Genetic architecture of subcortical brain structures in 38,851 individuals

Claudia L. Satizabal; Hieab H. H. Adams; Derrek P. Hibar; Charles C. White; Maria J. Knol; Jason L. Stein; Markus Scholz; Muralidharan Sargurupremraj; Neda Jahanshad; Gennady Roshchupkin; Albert Smith; Joshua C. Bis; Xueqiu Jian; Michelle Luciano; Edith Hofer; Alexander Teumer; Sven J. van der Lee; Jingyun Yang; Lisa R. Yanek; Tom Lee; Shuo Li; Yanhui Hu; Jia Yu Koh; John D. Eicher; Sylvane Desrivieres; Alejandro Arias-Vasquez; Ganesh Chauhan; Lavinia Athanasiu; Miguel E. Rentera; Sungeun Kim; David Hoehn; Nicola J. Armstrong; Qiang Chen; Avram J. Holmes; Anouk den Braber; Iwona Kloszewska; Micael Andersson; Thomas Espeseth; Oliver Grimm; Lucija Abramovic; Saud Alhusaini; Yuri Milaneschi; Martina Papmeyer; Tomas Axelsson; Stefan Ehrlich; Roberto Roiz-Santianez; Bernd Kraemer; Asta K. Haberg; Dennis van der Meer; Han G. Brunner; Author collaboration

doi:10.1038/s41588-019-0511-y

Genetic architecture of subcortical brain structures in 38,851 individuals

Claudia L. Satizabal^*, Hieab H. H. Adams, Derrek P. Hibar, Charles C. White, Maria J. Knol, Jason L. Stein, Markus Scholz, Muralidharan Sargurupremraj, Neda Jahanshad, Gennady Roshchupkin, Albert Smith, Joshua C. Bis, Xueqiu Jian, Michelle Luciano, Edith Hofer, Alexander Teumer, Sven J. van der Lee, Jingyun Yang, Lisa R. Yanek, Tom LeeShuo Li, Yanhui Hu, Jia Yu Koh, John D. Eicher, Sylvane Desrivieres, Alejandro Arias-Vasquez, Ganesh Chauhan, Lavinia Athanasiu, Miguel E. Rentera, Sungeun Kim, David Hoehn, Nicola J. Armstrong, Qiang Chen, Avram J. Holmes, Anouk den Braber, Iwona Kloszewska, Micael Andersson, Thomas Espeseth, Oliver Grimm, Lucija Abramovic, Saud Alhusaini, Yuri Milaneschi, Martina Papmeyer, Tomas Axelsson, Stefan Ehrlich, Roberto Roiz-Santianez, Bernd Kraemer, Asta K. Haberg, Dennis van der Meer, Han G. Brunner, Author collaboration

^*Corresponding author for this work

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

Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Original language	English
Pages (from-to)	1624-1636
Number of pages	16
Journal	Nature Genetics
Volume	51
Issue number	11
DOIs	https://doi.org/10.1038/s41588-019-0511-y
Publication status	Published - Nov 2019

Keywords

Genome-wide association
Ld score regression
Basal ganglia
Alkaline-phosphatase
Alzheimers-disease
Plasma-protein
Risk loci
Drosophila
Metaanalysis
Expression

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Satizabal, C. L., Adams, H. H. H., Hibar, D. P., White, C. C., Knol, M. J., Stein, J. L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G., Smith, A., Bis, J. C., Jian, X., Luciano, M., Hofer, E., Teumer, A., van der Lee, S. J., Yang, J., Yanek, L. R., ... Author collaboration (2019). Genetic architecture of subcortical brain structures in 38,851 individuals. Nature Genetics, 51(11), 1624-1636. https://doi.org/10.1038/s41588-019-0511-y

@article{9fd5ec80de254c27b6de413b0e81476f,

title = "Genetic architecture of subcortical brain structures in 38,851 individuals",

abstract = "Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.",

keywords = "Genome-wide association, Ld score regression, Basal ganglia, Alkaline-phosphatase, Alzheimers-disease, Plasma-protein, Risk loci, Drosophila, Metaanalysis, Expression",

author = "Satizabal, {Claudia L.} and Adams, {Hieab H. H.} and Hibar, {Derrek P.} and White, {Charles C.} and Knol, {Maria J.} and Stein, {Jason L.} and Markus Scholz and Muralidharan Sargurupremraj and Neda Jahanshad and Gennady Roshchupkin and Albert Smith and Bis, {Joshua C.} and Xueqiu Jian and Michelle Luciano and Edith Hofer and Alexander Teumer and {van der Lee}, {Sven J.} and Jingyun Yang and Yanek, {Lisa R.} and Tom Lee and Shuo Li and Yanhui Hu and Koh, {Jia Yu} and Eicher, {John D.} and Sylvane Desrivieres and Alejandro Arias-Vasquez and Ganesh Chauhan and Lavinia Athanasiu and Rentera, {Miguel E.} and Sungeun Kim and David Hoehn and Armstrong, {Nicola J.} and Qiang Chen and Holmes, {Avram J.} and {den Braber}, Anouk and Iwona Kloszewska and Micael Andersson and Thomas Espeseth and Oliver Grimm and Lucija Abramovic and Saud Alhusaini and Yuri Milaneschi and Martina Papmeyer and Tomas Axelsson and Stefan Ehrlich and Roberto Roiz-Santianez and Bernd Kraemer and Haberg, {Asta K.} and {van der Meer}, Dennis and Brunner, {Han G.} and {Author collaboration}",

note = "Funding Information: D.P.H. is currently an employee at Genentech. D.J. has received travel and speaker{\textquoteright}s honoraria from Janssen–Cilag, as well as research funding from DFG. R.L.B. is a consultant for Pfizer and Roche. P.A. is a scientific adviser for Genoscreen. T.Y.W. is a consultant and advisory board member for Allergan, Bayer, Boehringer–Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics) and Roche, and is a co-founder of Plano and EyRiS. A.M.M. has received grant support from Eli Lilly, Janssen, Pfizer and the Sackler Trust. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. A.M.-L. is a member of the advisory board for the Lundbeck International Neuroscience Foundation and Brainsway, a member of the editorial board for the American Association for the Advancement of Science and Elsevier, a faculty member of the Lundbeck International Neuroscience Foundation and a consultant for Boehringer Ingelheim. W.J.N. is the founder and scientific lead of Quantib BV, in addition to being a shareholder. M.M.N. is a shareholder of Life & Brain, receives a salary from Life & Brain, has received support from Shire for attending conferences and has received financial remuneration from the Lundbeck Foundation, Robert Bosch Foundation and Deutsches {\"A}rzteblatt for participation in scientific advisory boards. B.F. has received educational speaking fees from Shire and Medice. H.J.G. has received travel grants and speaker{\textquoteright}s honoraria from Fresenius Medical Care, Neuraxpharm and Janssen– Cilag, as well as research funding from Fresenius Medical Care. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = nov,

doi = "10.1038/s41588-019-0511-y",

language = "English",

volume = "51",

pages = "1624--1636",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "11",

}

Satizabal, CL, Adams, HHH, Hibar, DP, White, CC, Knol, MJ, Stein, JL, Scholz, M, Sargurupremraj, M, Jahanshad, N, Roshchupkin, G, Smith, A, Bis, JC, Jian, X, Luciano, M, Hofer, E, Teumer, A, van der Lee, SJ, Yang, J, Yanek, LR, Lee, T, Li, S, Hu, Y, Koh, JY, Eicher, JD, Desrivieres, S, Arias-Vasquez, A, Chauhan, G, Athanasiu, L, Rentera, ME, Kim, S, Hoehn, D, Armstrong, NJ, Chen, Q, Holmes, AJ, den Braber, A, Kloszewska, I, Andersson, M, Espeseth, T, Grimm, O, Abramovic, L, Alhusaini, S, Milaneschi, Y, Papmeyer, M, Axelsson, T, Ehrlich, S, Roiz-Santianez, R, Kraemer, B, Haberg, AK, van der Meer, D, Brunner, HG & Author collaboration 2019, 'Genetic architecture of subcortical brain structures in 38,851 individuals', Nature Genetics, vol. 51, no. 11, pp. 1624-1636. https://doi.org/10.1038/s41588-019-0511-y

TY - JOUR

T1 - Genetic architecture of subcortical brain structures in 38,851 individuals

AU - Satizabal, Claudia L.

AU - Adams, Hieab H. H.

AU - Hibar, Derrek P.

AU - White, Charles C.

AU - Knol, Maria J.

AU - Stein, Jason L.

AU - Scholz, Markus

AU - Sargurupremraj, Muralidharan

AU - Jahanshad, Neda

AU - Roshchupkin, Gennady

AU - Smith, Albert

AU - Bis, Joshua C.

AU - Jian, Xueqiu

AU - Luciano, Michelle

AU - Hofer, Edith

AU - Teumer, Alexander

AU - van der Lee, Sven J.

AU - Yang, Jingyun

AU - Yanek, Lisa R.

AU - Lee, Tom

AU - Li, Shuo

AU - Hu, Yanhui

AU - Koh, Jia Yu

AU - Eicher, John D.

AU - Desrivieres, Sylvane

AU - Arias-Vasquez, Alejandro

AU - Chauhan, Ganesh

AU - Athanasiu, Lavinia

AU - Rentera, Miguel E.

AU - Kim, Sungeun

AU - Hoehn, David

AU - Armstrong, Nicola J.

AU - Chen, Qiang

AU - Holmes, Avram J.

AU - den Braber, Anouk

AU - Kloszewska, Iwona

AU - Andersson, Micael

AU - Espeseth, Thomas

AU - Grimm, Oliver

AU - Abramovic, Lucija

AU - Alhusaini, Saud

AU - Milaneschi, Yuri

AU - Papmeyer, Martina

AU - Axelsson, Tomas

AU - Ehrlich, Stefan

AU - Roiz-Santianez, Roberto

AU - Kraemer, Bernd

AU - Haberg, Asta K.

AU - van der Meer, Dennis

AU - Brunner, Han G.

AU - Author collaboration

N1 - Funding Information: D.P.H. is currently an employee at Genentech. D.J. has received travel and speaker’s honoraria from Janssen–Cilag, as well as research funding from DFG. R.L.B. is a consultant for Pfizer and Roche. P.A. is a scientific adviser for Genoscreen. T.Y.W. is a consultant and advisory board member for Allergan, Bayer, Boehringer–Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics) and Roche, and is a co-founder of Plano and EyRiS. A.M.M. has received grant support from Eli Lilly, Janssen, Pfizer and the Sackler Trust. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. A.M.-L. is a member of the advisory board for the Lundbeck International Neuroscience Foundation and Brainsway, a member of the editorial board for the American Association for the Advancement of Science and Elsevier, a faculty member of the Lundbeck International Neuroscience Foundation and a consultant for Boehringer Ingelheim. W.J.N. is the founder and scientific lead of Quantib BV, in addition to being a shareholder. M.M.N. is a shareholder of Life & Brain, receives a salary from Life & Brain, has received support from Shire for attending conferences and has received financial remuneration from the Lundbeck Foundation, Robert Bosch Foundation and Deutsches Ärzteblatt for participation in scientific advisory boards. B.F. has received educational speaking fees from Shire and Medice. H.J.G. has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm and Janssen– Cilag, as well as research funding from Fresenius Medical Care. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2019/11

Y1 - 2019/11

N2 - Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

AB - Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

KW - Genome-wide association

KW - Ld score regression

KW - Basal ganglia

KW - Alkaline-phosphatase

KW - Alzheimers-disease

KW - Plasma-protein

KW - Risk loci

KW - Drosophila

KW - Metaanalysis

KW - Expression

U2 - 10.1038/s41588-019-0511-y

DO - 10.1038/s41588-019-0511-y

M3 - Article

C2 - 31636452

SN - 1061-4036

VL - 51

SP - 1624

EP - 1636

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

Genetic architecture of subcortical brain structures in 38,851 individuals

Abstract

Keywords

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