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JAMA Psychiatry. 2019 Jan 16. doi: 10.1001/jamapsychiatry.2018.4126. [Epub ahead of print]

Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents: A Voxelwise and Genome-Wide Association Study.

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.

Abstract

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.

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