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

Details

Serval ID
serval:BIB_B78577205737
Type
Article: article from journal or magazin.
Collection
Publications
Title
Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents: A Voxelwise and Genome-Wide Association Study.
Journal
JAMA psychiatry
Author(s)
Luo Q., Chen Q., Wang W., Desrivières S., Quinlan E.B., Jia T., Macare C., Robert G.H., Cui J., Guedj M., Palaniyappan L., Kherif F., Banaschewski T., Bokde ALW, Büchel C., Flor H., Frouin V., Garavan H., Gowland P., Heinz A., Ittermann B., Martinot J.L., Artiges E., Paillère-Martinot M.L., Nees F., Orfanos D.P., Poustka L., Fröhner J.H., Smolka M.N., Walter H., Whelan R., Callicott J.H., Mattay V.S., Pausova Z., Dartigues J.F., Tzourio C., Crivello F., Berman K.F., Li F., Paus T., Weinberger D.R., Murray R.M., Schumann G., Feng J.
Working group(s)
IMAGEN consortium
ISSN
2168-6238 (Electronic)
ISSN-L
2168-622X
Publication state
Published
Issued date
01/04/2019
Peer-reviewed
Oui
Volume
76
Number
4
Pages
435-445
Language
english
Notes
Publication types: Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
To identify genetic variants associated with adolescent brain structure and explore psychopathologic relevance of such associations.
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.
Gray matter volume was assessed by neuroimaging and genetic variants were genotyped by Illumina BeadChip.
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).
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.
Keywords
Adolescent, Adult, Case-Control Studies, Cation Transport Proteins/biosynthesis, Cation Transport Proteins/genetics, Female, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Gray Matter/pathology, Humans, Hypertrophy/genetics, Hypertrophy/pathology, Magnetic Resonance Imaging, Male, Mutation, Missense/genetics, Neuroimaging, Putamen/pathology, Schizophrenia/genetics, Schizophrenia/pathology, Siblings
Pubmed
Web of science
Open Access
Yes
Create date
08/02/2019 13:54
Last modification date
21/02/2020 7:19
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