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 Hedebrand; 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

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, 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 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 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 Hedebrand, 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

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 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.</p>

Original language	English
Pages (from-to)	539-544
Number of pages	7
Journal	Nature Genetics
Volume	44
Issue number	5
DOIs	https://doi.org/10.1038/ng.2245
Publication status	Published - May 2012

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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{9b1bce763e9c4bbc8c684929b0b8d852,

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 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.",

author = "Ikram, {M. Arfan} and Myriam Fornage and Smith, {Albert V.} and Sudha Seshadri and Reinhold Schmidt and Stephanie 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 Anna-Liisa Hartikainen and Pennell, {Craig E.} and Elisabeth Thiering and Steegers, {Eric A. P.} and Hakon Hakonarson and Joachim Heinrich and Palmer, {Lyle J.} and Marjo-Riitta Jarvelin and McCarthy, {Mark I.} and Grant, {Struan F. A.} and {St Pourcain}, Beate 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 Toos vanBeijsterveldt 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 Liang-Kee Goh 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 Hottenga, {Jouke Jan} and Momoko Horikoshi and Ville Huikari and Elina Hypponen and Kilpelainen, {Tuomas O.} and Mirna Kirin and Matthew Kowgier and Hanna-Maaria Lakka and Lange, {Leslie A.} and Lawlor, {Debbie A.} and Terho Lehtimaki 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 Yik-Ying Teo and Beatriz Valcarcel 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 Seang-Mei Saw and Andre Scherag and Olli Simell and Sorensen, {Thorkild I. A.} and Wilson, {James F.}",

year = "2012",

month = may,

doi = "10.1038/ng.2245",

language = "English",

volume = "44",

pages = "539--544",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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, A-L, Pennell, CE, Thiering, E, Steegers, EAP, Hakonarson, H, Heinrich, J, Palmer, LJ, Jarvelin, M-R, McCarthy, MI, Grant, SFA, St Pourcain, B, 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, vanBeijsterveldt, T, Bergen, N, Benke, K, Berry, D, Coin, L, Davis, OSP, Elliott, P, Flexeder, C, Frayling, T, Gaillard, R, Groen-Blokhuis, M, Goh, L-K, Haworth, CMA, Hadley, D, Hedebrand, J, Hinney, A, Hirschhorn, JN, Holloway, JW, Holst, C, Hottenga, JJ, Horikoshi, M, Huikari, V, Hypponen, E, Kilpelainen, TO, Kirin, M, Kowgier, M, Lakka, H-M, Lange, LA, Lawlor, DA, Lehtimaki, 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, Y-Y, Valcarcel, 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, S-M, Scherag, A, Simell, O, Sorensen, 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, Stephanie

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 - St Pourcain, Beate

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 - vanBeijsterveldt, 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 - Hottenga, Jouke Jan

AU - Horikoshi, Momoko

AU - Huikari, Ville

AU - Hypponen, Elina

AU - Kilpelainen, Tuomas O.

AU - Kirin, Mirna

AU - Kowgier, Matthew

AU - Lakka, Hanna-Maaria

AU - Lange, Leslie A.

AU - Lawlor, Debbie A.

AU - Lehtimaki, 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 - Valcarcel, 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 - Sorensen, 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 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.

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 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.

U2 - 10.1038/ng.2245

DO - 10.1038/ng.2245

M3 - Article

C2 - 22504418

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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