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

TY - JOUR

T1 - Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents: A Voxelwise and Genome-Wide Association Study

AU - Luo, Qiang

AU - Chen, Qiang

AU - Wang, Wenjia

AU - Desrivières, Sylvane

AU - Quinlan, Erin Burke

AU - Jia, Tianye

AU - Macare, Christine

AU - Robert, Gabriel H

AU - Cui, Jing

AU - Guedj, Mickaël

AU - Palaniyappan, Lena

AU - Kherif, Ferath

AU - Banaschewski, Tobias

AU - Bokde, Arun L W

AU - Büchel, Christian

AU - Flor, Herta

AU - Frouin, Vincent

AU - Garavan, Hugh

AU - Gowland, Penny

AU - Heinz, Andreas

AU - Ittermann, Bernd

AU - Martinot, Jean-Luc

AU - Artiges, Eric

AU - Paillère-Martinot, Marie-Laure

AU - Nees, Frauke

AU - Orfanos, Dimitri Papadopoulos

AU - Poustka, Luise

AU - Fröhner, Juliane H

AU - Smolka, Michael N

AU - Walter, Henrik

AU - Whelan, Robert

AU - Callicott, Joseph H

AU - Mattay, Venkata S

AU - Pausova, Zdenka

AU - Dartigues, Jean-François

AU - Tzourio, Christophe

AU - Crivello, Fabrice

AU - Berman, Karen F

AU - Li, Fei

AU - Paus, Tomáš

AU - Weinberger, Daniel R

AU - Murray, Robin M

AU - Schumann, Gunter

AU - Feng, Jianfeng

AU - IMAGEN Consortium

N1 - Version WoS und Pubmed nicht identisch!

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

U2 - 10.1001/jamapsychiatry.2018.4126

DO - 10.1001/jamapsychiatry.2018.4126

M3 - SCORING: Journal article

C2 - 30649180

VL - 76

SP - 435

EP - 445

JO - JAMA PSYCHIAT

JF - JAMA PSYCHIAT

SN - 2168-622X

IS - 4

ER -