Common genetic variants influence human subcortical brain structures

Derrek P Hibar; Jason L Stein; Miguel E Renteria; Alejandro Arias-Vasquez; Sylvane Desrivières; Neda Jahanshad; Roberto Toro; Katharina Wittfeld; Lucija Abramovic; Micael Andersson; Benjamin S Aribisala; Nicola J Armstrong; Manon Bernard; Marc M Bohlken; Marco P Boks; Janita Bralten; Andrew A Brown; M Mallar Chakravarty; Qiang Chen; Christopher R K Ching; Gabriel Cuellar-Partida; Anouk den Braber; Sudheer Giddaluru; Aaron L Goldman; Oliver Grimm; Tulio Guadalupe; Johanna Hass; Girma Woldehawariat; Avram J Holmes; Martine Hoogman; Deborah Janowitz; Tianye Jia; Sungeun Kim; Marieke Klein; Bernd Kraemer; Phil H Lee; Christine Macare; Adaikalavan Ramasamy; Esther Walton; Robert Johnson; Rocio Perez-Iglesias; Peter R Schofield; Robert W Williams; Gareth E Davies; Simon E Fisher; Simon Lovestone; Colm McDonald; Andy Simmons; Michael E Weale; Gunter Schumann; The Alzheimer’s Disease Neuroimaging Initiative

doi:10.1038/nature14101

Common genetic variants influence human subcortical brain structures

Derrek P Hibar, Jason L Stein, Miguel E Renteria, Alejandro Arias-Vasquez, Sylvane Desrivières, Neda Jahanshad, Roberto Toro, Katharina Wittfeld, Lucija Abramovic, Micael Andersson, Benjamin S Aribisala, Nicola J Armstrong, Manon Bernard, Marc M Bohlken, Marco P Boks, Janita Bralten, Andrew A Brown, M Mallar Chakravarty, Qiang Chen, Christopher R K ChingGabriel Cuellar-Partida, Anouk den Braber, Sudheer Giddaluru, Aaron L Goldman, Oliver Grimm, Tulio Guadalupe, Johanna Hass, Girma Woldehawariat, Avram J Holmes, Martine Hoogman, Deborah Janowitz, Tianye Jia, Sungeun Kim, Marieke Klein, Bernd Kraemer, Phil H Lee, Christine Macare, Adaikalavan Ramasamy, Esther Walton, Robert Johnson, Rocio Perez-Iglesias, Peter R Schofield, Robert W Williams, Gareth E Davies, Simon E Fisher, Simon Lovestone, Colm McDonald, Andy Simmons, Michael E Weale, Gunter Schumann, The Alzheimer’s Disease Neuroimaging Initiative

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

612 Citations (Scopus)

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
Pages (from-to)	224-229
Number of pages	21
Journal	NATURE
Volume	520
Issue number	7546
Early online date	21 Jan 2015
DOIs	https://doi.org/10.1038/nature14101
Publication status	Published - 9 Apr 2015

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Hibar, D. P., Stein, J. L., Renteria, M. E., Arias-Vasquez, A., Desrivières, S., Jahanshad, N., Toro, R., Wittfeld, K., Abramovic, L., Andersson, M., Aribisala, B. S., Armstrong, N. J., Bernard, M., Bohlken, M. M., Boks, M. P., Bralten, J., Brown, A. A., Mallar Chakravarty, M., Chen, Q., ... The Alzheimer’s Disease Neuroimaging Initiative (2015). Common genetic variants influence human subcortical brain structures. NATURE, 520(7546), 224-229. https://doi.org/10.1038/nature14101

@article{5428b4fef4b24887ac7f5b7287f5e142,

title = "Common genetic variants influence human subcortical brain structures",

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.",

author = "Hibar, {Derrek P} and Stein, {Jason L} and Renteria, {Miguel E} and Alejandro Arias-Vasquez and Sylvane Desrivi{\`e}res and Neda Jahanshad and Roberto Toro and Katharina Wittfeld and Lucija Abramovic and Micael Andersson and Aribisala, {Benjamin S} and Armstrong, {Nicola J} and Manon Bernard and Bohlken, {Marc M} and Boks, {Marco P} and Janita Bralten and Brown, {Andrew A} and {Mallar Chakravarty}, M and Qiang Chen and Ching, {Christopher R K} and Gabriel Cuellar-Partida and {den Braber}, Anouk and Sudheer Giddaluru and Goldman, {Aaron L} and Oliver Grimm and Tulio Guadalupe and Johanna Hass and Girma Woldehawariat and Holmes, {Avram J} and Martine Hoogman and Deborah Janowitz and Tianye Jia and Sungeun Kim and Marieke Klein and Bernd Kraemer and Lee, {Phil H} and Christine Macare and Adaikalavan Ramasamy and Esther Walton and Robert Johnson and Rocio Perez-Iglesias and Schofield, {Peter R} and Williams, {Robert W} and Davies, {Gareth E} and Fisher, {Simon E} and Simon Lovestone and Colm McDonald and Andy Simmons and Weale, {Michael E} and Gunter Schumann and {The Alzheimer{\textquoteright}s Disease Neuroimaging Initiative}",

year = "2015",

month = apr,

day = "9",

doi = "10.1038/nature14101",

language = "English",

volume = "520",

pages = "224--229",

journal = "NATURE",

issn = "0028-0836",

publisher = "Nature Publishing Group",

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Hibar, DP, Stein, JL, Renteria, ME, Arias-Vasquez, A, Desrivières, S, Jahanshad, N, Toro, R, Wittfeld, K, Abramovic, L, Andersson, M, Aribisala, BS, Armstrong, NJ, Bernard, M, Bohlken, MM, Boks, MP, Bralten, J, Brown, AA, Mallar Chakravarty, M, Chen, Q, Ching, CRK, Cuellar-Partida, G, den Braber, A, Giddaluru, S, Goldman, AL, Grimm, O, Guadalupe, T, Hass, J, Woldehawariat, G, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Kim, S, Klein, M, Kraemer, B, Lee, PH, Macare, C, Ramasamy, A, Walton, E , Johnson, R , Perez-Iglesias, R, Schofield, PR, Williams, RW , Davies, GE , Fisher, SE , Lovestone, S , McDonald, C , Simmons, A , Weale, ME , Schumann, G & The Alzheimer’s Disease Neuroimaging Initiative 2015, 'Common genetic variants influence human subcortical brain structures', NATURE, vol. 520, no. 7546, pp. 224-229. https://doi.org/10.1038/nature14101

TY - JOUR

T1 - Common genetic variants influence human subcortical brain structures

AU - Hibar, Derrek P

AU - Stein, Jason L

AU - Renteria, Miguel E

AU - Arias-Vasquez, Alejandro

AU - Desrivières, Sylvane

AU - Jahanshad, Neda

AU - Toro, Roberto

AU - Wittfeld, Katharina

AU - Abramovic, Lucija

AU - Andersson, Micael

AU - Aribisala, Benjamin S

AU - Armstrong, Nicola J

AU - Bernard, Manon

AU - Bohlken, Marc M

AU - Boks, Marco P

AU - Bralten, Janita

AU - Brown, Andrew A

AU - Mallar Chakravarty, M

AU - Chen, Qiang

AU - Ching, Christopher R K

AU - Cuellar-Partida, Gabriel

AU - den Braber, Anouk

AU - Giddaluru, Sudheer

AU - Goldman, Aaron L

AU - Grimm, Oliver

AU - Guadalupe, Tulio

AU - Hass, Johanna

AU - Woldehawariat, Girma

AU - Holmes, Avram J

AU - Hoogman, Martine

AU - Janowitz, Deborah

AU - Jia, Tianye

AU - Kim, Sungeun

AU - Klein, Marieke

AU - Kraemer, Bernd

AU - Lee, Phil H

AU - Macare, Christine

AU - Ramasamy, Adaikalavan

AU - Walton, Esther

AU - Johnson, Robert

AU - Perez-Iglesias, Rocio

AU - Schofield, Peter R

AU - Williams, Robert W

AU - Davies, Gareth E

AU - Fisher, Simon E

AU - Lovestone, Simon

AU - McDonald, Colm

AU - Simmons, Andy

AU - Weale, Michael E

AU - Schumann, Gunter

AU - The Alzheimer’s Disease Neuroimaging Initiative

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.

U2 - 10.1038/nature14101

DO - 10.1038/nature14101

M3 - Article

C2 - 25607358

SN - 0028-0836

VL - 520

SP - 224

EP - 229

JO - NATURE

JF - NATURE

IS - 7546

ER -

Common genetic variants influence human subcortical brain structures

Abstract

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