Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents

Qiang Luo, Qiang Chen, Wenjia Wang, Sylvane Desrivières, Erin Burke Quinlan, Tianye Jia, Christine Macare, Gabriel H. Robert, Jing Cui, Mickaël Guedj, Lena Palaniyappan, Ferath Kherif, Tobias Banaschewski, Arun L. W. Bokde, Christian Büchel, Herta Flor, Vincent Frouin, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Eric Artiges, Marie-Laure Paillère-Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Luise Poustka, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Joseph H. Callicott, Venkata S. Mattay, Zdenka Pausova, Jean-François Dartigues, Christophe Tzourio, Fabrice Crivello, Karen F. Berman, Fei Li, Tomáš Paus, Daniel R. Weinberger, Robin M. Murray, Gunter Schumann, Jianfeng Feng,
JAMA Psychiatry. 2019-04-01; 76(4): 435
DOI: 10.1001/jamapsychiatry.2018.4126

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Luo Q(1)(2)(3)(4), Chen Q(5), Wang W(6)(7), Desrivières S(4), Quinlan EB(4), Jia
T(1)(2)(4), Macare C(4), Robert GH(8), Cui J(9), Guedj M(6), Palaniyappan L(10),
Kherif F(9), Banaschewski T(11), Bokde ALW(12), Büchel C(13), Flor H(14)(15),
Frouin V(16), Garavan H(17), Gowland P(18), Heinz A(19), Ittermann B(20),
Martinot JL(21)(22)(23), Artiges E(21)(22)(24), Paillère-Martinot ML(21)(25),
Nees F(11)(14), Orfanos DP(16), Poustka L(26)(27), Fröhner JH(28), Smolka
MN(28), Walter H(19), Whelan R(29), Callicott JH(30), Mattay VS(5)(31)(32),
Pausova Z(33), Dartigues JF(34), Tzourio C(34), Crivello F(35)(36)(37), Berman
KF(30), Li F(38), Paus T(39)(40), Weinberger DR(5)(31)(41)(42)(43), Murray
RM(4), Schumann G(4), Feng J(1)(2)(3)(44)(45)(46); IMAGEN consortium.

Author information:
(1)Institute of Science and Technology for Brain-Inspired Intelligence, Fudan
University, Shanghai, China.
(2)Ministry of Education-Key Laboratory of Computational Neuroscience and
Brain-Inspired Intelligence, Fudan University, Shanghai, China.
(3)School of Life Sciences and State Key Laboratory of Genetic Engineering,
Fudan University, Shanghai, China.
(4)Centre for Population Neuroscience and Precision Medicine, Institute of
Psychiatry, Psychology and Neuroscience, King’s College London, Social Genetic
and Developmental Psychiatry Centre, London, England.
(5)Lieber Institute for Brain Development, Johns Hopkins Medical Campus,
Baltimore, Maryland.
(6)Pharnext, Issy-les-Moulineaux, Ile de France, France.
(7)Institut National de la Santé et de la Recherche Médicale Unit 897,
University of Bordeaux, Bordeaux, Aquitaine, France.
(8)EA 4712 “Behavior and Basal Ganglia,” Rennes University 1, Rennes, France.
(9)Laboratory for Research in Neuroimaging, Department of Clinical
Neurosciences, Centre Hospitalier Universitaire Vaudois, University of Lausanne,
Lausanne, Switzerland.
(10)Departments of Psychiatry and Medical Biophysics, Robarts Research
Institute, University of Western Ontario, London, Ontario, Canada.
(11)Department of Child and Adolescent Psychiatry and Psychotherapy, Central
Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University,
Square J5, Mannheim, Germany.
(12)Discipline of Psychiatry, School of Medicine and Trinity College Institute
of Neuroscience, Trinity College Dublin, Dublin, Ireland.
(13)University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
(14)Department of Cognitive and Clinical Neuroscience, Central Institute of
Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim,
Germany.
(15)Department of Psychology, School of Social Sciences, University of Mannheim,
Mannheim, Germany.
(16)NeuroSpin, Commissariat à L’énergie Atomique, Université Paris-Saclay,
Gif-sur-Yvette, France.
(17)Departments of Psychiatry and Psychology, University of Vermont, Burlington.
(18)Sir Peter Mansfield Imaging Centre School of Physics and Astronomy,
University of Nottingham, University Park, Nottingham, England.
(19)Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité,
Universitätsmedizin Berlin, Germany.
(20)Physikalisch-Technische Bundesanstalt Braunschweig and Berlin, Berlin,
Germany.
(21)Institut National de la Santé et de la Recherche Médicale Unit 1000,
Neuroimaging and Psychiatry, University Paris Sud-Paris Saclay, University Paris
Descartes, Paris, France.
(22)Service Hospitalier Frédéric Joliot, Orsay, France.
(23)Maison de Solenn, Paris, France.
(24)GH Nord Essonne Psychiatry Department, Orsay, France.
(25)Assistance Publique-Hôpitaux de Paris, Department of Child and Adolescent
Psychiatry, Pitié-Salpêtrière Hospital, Paris, France.
(26)Department of Child and Adolescent Psychiatry and Psychotherapy, University
Medical Centre Göttingen, Göttingen, Germany.
(27)Clinic for Child and Adolescent Psychiatry, Medical University of Vienna,
Währinger Gürtel, Vienna, Austria.
(28)Department of Psychiatry and Neuroimaging Center, Technische Universität
Dresden, Dresden, Germany.
(29)School of Psychology and Global Brain Health Institute, Trinity College
Dublin, Dublin, Ireland.
(30)Clinical and Translational Neuroscience Branch, National Institute of Mental
Health, National Institutes of Health, Bethesda, Maryland.
(31)Departments of Neurology, Johns Hopkins University School of Medicine,
Baltimore, Maryland.
(32)Departments of Radiology, Johns Hopkins University School of Medicine,
Baltimore, Maryland.
(33)The Hospital for Sick Children, University of Toronto, Toronto, Ontario,
Canada.
(34)Institut National de la Santé et de la Recherche Médicale Unit 1219,
Université de Bordeaux, Bordeaux, France.
(35)University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux,
France.
(36)Centre National de la Recherche Scientifique, Institut des Maladies
Neurodégénératives, Bordeaux, France.
(37)Commissariat à L’énergie Atomiquecea, Institut des Maladies
Neurodégénératives-Equipe 5, Bordeaux, France.
(38)Developmental and Behavioral Pediatric Department and Child Primary Care
Department, MOE-Shanghai Key Lab for Children’s Environmental Health, Xinhua
Hospital Affiliated To Shang Jiaotong University School of Medicine, Shanghai,
China.
(39)Bloorview Research Institute, Holland Bloorview Kids Rehabilitation
Hospital, Toronto, Ontario, Canada.
(40)Departments of Psychology and Psychiatry, University of Toronto, Toronto,
Ontario, Canada.
(41)McKusick Nathans Institute of Genetic Medicine, Johns Hopkins School of
Medicine, Baltimore, Maryland.
(42)Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
School of Medicine, Baltimore, Maryland.
(43)Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore,
Maryland.
(44)Department of Computer Science, University of Warwick, Coventry, England.
(45)Collaborative Innovation Center for Brain Science, Fudan University,
Shanghai, China.
(46)Shanghai Center for Mathematical Sciences, Shanghai, China.

IMPORTANCE: Deviation from normal adolescent brain development precedes
manifestations of many major psychiatric symptoms. Such altered developmental
trajectories in adolescents may be linked to genetic risk for psychopathology.
OBJECTIVE: To identify genetic variants associated with adolescent brain
structure and explore psychopathologic relevance of such associations.
DESIGN, SETTING, AND PARTICIPANTS: Voxelwise genome-wide association study in a
cohort of healthy adolescents aged 14 years and validation of the findings using
4 independent samples across the life span with allele-specific expression
analysis of top hits. Group comparison of the identified gene-brain association
among patients with schizophrenia, unaffected siblings, and healthy control
individuals. This was a population-based, multicenter study combined with a
clinical sample that included participants from the IMAGEN cohort, Saguenay
Youth Study, Three-City Study, and Lieber Institute for Brain Development sample
cohorts and UK biobank who were assessed for both brain imaging and genetic
sequencing. Clinical samples included patients with schizophrenia and unaffected
siblings of patients from the Lieber Institute for Brain Development study. Data
were analyzed between October 2015 and April 2018.
MAIN OUTCOMES AND MEASURES: Gray matter volume was assessed by neuroimaging and
genetic variants were genotyped by Illumina BeadChip.
RESULTS: The discovery sample included 1721 adolescents (873 girls [50.7%]),
with a mean (SD) age of 14.44 (0.41) years. The replication samples consisted of
8690 healthy adults (4497 women [51.8%]) from 4 independent studies across the
life span. A nonsynonymous genetic variant (minor T allele of rs13107325 in
SLC39A8, a gene implicated in schizophrenia) was associated with greater gray
matter volume of the putamen (variance explained of 4.21% in the left
hemisphere; 8.66; 95% CI, 6.59-10.81; P = 5.35 × 10-18; and 4.44% in the right
hemisphere; t = 8.90; 95% CI, 6.75-11.19; P = 6.80 × 10-19) and also with a
lower gene expression of SLC39A8 specifically in the putamen (t127 = -3.87;
P = 1.70 × 10-4). The identified association was validated in samples across the
life span but was significantly weakened in both patients with schizophrenia
(z = -3.05; P = .002; n = 157) and unaffected siblings (z = -2.08; P = .04;
n = 149).
CONCLUSIONS AND RELEVANCE: Our results show that a missense mutation in gene
SLC39A8 is associated with larger gray matter volume in the putamen and that
this association is significantly weakened in schizophrenia. These results may
suggest a role for aberrant ion transport in the etiology of psychosis and
provide a target for preemptive developmental interventions aimed at restoring
the functional effect of this mutation.

DOI: 10.1001/jamapsychiatry.2018.4126
PMCID: PMC6450291
PMID: 30649180 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of Interest Disclosures: Dr
Banaschewski has served as an advisor or consultant to Bristol-Myers Squibb,
Desitin Arzneimittel, Eli Lilly, Medice, Novartis, Pfizer, Shire, UCB, and Vifor
Pharma; has received conference attendance support, conference support, or
speaking fees from Eli Lilly, Janssen McNeil, Medice, Novartis, Shire, and UCB;
and is involved in clinical trials conducted by Eli Lilly, Novartis, and Shire
and the present work is unrelated to these relationships. Dr Walter received a
speaker honorarium from Servier (2014). Dr Mickaël Guedj and Wenjia Wang are
employees of Pharnext. Dr Mickaël Guedj has shares in Pharnext and holds patents
by Pharnext. Dr Palaniyappan received speaker fees from Otsuka in 2017 and
unrestricted educational grants from Otsuka Canada and Janssen Canada in 2017.
No other disclosures were supported.

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