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 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 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

doi:10.1038/ng.2245

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

Research output: Contribution to journal › Article › peer-review

97 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	539-544
Number of pages	6
Journal	Nature Genetics
Volume	44
Issue number	5
DOIs	https://doi.org/10.1038/ng.2245
Publication status	Published or Issued - May 2012

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/ng.2245

Cite this

Ikram, M. A., Fornage, M., Smith, A. V., Seshadri, S., Schmidt, R., Debette, S., Vrooman, H. A., Sigurdsson, S., Ropele, S., Taal, H. R., Mook-Kanamori, D. O., Coker, L. H., Longstreth, W. T., Niessen, W. J., Destefano, A. L., Beiser, A., Zijdenbos, A. P., Struchalin, M., Jack, C. R., ... Wilson, J. F. (2012). Common variants at 6q22 and 17q21 are associated with intracranial volume. Nature Genetics, 44(5), 539-544. https://doi.org/10.1038/ng.2245

@article{51901d501c924a9392d0b06aefec44f2,

title = "Common variants at 6q22 and 17q21 are associated with intracranial volume",

abstract = "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.",

author = "Ikram, {M. Arfan} and Myriam Fornage and Smith, {Albert V.} and Sudha Seshadri and Reinhold Schmidt and St{\'e}phanie Debette and Vrooman, {Henri A.} and Sigurdur Sigurdsson and Stefan Ropele and Taal, {H. Rob} and Mook-Kanamori, {Dennis O.} and Coker, {Laura H.} and Longstreth, {W. T.} and Niessen, {Wiro J.} and Destefano, {Anita L.} and Alexa Beiser and Zijdenbos, {Alex P.} and Maksim Struchalin and Jack, {Clifford R.} and Fernando Rivadeneira and Uitterlinden, {Andre G.} and Knopman, {David S.} and Hartikainen, {Anna Liisa} and Pennell, {Craig E.} and Elisabeth Thiering and Steegers, {Eric A P} and Hakon Hakonarson and Joachim Heinrich and Palmer, {Lyle J.} and Jarvelin, {Marjo Riitta} and Mccarthy, {Mark I.} and Grant, {Struan F A} and Pourcain, {Beate St} and Timpson, {Nicholas J.} and Smith, {George Davey} and Ulla Sovio and Nalls, {Mike A.} and Rhoda Au and Albert Hofman and Haukur Gudnason and {Van Der Lugt}, Aad and Harris, {Tamara B.} and Meeks, {William M.} and Vernooij, {Meike W.} and {Van Buchem}, {Mark A.} and Diane Catellier and Jaddoe, {Vincent W V} and Vilmundur Gudnason and Windham, {B. Gwen} and Wolf, {Philip A.} and {Van Duijn}, {Cornelia M.} and Mosley, {Thomas H.} and Helena Schmidt and Launer, {Lenore J.} and Breteler, {Monique M B} and Charles Decarli and Adair, {Linda S.} and Wei Ang and Mustafa Atalay and {Van Beijsterveldt}, Toos and Nienke Bergen and Kelly Benke and Diane Berry and Lachlan Coin and Davis, {Oliver S P} and Paul Elliott and Claudia Flexeder and Tim Frayling and Romy Gaillard and Maria Groen-Blokhuis and Goh, {Liang Kee} and Haworth, {Claire M A} and Dexter Hadley and Johannes Hedebrand and Anke Hinney and Hirschhorn, {Joel N.} and Holloway, {John W.} and Claus Holst and {Jan Hottenga}, Jouke and Momoko Horikoshi and Ville Huikari and Elina Hypponen and Kilpel{\"a}inen, {Tuomas O.} and Mirna Kirin and Matthew Kowgier and Lakka, {Hanna Maaria} and Lange, {Leslie A.} and Lawlor, {Debbie A.} and Terho Lehtim{\"a}ki and Alex Lewin and Cecilia Lindgren and Virpi Lindi and Reedik Maggi and Julie Marsh and Christel Middeldorp and Iona Millwood and Murray, {Jeffrey C.} and Michel Nivard and Nohr, {Ellen Aagaard} and Ioanna Ntalla and Emily Oken and Kalliope Panoutsopoulou and Jennifer Pararajasingham and Alina Rodriguez and Salem, {Rany M.} and Sylvain Sebert and Niina Siitonen and Strachan, {David P.} and Teo, {Yik Ying} and Beatriz Valc{\'a}rcel and Gonneke Willemsen and Eleftheria Zeggini and Boomsma, {Dorret I.} and Cyrus Cooper and Matthew Gillman and Berthold Hocher and Lakka, {Timo A.} and Mohlke, {Karen L.} and Dedoussis, {George V.} and Ong, {Ken K.} and Pearson, {Ewan R.} and Price, {Thomas S.} and Chris Power and Raitakari, {Olli T.} and Saw, {Seang Mei} and Andre Scherag and Olli Simell and S{\o}rensen, {Thorkild I A} and Wilson, {James F.}",

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{\textquoteright}s Hospital in Philadelphia. The research was financially supported by an Institute Development Award from the Children{\textquoteright}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 f{\"u}r Umweltforschung (UFZ)-Centre for Environmental Research Leipzig–Halle; the Institut f{\"u}r 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).",

year = "2012",

month = may,

doi = "10.1038/ng.2245",

language = "English",

volume = "44",

pages = "539--544",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

}

Ikram, MA, Fornage, M, Smith, AV, Seshadri, S, Schmidt, R, Debette, S, Vrooman, HA, Sigurdsson, S, Ropele, S, Taal, HR, Mook-Kanamori, DO, Coker, LH, Longstreth, WT, Niessen, WJ, Destefano, AL, Beiser, A, Zijdenbos, AP, Struchalin, M, Jack, CR, Rivadeneira, F, Uitterlinden, AG, Knopman, DS, Hartikainen, AL, Pennell, CE, Thiering, E, Steegers, EAP, Hakonarson, H, Heinrich, J, Palmer, LJ, Jarvelin, MR, Mccarthy, MI, Grant, SFA, Pourcain, BS, Timpson, NJ, Smith, GD, Sovio, U, Nalls, MA, Au, R, Hofman, A, Gudnason, H, Van Der Lugt, A, Harris, TB, Meeks, WM, Vernooij, MW, Van Buchem, MA, Catellier, D, Jaddoe, VWV, Gudnason, V, Windham, BG, Wolf, PA, Van Duijn, CM, Mosley, TH, Schmidt, H, Launer, LJ, Breteler, MMB, Decarli, C, Adair, LS, Ang, W, Atalay, M, Van Beijsterveldt, T, Bergen, N, Benke, K, Berry, D, Coin, L, Davis, OSP, Elliott, P, Flexeder, C, Frayling, T, Gaillard, R, Groen-Blokhuis, M, Goh, LK, Haworth, CMA, Hadley, D, Hedebrand, J, Hinney, A, Hirschhorn, JN, Holloway, JW, Holst, C, Jan Hottenga, J, Horikoshi, M, Huikari, V, Hypponen, E, Kilpeläinen, TO, Kirin, M, Kowgier, M, Lakka, HM, Lange, LA, Lawlor, DA, Lehtimäki, T, Lewin, A, Lindgren, C, Lindi, V, Maggi, R, Marsh, J, Middeldorp, C, Millwood, I, Murray, JC, Nivard, M, Nohr, EA, Ntalla, I, Oken, E, Panoutsopoulou, K, Pararajasingham, J, Rodriguez, A, Salem, RM, Sebert, S, Siitonen, N, Strachan, DP, Teo, YY, Valcárcel, B, Willemsen, G, Zeggini, E, Boomsma, DI, Cooper, C, Gillman, M, Hocher, B, Lakka, TA, Mohlke, KL, Dedoussis, GV, Ong, KK, Pearson, ER, Price, TS, Power, C, Raitakari, OT, Saw, SM, Scherag, A, Simell, O, Sørensen, TIA & Wilson, JF 2012, 'Common variants at 6q22 and 17q21 are associated with intracranial volume', Nature Genetics, vol. 44, no. 5, pp. 539-544. https://doi.org/10.1038/ng.2245

TY - JOUR

T1 - Common variants at 6q22 and 17q21 are associated with intracranial volume

AU - Ikram, M. Arfan

AU - Fornage, Myriam

AU - Smith, Albert V.

AU - Seshadri, Sudha

AU - Schmidt, Reinhold

AU - Debette, Stéphanie

AU - Vrooman, Henri A.

AU - Sigurdsson, Sigurdur

AU - Ropele, Stefan

AU - Taal, H. Rob

AU - Mook-Kanamori, Dennis O.

AU - Coker, Laura H.

AU - Longstreth, W. T.

AU - Niessen, Wiro J.

AU - Destefano, Anita L.

AU - Beiser, Alexa

AU - Zijdenbos, Alex P.

AU - Struchalin, Maksim

AU - Jack, Clifford R.

AU - Rivadeneira, Fernando

AU - Uitterlinden, Andre G.

AU - Knopman, David S.

AU - Hartikainen, Anna Liisa

AU - Pennell, Craig E.

AU - Thiering, Elisabeth

AU - Steegers, Eric A P

AU - Hakonarson, Hakon

AU - Heinrich, Joachim

AU - Palmer, Lyle J.

AU - Jarvelin, Marjo Riitta

AU - Mccarthy, Mark I.

AU - Grant, Struan F A

AU - Pourcain, Beate St

AU - Timpson, Nicholas J.

AU - Smith, George Davey

AU - Sovio, Ulla

AU - Nalls, Mike A.

AU - Au, Rhoda

AU - Hofman, Albert

AU - Gudnason, Haukur

AU - Van Der Lugt, Aad

AU - Harris, Tamara B.

AU - Meeks, William M.

AU - Vernooij, Meike W.

AU - Van Buchem, Mark A.

AU - Catellier, Diane

AU - Jaddoe, Vincent W V

AU - Gudnason, Vilmundur

AU - Windham, B. Gwen

AU - Wolf, Philip A.

AU - Van Duijn, Cornelia M.

AU - Mosley, Thomas H.

AU - Schmidt, Helena

AU - Launer, Lenore J.

AU - Breteler, Monique M B

AU - Decarli, Charles

AU - Adair, Linda S.

AU - Ang, Wei

AU - Atalay, Mustafa

AU - Van Beijsterveldt, Toos

AU - Bergen, Nienke

AU - Benke, Kelly

AU - Berry, Diane

AU - Coin, Lachlan

AU - Davis, Oliver S P

AU - Elliott, Paul

AU - Flexeder, Claudia

AU - Frayling, Tim

AU - Gaillard, Romy

AU - Groen-Blokhuis, Maria

AU - Goh, Liang Kee

AU - Haworth, Claire M A

AU - Hadley, Dexter

AU - Hedebrand, Johannes

AU - Hinney, Anke

AU - Hirschhorn, Joel N.

AU - Holloway, John W.

AU - Holst, Claus

AU - Jan Hottenga, Jouke

AU - Horikoshi, Momoko

AU - Huikari, Ville

AU - Hypponen, Elina

AU - Kilpeläinen, Tuomas O.

AU - Kirin, Mirna

AU - Kowgier, Matthew

AU - Lakka, Hanna Maaria

AU - Lange, Leslie A.

AU - Lawlor, Debbie A.

AU - Lehtimäki, Terho

AU - Lewin, Alex

AU - Lindgren, Cecilia

AU - Lindi, Virpi

AU - Maggi, Reedik

AU - Marsh, Julie

AU - Middeldorp, Christel

AU - Millwood, Iona

AU - Murray, Jeffrey C.

AU - Nivard, Michel

AU - Nohr, Ellen Aagaard

AU - Ntalla, Ioanna

AU - Oken, Emily

AU - Panoutsopoulou, Kalliope

AU - Pararajasingham, Jennifer

AU - Rodriguez, Alina

AU - Salem, Rany M.

AU - Sebert, Sylvain

AU - Siitonen, Niina

AU - Strachan, David P.

AU - Teo, Yik Ying

AU - Valcárcel, Beatriz

AU - Willemsen, Gonneke

AU - Zeggini, Eleftheria

AU - Boomsma, Dorret I.

AU - Cooper, Cyrus

AU - Gillman, Matthew

AU - Hocher, Berthold

AU - Lakka, Timo A.

AU - Mohlke, Karen L.

AU - Dedoussis, George V.

AU - Ong, Ken K.

AU - Pearson, Ewan R.

AU - Price, Thomas S.

AU - Power, Chris

AU - Raitakari, Olli T.

AU - Saw, Seang Mei

AU - Scherag, Andre

AU - Simell, Olli

AU - Sørensen, Thorkild I A

AU - Wilson, James F.

N1 - 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).

PY - 2012/5

Y1 - 2012/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84860342407&partnerID=8YFLogxK

U2 - 10.1038/ng.2245

DO - 10.1038/ng.2245

M3 - Article

C2 - 22504418

AN - SCOPUS:84860342407

SN - 1061-4036

VL - 44

SP - 539

EP - 544

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

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

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