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 journalArticle

77 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 languageEnglish (US)
Pages (from-to)539-544
Number of pages6
JournalNature Genetics
Volume44
Issue number5
DOIs
StatePublished - May 2012

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Brain
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Independent Living
Biological Phenomena
Genome-Wide Association Study
Chromosomes
Genome

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  • Genetics

Cite this

Ikram, M. A., Fornage, M., Smith, A. V., Seshadri, S., Schmidt, R., Debette, S., ... 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

Common variants at 6q22 and 17q21 are associated with intracranial volume. / Ikram, M. Arfan; Fornage, Myriam; Smith, Albert V.; Seshadri, Sudha; Schmidt, Reinhold; Debette, Stéphanie; Vrooman, Henri A.; Sigurdsson, Sigurdur; Ropele, Stefan; Taal, H. Rob; Mook-Kanamori, Dennis O.; Coker, Laura H.; Longstreth, W. T.; Niessen, Wiro J.; Destefano, Anita L.; Beiser, Alexa; Zijdenbos, Alex P.; Struchalin, Maksim; Jack, Clifford R.; Rivadeneira, Fernando; Uitterlinden, Andre G.; Knopman, David S.; Hartikainen, Anna Liisa; Pennell, Craig E.; Thiering, Elisabeth; Steegers, Eric A P; Hakonarson, Hakon; Heinrich, Joachim; Palmer, Lyle J.; Jarvelin, Marjo Riitta; Mccarthy, Mark I.; Grant, Struan F A; Pourcain, Beate St; Timpson, Nicholas J.; Smith, George Davey; Sovio, Ulla; Nalls, Mike A.; Au, Rhoda; Hofman, Albert; Gudnason, Haukur; Van Der Lugt, Aad; Harris, Tamara B.; Meeks, William M.; Vernooij, Meike W.; Van Buchem, Mark A.; Catellier, Diane; Jaddoe, Vincent W V; Gudnason, Vilmundur; Windham, B. Gwen; Wolf, Philip A.; Van Duijn, Cornelia M.; Mosley, Thomas H.; Schmidt, Helena; Launer, Lenore J.; Breteler, Monique M B; DeCarli, Charles; Adair, Linda S.; Ang, Wei; Atalay, Mustafa; Van Beijsterveldt, Toos; Bergen, Nienke; Benke, Kelly; Berry, Diane; Coin, Lachlan; Davis, Oliver S P; Elliott, Paul; Flexeder, Claudia; Frayling, Tim; Gaillard, Romy; Groen-Blokhuis, Maria; Goh, Liang Kee; Haworth, Claire M A; Hadley, Dexter; Hedebrand, Johannes; Hinney, Anke; Hirschhorn, Joel N.; Holloway, John W.; Holst, Claus; Jan Hottenga, Jouke; Horikoshi, Momoko; Huikari, Ville; Hypponen, Elina; Kilpeläinen, Tuomas O.; Kirin, Mirna; Kowgier, Matthew; Lakka, Hanna Maaria; Lange, Leslie A.; Lawlor, Debbie A.; Lehtimäki, Terho; Lewin, Alex; Lindgren, Cecilia; Lindi, Virpi; Maggi, Reedik; Marsh, Julie; Middeldorp, Christel; Millwood, Iona; Murray, Jeffrey C.; Nivard, Michel; Nohr, Ellen Aagaard; Ntalla, Ioanna; Oken, Emily; Panoutsopoulou, Kalliope; Pararajasingham, Jennifer; Rodriguez, Alina; Salem, Rany M.; Sebert, Sylvain; Siitonen, Niina; Strachan, David P.; Teo, Yik Ying; Valcárcel, Beatriz; Willemsen, Gonneke; Zeggini, Eleftheria; Boomsma, Dorret I.; Cooper, Cyrus; Gillman, Matthew; Hocher, Berthold; Lakka, Timo A.; Mohlke, Karen L.; Dedoussis, George V.; Ong, Ken K.; Pearson, Ewan R.; Price, Thomas S.; Power, Chris; Raitakari, Olli T.; Saw, Seang Mei; Scherag, Andre; Simell, Olli; Sørensen, Thorkild I A; Wilson, James F.

In: Nature Genetics, Vol. 44, No. 5, 05.2012, p. 539-544.

Research output: Contribution to journalArticle

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
Ikram MA, Fornage M, Smith AV, Seshadri S, Schmidt R, Debette S et al. Common variants at 6q22 and 17q21 are associated with intracranial volume. Nature Genetics. 2012 May;44(5):539-544. https://doi.org/10.1038/ng.2245
Ikram, M. Arfan ; Fornage, Myriam ; Smith, Albert V. ; Seshadri, Sudha ; Schmidt, Reinhold ; Debette, Stéphanie ; Vrooman, Henri A. ; Sigurdsson, Sigurdur ; Ropele, Stefan ; Taal, H. Rob ; Mook-Kanamori, Dennis O. ; Coker, Laura H. ; Longstreth, W. T. ; Niessen, Wiro J. ; Destefano, Anita L. ; Beiser, Alexa ; Zijdenbos, Alex P. ; Struchalin, Maksim ; Jack, Clifford R. ; Rivadeneira, Fernando ; Uitterlinden, Andre G. ; Knopman, David S. ; Hartikainen, Anna Liisa ; Pennell, Craig E. ; Thiering, Elisabeth ; Steegers, Eric A P ; Hakonarson, Hakon ; Heinrich, Joachim ; Palmer, Lyle J. ; Jarvelin, Marjo Riitta ; Mccarthy, Mark I. ; Grant, Struan F A ; Pourcain, Beate St ; Timpson, Nicholas J. ; Smith, George Davey ; Sovio, Ulla ; Nalls, Mike A. ; Au, Rhoda ; Hofman, Albert ; Gudnason, Haukur ; Van Der Lugt, Aad ; Harris, Tamara B. ; Meeks, William M. ; Vernooij, Meike W. ; Van Buchem, Mark A. ; Catellier, Diane ; Jaddoe, Vincent W V ; Gudnason, Vilmundur ; Windham, B. Gwen ; Wolf, Philip A. ; Van Duijn, Cornelia M. ; Mosley, Thomas H. ; Schmidt, Helena ; Launer, Lenore J. ; Breteler, Monique M B ; DeCarli, Charles ; Adair, Linda S. ; Ang, Wei ; Atalay, Mustafa ; Van Beijsterveldt, Toos ; Bergen, Nienke ; Benke, Kelly ; Berry, Diane ; Coin, Lachlan ; Davis, Oliver S P ; Elliott, Paul ; Flexeder, Claudia ; Frayling, Tim ; Gaillard, Romy ; Groen-Blokhuis, Maria ; Goh, Liang Kee ; Haworth, Claire M A ; Hadley, Dexter ; Hedebrand, Johannes ; Hinney, Anke ; Hirschhorn, Joel N. ; Holloway, John W. ; Holst, Claus ; Jan Hottenga, Jouke ; Horikoshi, Momoko ; Huikari, Ville ; Hypponen, Elina ; Kilpeläinen, Tuomas O. ; Kirin, Mirna ; Kowgier, Matthew ; Lakka, Hanna Maaria ; Lange, Leslie A. ; Lawlor, Debbie A. ; Lehtimäki, Terho ; Lewin, Alex ; Lindgren, Cecilia ; Lindi, Virpi ; Maggi, Reedik ; Marsh, Julie ; Middeldorp, Christel ; Millwood, Iona ; Murray, Jeffrey C. ; Nivard, Michel ; Nohr, Ellen Aagaard ; Ntalla, Ioanna ; Oken, Emily ; Panoutsopoulou, Kalliope ; Pararajasingham, Jennifer ; Rodriguez, Alina ; Salem, Rany M. ; Sebert, Sylvain ; Siitonen, Niina ; Strachan, David P. ; Teo, Yik Ying ; Valcárcel, Beatriz ; Willemsen, Gonneke ; Zeggini, Eleftheria ; Boomsma, Dorret I. ; Cooper, Cyrus ; Gillman, Matthew ; Hocher, Berthold ; Lakka, Timo A. ; Mohlke, Karen L. ; Dedoussis, George V. ; Ong, Ken K. ; Pearson, Ewan R. ; Price, Thomas S. ; Power, Chris ; Raitakari, Olli T. ; Saw, Seang Mei ; Scherag, Andre ; Simell, Olli ; Sørensen, Thorkild I A ; Wilson, James F. / Common variants at 6q22 and 17q21 are associated with intracranial volume. In: Nature Genetics. 2012 ; Vol. 44, No. 5. pp. 539-544.
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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.",
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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.

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.

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