Dataset Information

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

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.

SUBMITTER: Luo Q

PROVIDER: S-EPMC6450291 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Luo Qiang Q Chen Qiang Q Wang Wenjia W Desrivières Sylvane S Quinlan Erin Burke EB Jia Tianye T Macare Christine C Robert Gabriel H GH Cui Jing J Guedj Mickaël M Palaniyappan Lena L Kherif Ferath F Banaschewski Tobias T Bokde Arun L W ALW Büchel Christian C Flor Herta H Frouin Vincent V Garavan Hugh H Gowland Penny P Heinz Andreas A Ittermann Bernd B Martinot Jean-Luc JL Artiges Eric E Paillère-Martinot Marie-Laure ML Nees Frauke F Orfanos Dimitri Papadopoulos DP Poustka Luise L Fröhner Juliane H JH Smolka Michael N MN Walter Henrik H Whelan Robert R Callicott Joseph H JH Mattay Venkata S VS Pausova Zdenka Z Dartigues Jean-François JF Tzourio Christophe C Crivello Fabrice F Berman Karen F KF Li Fei F Paus Tomáš T Weinberger Daniel R DR Murray Robin M RM Schumann Gunter G Feng Jianfeng J

JAMA psychiatry 20190401 4

<h4>Importance</h4>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.<h4>Objective</h4>To identify genetic variants associated with adolescent brain structure and explore psychopathologic relevance of such associations.<h4>Design, setting, and participants</h4>Voxelwise genome-wide association study in a cohort of healthy adolescent ...[more]

PMID: 30649180

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Project description:Diversity in the human genome is one factor that confers resistance and susceptibility to infectious diseases. This is observed most dramatically during pandemics, where individuals exhibit large differences in risk and clinical outcomes against a pathogen infecting large portions of the world’s populations. Here, we developed scHi-HOST (single cell High-throughput Human in vitrO Susceptibility Testing), a method for rapidly identifying genetic variants that confer resistance and susceptibility to pathogens. scHi-HOST leverages scRNA-seq (single-cell RNA-sequencing) to simultaneously assign genetic identity to individual cells in mixed infections of cell lines of European, African, and Asian origin, reveal associated genetic variants for viral entry and replication, and identify expression quantitative trait loci (eQTLs). Applying scHi-HOST to influenza A virus (IAV), we identified eQTLs at baseline and in genes that are induced by IAV infection. Integration of scHi-HOST with a human IAV challenge study (Prometheus) revealed that a missense variant in ERAP1 (Endoplasmic reticulum aminopeptidase 1; rs27895) was associated with IAV burden in cells and human volunteers. Functional studies using RNA interference, ERAP1 inhibitor, and overexpression of alternative alleles demonstrated that ERAP1 is exploited by IAV to promote infection. Specifically, the nonsynonymous substitution, which results in a glycine to aspartate substitution at ERAP1 residue 348, would disrupt the substrate binding pocket of ERAP1, likely resulting in a significantly altered preference for substrates, poorer catalytic efficiency, or both. Finally, rs27895 exhibits substantial population differentiation, with the higher frequency of the minor T allele in two African populations likely contributing to the greater permissivity of cells from these populations to IAV infection. scHi-HOST is an important resource for understanding susceptibility to influenza and is a broadly applicable method for decoding human genetics of infectious disease.

Project description:OBJECTIVE:The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs). METHOD:The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs. RESULTS:No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10(-17), explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families. CONCLUSIONS:Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.

Dataset Information

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

Publications

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

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