Abstract
The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08×10 -33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 224-229 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 520 |
| Issue number | 7546 |
| DOIs | |
| State | Published - Apr 9 2015 |
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In: Nature, Vol. 520, No. 7546, 09.04.2015, p. 224-229.
Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Common genetic variants influence human subcortical brain structures
AU - Hibar, Derrek P.
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AU - Van Donkelaar, Marjolein M.J.
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AU - Steen, Vidar M.
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AU - Djurovic, Srdjan
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AU - Kahn, René S.
AU - Le Hellard, Stephanie
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AU - Müller-Myhsok, Bertram
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AU - Nyberg, Lars
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AU - Penninx, Brenda W.J.H.
AU - Roffman, Joshua L.
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AU - Smoller, Jordan W.
AU - Van Bokhoven, Hans
AU - Van Haren, Neeltje E.M.
AU - Völzke, Henry
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AU - Agartz, Ingrid
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AU - Francks, Clyde
AU - Glahn, David C.
AU - Grabe, Hans J.
AU - Gruber, Oliver
AU - Hardy, John
AU - Hashimoto, Ryota
AU - Hulshoff Pol, Hilleke E.
AU - Jönsson, Erik G.
AU - Kloszewska, Iwona
AU - Lovestone, Simon
AU - Mattay, Venkata S.
AU - Mecocci, Patrizia
AU - McDonald, Colm
AU - McIntosh, Andrew M.
AU - Ophoff, Roel A.
AU - Paus, Tomas
AU - Pausova, Zdenka
AU - Ryten, Mina
AU - Sachdev, Perminder S.
AU - Saykin, Andrew J.
AU - Simmons, Andy
AU - Singleton, Andrew
AU - Soininen, Hilkka
AU - Wardlaw, Joanna M.
AU - Weale, Michael E.
AU - Weinberger, Daniel R.
AU - Adams, Hieab H.H.
AU - Launer, Lenore J.
AU - Seiler, Stephan
AU - Schmidt, Reinhold
AU - Chauhan, Ganesh
AU - Satizabal, Claudia L.
AU - Becker, James T.
AU - Yanek, Lisa
AU - Van Der Lee, Sven J.
AU - Ebling, Maritza
AU - Fischl, Bruce
AU - Longstreth, W. T.
AU - Greve, Douglas
AU - Schmidt, Helena
AU - Nyquist, Paul
AU - Vinke, Louis N.
AU - Van Duijn, Cornelia M.
AU - Xue, Luting
AU - Mazoyer, Bernard
AU - Bis, Joshua C.
AU - Gudnason, Vilmundur
AU - Seshadri, Sudha
AU - Ikram, M. Arfan
AU - Martin, Nicholas G.
AU - Wright, Margaret J.
AU - Schumann, Gunter
AU - Franke, Barbara
AU - Thompson, Paul M.
AU - Medland, Sarah E.
N1 - Publisher Copyright: ©2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/4/9
Y1 - 2015/4/9
N2 - The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08×10 -33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
AB - The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08×10 -33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
UR - http://www.scopus.com/inward/record.url?scp=84926395609&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84926395609&partnerID=8YFLogxK
U2 - 10.1038/nature14101
DO - 10.1038/nature14101
M3 - Article
C2 - 25607358
AN - SCOPUS:84926395609
SN - 0028-0836
VL - 520
SP - 224
EP - 229
JO - Nature
JF - Nature
IS - 7546
ER -