Resequencing and association analysis of coding regions at twenty candidate genes suggest a role for rare risk variation at AKAP9 and protective variation at NRXN1 in schizophrenia susceptibility

Suárez-Rama, José Javier; Arrojo, Manuel; Amigo, Jorge; Brenlla, Julio; Agra, Santiago; Paz, Eduardo; Brión, Marı́a; Carracedo, Ángel; Páramo, Mario; Costas, Javier

doi:10.1016/j.jpsychires.2015.04.013

Cited by 21 publications

(15 citation statements)

References 63 publications

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“…Indeed, we have shown previously that disruption of the Disc1 gene in mice results in altered expression of Nrxn1, 32 a gene in which copy number variation, common variants and rare variants are associated with schizophrenia. 47,55,56 The hypothesis of a distal effect of variants in the Interactome on disease risk is also consistent with the recent association of copy number variants linked to intellectual disability with schizophrenia in a much larger sample. 57 The DISC1 Interactome is enriched for proteins involved in regulation of nervous system development, microtubule cytoskeleton organization, and vesicle localization ( Supplementary Tables S17 & 18, Supplementary Figures S9-11).…”

Section: This Mirrors the Observation Of Association With Common Varisupporting

confidence: 79%

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia

Teng

Thomson

McCarthy

et al. 2016

Preprint

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Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here, we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results suggest that variants in the DISC1 Interactome effect the risk of psychiatric illness through altered expression of schizophrenia-associated genes. The biological impact of rare variants highlighted here merit further study.All rights reserved. No reuse allowed without permission.

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Section: This Mirrors the Observation Of Association With Common Varisupporting

confidence: 79%

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia

Teng

Thomson

McCarthy

et al. 2016

Preprint

View full text Add to dashboard Cite

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“…We observed high enrichment (pvalue < 8.0E-4) of gene clusters involved in the 'reactome' pathways, that is, neuronal system, retinoid metabolism, diseases associated with visual transduction, visual photo-transduction and neurotransmitter receptor binding (Additional file 1: Figure S10). Genes within these clusters including ADCY2 and AKAP have been associated with bipolar disorder and schizophrenia [37,38]. Furthermore genes associated with gamma-aminobutyric acid (GABRA2, GABRB) have been implicated in sleep disorders [39] including ApoB [40].…”

Section: Anti-inflammation and Neuro-activation During Second Stage Cmentioning

confidence: 99%

Blood signatures for second stage human African trypanosomiasis: a transcriptomic approach

et al. 2020

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Background: Rhodesiense sleeping sickness is caused by infection with T. b rhodesiense parasites resulting in an acute disease that is fatal if not treated in time. The aim of this study was to understand the global impact of active T. b rhodesiense infection on the patient's immune response in the early and late stages of the disease. Methods: RNASeq was carried out on blood and cerebral spinal fluid (CSF) samples obtained from T. b. rhodesiense infected patients. The control samples used were from healthy individuals in the same foci. The Illumina sequenced reads were analysed using the Tuxedo suite pipeline (Tophat, Cufflinks, Cuffmerge, Cuffdiff) and differential expression analysis carried out using the R package DESeq2. The gene enrichment and function annotation analysis were done using the ToppCluster, DAVID and InnateDB algorithms. Results: We previously described the transcriptomes of T. b rhodesiense from infected early stage blood (n = 3) and late stage CSF (n = 3) samples from Eastern Uganda. We here identify human transcripts that were differentially expressed (padj < 0.05) in the early stage blood versus healthy controls (n = 3) and early stage blood versus late stage CSF. Differential expression in infected blood showed an enrichment of innate immune response genes whereas that of the CSF showed enrichment for anti-inflammatory and neuro-degeneration signalling pathways. We also identified genes (C1QC, MARCO, IGHD3-10) that were up-regulated (log 2 FC > 2.5) in both the blood and CSF. Conclusion: The data yields insights into the host's response to T. b rhodesiense parasites in the blood and central nervous system. We identified key pathways and signalling molecules for the predominant innate immune response in the early stage infection; and anti-inflammatory and neuro-degeneration pathways associated with sleep disorders in second stage infection. We further identified potential blood biomarkers that can be used for diagnosis of late stage disease without the need for lumbar puncture.

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“…We observed high enrichment (pvalue < 8.0E-4) of gene clusters involved in the 'reactome' pathways, that is, neuronal system, retinoid metabolism, diseases associated with visual transduction, visual phototransduction and neurotransmitter receptor binding ( Figure S10). Genes within these clusters including ADCY2 and AKAP have been associated with bipolar disorder and schizophrenia [37,38].…”

Section: Anti-inflammation and Neuro-activation During Second Stage Cmentioning

confidence: 99%

Blood signatures for second stage Human African Trypanosomiasis: A transcriptomic approach.

Mulindwa

Matovu

Enyaru

et al. 2020

Preprint

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Background: Rhodesiense sleeping sickness is caused by infection with T. b rhodesiense parasites resulting in an acute disease that is fatal if not treated in time. The global impact of active T. b rhodesiense infection on the patient’s immune response in the early and late stages of the disease is not known. Methods: RNASeq was carried out on blood and cerebral spinal fluid (CSF) samples obtained from T. b. rhodesiense infected patients. The control samples used were from healthy individuals in the same foci. The Illumina sequenced reads were analysed using the Tuxedo suite pipeline (Tophat, Cufflinks, Cuffmerge, Cuffdiff) and differential expression analysis carried out using the R package DESeq2. The gene enrichment and function annotation analysis were done using the ToppCluster, DAVID and InnateDB algorithms. Results: We previously described the transcriptomes of T. b rhodesiense from infected early stage blood (n=3) and late stage CSF (n=3) samples from Eastern Uganda. We here identify human transcripts that were differentially expressed (padj < 0.05) in the early stage blood versus healthy controls (n=3) and early stage blood versus late stage CSF. Differential expression in infected blood showed an enrichment of innate immune response genes whereas that of the CSF showed enrichment for anti-inflammatory and neuro-degeneration signalling pathways. We also identified genes (C1QC, MARCO, IGHD3-10) that were up-regulated (log 2 FC > 2.5) in both the blood and CSF. Conclusion: The data yields insights into the host’s response to T. b rhodesiense parasites in the blood and central nervous system. We identified key pathways and signalling molecules for the predominant innate immune response in the early stage infection; and anti-inflammatory and neuro-degeneration pathways associated with sleep disorders in second stage infection. We further identified potential blood biomarkers that can be used for diagnosis of late stage disease without the need for lumbar puncture.

show abstract

Resequencing and association analysis of coding regions at twenty candidate genes suggest a role for rare risk variation at AKAP9 and protective variation at NRXN1 in schizophrenia susceptibility

Cited by 21 publications

References 63 publications

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia

Blood signatures for second stage human African trypanosomiasis: a transcriptomic approach

Blood signatures for second stage Human African Trypanosomiasis: A transcriptomic approach.

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