Targeted resequencing of regulatory regions at schizophrenia risk loci: Role of rare functional variants at chromatin repressive states

González-Peñas, Javier; Amigo, Jorge; Santomé, Luis; Brenlla, Julio; Agra, Santiago; Paz, Eduardo; Páramo, Mario; Carracedo, Ángel; Arrojo, Manuel; Costas, Javier

doi:10.1016/j.schres.2016.03.029

Cited by 6 publications

(5 citation statements)

References 48 publications

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“…To study how gene expression is associated with actual clinical illness, we compared ST twins with their healthy co-twins and found decreased expression of LHX1 , a transcription factor previously linked to schizophrenia 7,8 (Fig. 1d).…”

Section: Resultsmentioning

confidence: 99%

Sex-specific transcriptional and proteomic signatures in schizophrenia

et al. 2019

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It has remained unclear why schizophrenia typically manifests after adolescence and which neurobiological mechanisms are underlying the cascade leading to the actual onset of the illness. Here we show that the use of induced pluripotent stem cell-derived neurons of monozygotic twins from pairs discordant for schizophrenia enhances disease-specific signal by minimizing genetic heterogeneity. In proteomic and pathway analyses, clinical illness is associated especially with altered glycosaminoglycan, GABAergic synapse, sialylation, and purine metabolism pathways. Although only 12% of all 19,462 genes are expressed differentially between healthy males and females, up to 61% of the illness-related genes are sex specific. These results on sex-specific genes are replicated in another dataset. This implies that the pathophysiology differs between males and females, and may explain why symptoms appear after adolescence when the expression of many sex-specific genes change, and suggests the need for sex-specific treatments.

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Section: Resultsmentioning

confidence: 99%

Sex-specific transcriptional and proteomic signatures in schizophrenia

et al. 2019

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“…There is substantial evidence for the involvement of chromatin-modulating genes in the development of autism, 114 , 115 , 116 , 117 , 118 , 119 schizophrenia 120 , 121 , 122 , 123 , 124 and body mass index changes. 114 Given the comorbidity of these disorders with AN, and the potential overlap with autism indicated in the pathway analysis results, we tested for enrichment of chromatin-modulating genes in these results.…”

Section: Discussionmentioning

confidence: 99%

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

et al. 2017

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Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified(1). We performed an exome-chip based GWAS in 2,158 cases from nine populations of European origin and 15,485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common, 5 rare). No findings reached genome-wide significance. Two notable common variants were identified; rs10791286, an intronic variant in OPCML (p=9.89x10-6), and rs7700147, an intergenic variant (p=2.93x10-5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

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“…Moreover, due to the complexity of schizophrenia and different genetic backgrounds among various ethnic groups, it is even harder to find out the causal genes conferring the risk of schizophrenia. Considering the fact that most of the identified genetic risk loci are located in non-coding regions, these factors may confer the risk of schizophrenia by affecting the expression of nearby gene (s) and/or changing the chromatin state [13,14,60]. Integrative studies with brain gene expression data or other multiple-omics data like DNA methylation, proteins or metabolites can help us parse the result of GWAS studies, as we and others had done recently [[12], [13], [14], [15], [16]].…”

Section: Discussionmentioning

confidence: 99%

Identification of the primate-specific gene BTN3A2 as an additional schizophrenia risk gene in the MHC loci

Zeng

et al. 2019

eBioMedicine

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Background: Schizophrenia is a complex mental disorder resulting in poor life quality and high social and economic burden. Despite the fact that genome-wide association studies (GWASs) have successfully identified a number of risk loci for schizophrenia, identifying the causal genes at the risk loci and elucidating their roles in disease pathogenesis remain major challenges. Methods: The summary data-based Mendelian randomization analysis (SMR) was used to integrate a large-scale GWAS of schizophrenia with brain expression quantitative trait loci (eQTL) data and brain methylation expression quantitative trait loci (meQTL) data, to identify novel risk gene(s) for schizophrenia. We then analyzed the mRNA expression and methylation statuses of the gene hit BTN3A2 during the early brain development. Electrophysiological analyses of CA1 pyramidal neurons were performed to evaluate the excitatory and inhibitory synaptic activity after overexpression of BTN3A2 in rat hippocampal slices. Cell surface binding assay was used to test the interaction of BTN3A2 and neurexins. Findings: We identified BTN3A2 as a potential risk gene for schizophrenia. The mRNA expression and methylation data showed that BTN3A2 expression in human brain is highest post-natally. Further electrophysiological analyses of rat hippocampal slices showed that BTN3A2 overexpression specifically suppressed the excitatory synaptic activity onto CA1 pyramidal neurons, most likely through its interaction with the presynaptic adhesion molecule neurexins. Interpretation: Increased expression of BTN3A2 might confer risk for schizophrenia by altering excitatory synaptic function. Our result constitutes a paradigm for distilling risk gene using an integrative analysis and functional characterization in the post-GWAS era.

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Targeted resequencing of regulatory regions at schizophrenia risk loci: Role of rare functional variants at chromatin repressive states

Cited by 6 publications

References 48 publications

Sex-specific transcriptional and proteomic signatures in schizophrenia

Sex-specific transcriptional and proteomic signatures in schizophrenia

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

Identification of the primate-specific gene BTN3A2 as an additional schizophrenia risk gene in the MHC loci

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