A Voxelwise and Genome-Wide Association Study

Autor: Luo, Qiang, Chen, Qiang, Wang, Wenjia, Desrivières, Sylvane, Quinlan, Erin Burke, Jia, Tianye, Macare, Christine, Robert, Gabriel H., Cui, Jing, Guedj, Mickaël, Palaniyappan, Lena, Kherif, Ferath, Banaschewski, Tobias, Bokde, Arun L. W., Büchel, Christian, Flor, Herta, Frouin, Vincent, Garavan, Hugh, Gowland, Penny, Heinz, Andreas, Ittermann, Bernd, Martinot, Jean-Luc, Artiges, Eric, Paillère-Martinot, Marie-Laure, Nees, Frauke, Orfanos, Dimitri Papadopoulos, Poustka, Luise, Fröhner, Juliane H., Smolka, Michael N., Walter, Henrik, Whelan, Robert, Callicott, Joseph H., Mattay, Venkata S., Pausova, Zdenka, Dartigues, Jean-François, Tzourio, Christophe, Crivello, Fabrice, Berman, Karen F., Li, Fei, Paus, Tomáš, Weinberger, Daniel R., Murray, Robin M., Schumann, Gunter, Feng, Jianfeng
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: JAMA Psychiatry
ISSN: 2168-622X
Popis: Key Points Question Is there any genetic variant associated with adolescent brain development that can inform psychopathology of schizophrenia? Findings In this imaging genetics study of brain structure, a significant association between a missense mutation in SLC39A8 (a gene previously associated with schizophrenia) and gray matter volume in putamen was discovered and replicated using 10 411 healthy participants from 5 independent studies. Compared with healthy control individuals, such association was significantly weakened in both patients with schizophrenia and unaffected siblings. Meaning Common genetic variant indicates an involvement of neuronal ion transport in both pathophysiology of schizophrenia and structural development of putamen.
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.
This imaging genetics study examines genetic variants associated with adolescent brain structure and explores the psychopathologic relevance of such associations in the development of schizophrenia.
Databáze: OpenAIRE
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