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

M. Arfan Ikram, Myriam Fornage, Albert V. Smith, Sudha Seshadri, Reinhold Schmidt, Stephanie 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 Rivadeneira, Andre 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 vanBeijsterveldt, 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 Hebebrand, Anke Hinney, Joel N. Hirschhorn, John W. Holloway, Claus Holst, Jouke Jan Hottenga, Momoko Horikoshi, Ville Huikari, Elina Hypponen, Tuomas O. Kilpelainen, Mirna Kirin, Matthew Kowgier, Hanna-Maaria Lakka, Leslie A. Lange, Debbie A. Lawlor, Terho Lehtimaki, 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 Valcarcel, 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. Sorensen, James F. Wilson

  • 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 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 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 x 10(-3) for 6q22 and 1.2 x 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 associatedDuring 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 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 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 x 10(-3) for 6q22 and 1.2 x 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.show moreshow less

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Author:M. Arfan Ikram, Myriam Fornage, Albert V. Smith, Sudha Seshadri, Reinhold Schmidt, Stephanie 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 Rivadeneira, Andre 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 vanBeijsterveldt, 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 Hebebrand, Anke Hinney, Joel N. Hirschhorn, John W. Holloway, Claus Holst, Jouke Jan Hottenga, Momoko Horikoshi, Ville Huikari, Elina Hypponen, Tuomas O. Kilpelainen, Mirna Kirin, Matthew Kowgier, Hanna-Maaria Lakka, Leslie A. Lange, Debbie A. Lawlor, Terho Lehtimaki, 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 Valcarcel, Gonneke Willemsen, Eleftheria Zeggini, Dorret I. Boomsma, Cyrus Cooper, Matthew Gillman, Berthold HocherGND, 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. Sorensen, James F. Wilson
DOI:https://doi.org/10.1038/ng.2245
ISSN:1061-4036 (print)
Parent Title (English):Nature genetics
Publisher:Nature Publ. Group
Place of publication:New York
Document Type:Article
Language:English
Year of first Publication:2012
Year of Completion:2012
Creating Corporation:Early Growth Genetics EGG Consorti, Cohorts Heart Aging Res Genomic Ep
Release Date:2017/03/26
Volume:44
Issue:5
Pagenumber:7
First Page:539
Last Page:+
Funder:US National Institute on Aging (NIA) [N01-AG-12100]; 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, R01-HL093029]; National Human Genome Research Institute [U01-HG004402]; NIH [HHSN268200625226C]; NIH Roadmap for Medical Research [UL1RR025005]; Austrian Science Fond (FWF) [P20545-P05, P13180]; Framingham Heart Study of the NHLBI [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; National Institute of Neurological Disorders and Stroke [NS17950]; NHLBI [HL093029, 5R01HL087679-02, 1RL1MH083268-01]; NIA [AG08122, AG16495, AG033193, AG033040, AG031287, P30AG013846]; Netherlands Organisation of Scientific Research (NWO) [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)- NWO [050-060-810]; Erasmus Medical Center; Erasmus University Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; NWO [918-46-615, 904-61-096, 904-61-133, 948-00-010]; Nederlandse Hartstichting [2009B102]; Internationaal Parkinson Fonds; Academy of Finland [104781, 120315, 1114194]; University Hospital Oulu, Biocenter, University of Oulu; ENGAGE; UK MRC [G0500539, 74882]; Wellcome Trust [GR069224, 076467]; Biocentrum Helsinki; Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development (ZonMw) [21000074, 90700303, 916.10159]; Dutch Kidney Foundation [C08.2251]; Children's Hospital of Philadelphia; Cotswold Foundation; US NIH [1R01HD056465-01A1]; Healthway Western Australia; National Health and Medical Research Council of Australia [572613]; Canadian Institutes of Health Research [MOP 82893]; University of Bristol; [HEALTH-F4-2007-201413]
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft
Peer Review:Referiert