Telethon Institute for Child Health Research and the RAINE Medical Research Foundation of the University of Western Australia. The authors wish to acknowledge the following: Helmholtz Zentrum Muenchen–German Research Center for Environment and Health, Institute of Epidemiology; the Department of Pediatrics, University of Leipzig; Department of Pediatrics, Marien-Hospital; Bad Honnef; the Department of Human Exposure Research and Epidemiology, UFZ-Centre for Environmental Research Leipzig–Halle; the Department of Environmental Immunology, Zentrum für Umweltforschung (UFZ)-Centre for Environmental Research Leipzig–Halle; the Institut für Umweltmedizinische Forschung (IUF) and the Department of Pediatrics, Technical University. The UK MRC (74882), the Wellcome Trust (076467) and the University of Bristol provide core support for the Avon Longitudinal Study of Parents and Children (ALSPAC). We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.

Funding Information:
Rotterdam Study (RS): The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The authors thank P. Arp, M. Jhamai, M. Verkerk, L. Herrera and M. Peters for their help in creating the GWAS database and K. Estrada and M.V. Struchalin for their support in creation and analysis of imputed data. The generation and management of GWAS genotype data for the Rotterdam Study were supported by the Netherlands Organisation of Scientific Research (NWO) Investments (nr. 175.010.2005.011 and 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)-NWO project (nr. 050-060-810). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. The Rotterdam Scan Study is supported by the NWO (nrs. 918-46-615, 904-61-096, 904-61-133 and 948-00-010), the Nederlandse Hartstichting (2009B102) and the Internationaal Parkinson Fonds.

Funding Information:
was funded by the US National Institute on Aging (NIA) (N01-AG-12100), with contributions from the US National Eye Institute (NEI), National Institute on Deafness and Other Communication Disorders (NIDCD) and the NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).

Funding Information:
staff and participants of the ARIC study for their important contributions. Research is carried out as a collaborative study supported by the US NHLBI (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01-HL087641 and R01-HL093029), the National Human Genome Research Institute (U01-HG004402) and the NIH (HHSN268200625226C). Infrastructure was partly supported by a component of the NIH and NIH Roadmap for Medical Research (UL1RR025005).

Funding Information:
EGG Consortium: We gratefully acknowledge the contribution of general practitioners, hospitals, midwives and pharmacies in Rotterdam. Financial support was received from the Academy of Finland (104781, 120315, 1114194 and Center of Excellence in Complex Disease Genetics), University Hospital Oulu, Biocenter, University of Oulu, the US NHLBI (5R01HL087679-02, through the STAMPEED program 1RL1MH083268-01), the ENGAGE project and grant agreement HEALTH-F4-2007-201413, the UK MRC (G0500539 and PrevMetSyn/ Salve/MRC) and the Wellcome Trust (GR069224). DNA extraction, sample quality control, biobank upkeep and aliquotting were performed at the National Public Health Institute, Biomedicum Helsinki (Helsinki, Finland) and supported financially by the Academy of Finland and Biocentrum Helsinki. The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR). The Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development (ZonMw 21000074). V.J. received additional grants from the Netherlands Organization for Health Research and Development (ZonMw 90700303 and 916.10159). Additional support was provided by a grant from the Dutch Kidney Foundation (C08.2251).


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