De novo variants in sporadic cases of childhood onset schizophrenia

Ambalavanan, Amirthagowri; Girard, Simon L.; Ahn, Kwangmi; Zhou, Sirui; Dionne‐Laporte, Alexandre; Spiegelman, Dan; Bourassa, Cynthia V.; Gauthier, Julie; Hamdan, Fadi F.; Xiong, Lan; Dion, Patrick A.; Joober, Ridha; Rapoport, Judith L.; Rouleau, Guy A.

doi:10.1038/ejhg.2015.218

Cited by 77 publications

(62 citation statements)

References 42 publications

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“…In that pilot study there was a significantly enriched burden of high quality non-synonymous deleterious missense and loss of function sequence variants brain related genes in the schizophrenia cases (9). Genes involved included RYR2 (3, 37) and BSN (38), the latter encoding a pre-synaptic scaffolding protein, bassoon (9). Results of the current study (Table 3) further implicate these more novel genes and pathways for schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome

Bassett¹,

Lowther²,

Merico³

et al. 2017

AJP

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Objective 22q11.2 deletion syndrome (22q11.2DS) is associated with a >20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., “second hits”) that may contribute to schizophrenia expression. Methods Through an international consortium we obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), we compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: with and, at age ≥25 years, without a psychotic disorder. We assessed whether genes overlapped by rare CNVs were over-represented in functional pathways relevant to schizophrenia. Results Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene-sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a step-wise logistic regression model (p=0.00062) and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had on average more genes overlapped (p=0.0058). The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. Conclusions The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness, and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome

Bassett¹,

Lowther²,

Merico³

et al. 2017

AJP

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“…For further comparison with psychiatric and non-psychiatric diseases, SNVs described in exome studies of schizophrenia [Need et al, 2012;Xu et al, 2012a, b;Timms et al, 2013;Fromer et al, 2014;Guipponi et al, 2014;McCarthy et al, 2014;Ambalavanan et al, 2015;Kranz et al, 2015] and type 2 diabetes (T2D; [Lohmueller et al, 2013;Estrada et al, 2014;Steinthorsdottir et al, 2014]) were also included in the analyses. A total of 154 SNVs in 136 proteins were retrieved from schizophrenia exome studies.…”

Section: Methods Datasetsmentioning

confidence: 99%

The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies

Schuch

Paixão‐Côrtes

Friedrich

et al. 2016

American J of Med Genetics Pt B

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Several autism spectrum disorders (ASD) exome studies suggest that coding single nucleotide variants (SNVs) play an important role on ASD etiology. Usually, the pathogenic effect of missense mutations is estimated through predictors that lose accuracy for those SNVs placed in intrinsically disordered regions of protein. Here, we used bioinformatics tools to investigate the effect of mutations described in ASD published exome studies (549 mutations) in protein disorder, considering post-translational modification, PEST and Molecular Recognition Features (MoRFs) motifs. Schizophrenia and type 2 diabetes (T2D) datasets were created for comparison purposes. The frequency of mutations predicted as disordered was comparable among the three datasets (38.1% in ASD, 35.7% in schizophrenia, 46.4% in T2D). However, the frequency of SNVs predicted to lead a gain or loss of functional sites or change intrinsic disorder tendencies was higher in ASD and schizophrenia than T2D (46.9%, 36.4%, and 23.1%, respectively). The results obtained by SIFT and PolyPhen-2 indicated that 38.9% and 34.4% of the mutations predicted, respectively, as tolerated and benign showed functional alterations in disorder properties. Given the frequency of mutations placed in IDRs and their functional impact, this study suggests that alterations in intrinsic disorder properties might play a role in ASD and schizophrenia etiologies. They should be taken into consideration when researching the pathogenicity of mutations in neurodevelopmental and psychiatric diseases. Finally, mutations with functional alterations in disorder properties must be potential targets for in vitro and in vivo functional studies.

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“…De novo mutations were derived (66) from previously published exome sequencing studies of, collectively, 1136 schizophrenia-proband parent trios (12,(67)(68)(69)(70)(71)(72)(73)(74) ( Supplementary Table 1).…”

Section: De Novo Coding Variantsmentioning

confidence: 99%

Genetic association of FMRP targets with psychiatric disorders

Clifton

Rees

Holmans

et al. 2020

Preprint

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Genes encoding the mRNA targets of Fragile X mental retardation protein (FMRP) are enriched for genetic association with psychiatric disorders. However, many FMRP targets possess functions that are themselves genetically associated with psychiatric disorders, including synaptic transmission and plasticity, making it unclear whether the genetic risk is truly related to binding by FMRP or is alternatively mediated by the sampling of genes better characterised by another trait or functional annotation. Using published common variant, rare coding variant and copy number variant data, we examined the relationship between FMRP binding and genetic association with schizophrenia, major depressive disorder and bipolar disorder. We then explored the partitioning of genetic association between overrepresented functional categories. High-confidence targets of FMRP were enriched for common schizophrenia risk alleles, as well as rare loss-of-function and de novo nonsynonymous variants in cases. Similarly, through common variation, FMRP targets were associated with major depressive disorder, and we present novel evidence of association with bipolar disorder. These relationships could not be explained by membership of other functional annotations known to be associated with psychiatric disorders, including those related to synaptic structure and function. This study reinforces the evidence that targeting by FMRP captures a subpopulation of genes enriched for genetic association with a range of psychiatric disorders, across traditional diagnostic boundaries.

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De novo variants in sporadic cases of childhood onset schizophrenia

Cited by 77 publications

References 42 publications

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome

The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies

Genetic association of FMRP targets with psychiatric disorders

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