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

Qiang Luo 1, 2 Qiang Chen 3 Wenjia Wang 4, 5 Sylvane Desrivières 2 Erin Burke Quinlan 2 Tianye Jia 1, 2 Christine Macare 2 Gabriel H Robert 6 Jing Cui 7 Mickael Guedj 4 Lena Palaniyappan 8 Ferath Kherif 7 Tobias Banaschewski 9 Arun L W Bokde 10 Christian Büchel Herta Flor 11, 9 Vincent Frouin 12 Hugh Garavan 13 Penny Gowland 14 Andreas Heinz Bernd Ittermann Jean-Luc Martinot 15, 16, 17 Eric Artiges 15, 18, 17 Marie-Laure Paillère-Martinot 19, 17 Frauke Nees 9 Dimitri Papadopoulos-Orfanos 12 Luise Poustka 20, 21 Juliane H Fröhner 22 Michael N Smolka 22 Henrik Walter Robert Whelan Joseph H Callicott Venkata S Mattay 3, 23 Zdenka Pausova 24 Jean-François Dartigues 25 Christophe Tzourio 25 Fabrice Crivello 26 Karen F Berman Fei Li Tomáš Paus 27, 24 Daniel R Weinberger 3, 23, 28 Robin M Murray Gunter Schumann Jianfeng Feng 1, 29, * 
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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Qiang Luo, Qiang Chen, Wenjia Wang, Sylvane Desrivières, Erin Burke Quinlan, et al.. Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents A Voxelwise and Genome-Wide Association Study. JAMA Psychiatry, 2019, 76 (4), pp.435. ⟨10.1001/jamapsychiatry.2018.4126⟩. ⟨hal-02020866⟩



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