Titre
Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents: A Voxelwise and Genome-Wide Association Study.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Luo, Q.
Auteure/Auteur
Chen, Q.
Auteure/Auteur
Wang, W.
Auteure/Auteur
Desrivières, S.
Auteure/Auteur
Quinlan, E.B.
Auteure/Auteur
Jia, T.
Auteure/Auteur
Macare, C.
Auteure/Auteur
Robert, G.H.
Auteure/Auteur
Cui, J.
Auteure/Auteur
Guedj, M.
Auteure/Auteur
Palaniyappan, L.
Auteure/Auteur
Kherif, F.
Auteure/Auteur
Banaschewski, T.
Auteure/Auteur
Bokde, ALW
Auteure/Auteur
Büchel, C.
Auteure/Auteur
Flor, H.
Auteure/Auteur
Frouin, V.
Auteure/Auteur
Garavan, H.
Auteure/Auteur
Gowland, P.
Auteure/Auteur
Heinz, A.
Auteure/Auteur
Ittermann, B.
Auteure/Auteur
Martinot, J.L.
Auteure/Auteur
Artiges, E.
Auteure/Auteur
Paillère-Martinot, M.L.
Auteure/Auteur
Nees, F.
Auteure/Auteur
Orfanos, D.P.
Auteure/Auteur
Poustka, L.
Auteure/Auteur
Fröhner, J.H.
Auteure/Auteur
Smolka, M.N.
Auteure/Auteur
Walter, H.
Auteure/Auteur
Whelan, R.
Auteure/Auteur
Callicott, J.H.
Auteure/Auteur
Mattay, V.S.
Auteure/Auteur
Pausova, Z.
Auteure/Auteur
Dartigues, J.F.
Auteure/Auteur
Tzourio, C.
Auteure/Auteur
Crivello, F.
Auteure/Auteur
Berman, K.F.
Auteure/Auteur
Li, F.
Auteure/Auteur
Paus, T.
Auteure/Auteur
Weinberger, D.R.
Auteure/Auteur
Murray, R.M.
Auteure/Auteur
Schumann, G.
Auteure/Auteur
Feng, J.
Auteure/Auteur
Groupes de travail
IMAGEN consortium
Liens vers les personnes
Liens vers les unités
ISSN
2168-6238
Statut éditorial
Publié
Date de publication
2019-04-01
Volume
76
Numéro
4
Première page
435
Dernière page/numéro d’article
445
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
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.
Sujets
PID Serval
serval:BIB_B78577205737
PMID
Open Access
Oui
Date de création
2019-02-08T11:54:07.715Z
Date de création dans IRIS
2025-05-21T04:50:53Z
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Nom
30649180_BIB_B78577205737.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
2.09 MB
Format
Adobe PDF
PID Serval
serval:BIB_B78577205737.P001
URN
urn:nbn:ch:serval-BIB_B785772057372
Somme de contrôle
(MD5):cf23b96aba770463b4a7c02a12cc935c