Characterization of a human-specific tandem repeat associated with bipolar disorder and schizophrenia

Song, Janet; Lowe, Craig B.; Kingsley, David M.

doi:10.1101/311795

Cited by 17 publications

(32 citation statements)

References 61 publications

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“…117 However, a recent study showed that the risk allele of CACNA1C associated with BD is associated with the number of human-specific 30-base tandem repeats, and this repeat sequence acts as an enhancer that potentially changes the expression of CACNA1C or neighboring genes. 118 Thus, simple knockout mice may not reveal the mechanism of this genetic association.…”

Section: Animal Modelsmentioning

confidence: 99%

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

Kato

2019

Psychiatry Clin Neurosci

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Biological studies of bipolar disorder initially focused on the mechanism of action for antidepressants and antipsychotic drugs, and the roles of monoamines (e.g., serotonin, dopamine) have been extensively studied. Thereafter, based on the mechanism of action of lithium, intracellular signal transduction systems, including inositol metabolism and intracellular calcium signaling, have drawn attention. Involvement of intracellular calcium signaling has been supported by genetics and cellular studies. Elucidation of the neural circuits affected by calcium signaling abnormalities is critical, and our previous study suggested a role of the paraventricular thalamic nucleus. The genetic vulnerability of mitochondria causes calcium dysregulation and results in the hyperexcitability of serotonergic neurons, which are suggested to be susceptible to oxidative stress. Efficacy of anticonvulsants, animal studies of candidate genes, and studies using induced pluripotent stem cell‐derived neurons have suggested a relation between bipolar disorder and the hyperexcitability of neurons. Recent genetic findings suggest the roles of polyunsaturated acids. At the systems level, social rhythm therapy targets circadian rhythm abnormalities, and cognitive behavioral therapy may target emotion/cognition (E/C) imbalance. In the future, pharmacological and psychosocial treatments may be combined and optimized based on the biological basis of each patient, which will realize individualized treatment.

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Section: Animal Modelsmentioning

confidence: 99%

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

Kato

2019

Psychiatry Clin Neurosci

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“…This is consistent with previous work detecting SVs from long read sequencing 15,17 and may result from instability of tandem repeats in the BAC clones used to create the reference genome. 42 (a) (b) when in fact they were likely homozygous variant or complex (2:232734665 and 8:43034905).…”

Section: Benchmark Calls Are Well-supportedmentioning

confidence: 99%

A robust benchmark for germline structural variant detection

Zook¹,

Nf²,

Nd³

et al. 2019

Preprint

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New technologies and analysis methods are enabling genomic structural variants (SVs) to be detected with ever-increasing accuracy, resolution, and comprehensiveness. Translating these methods to routine research and clinical practice requires robust benchmark sets. We developed the first benchmark set for identification of both false negative and false positive germline SVs, which complements recent efforts emphasizing increasingly comprehensive characterization of SVs. To create this benchmark for a broadly consented son in a Personal Genome Project trio with broadly available cells and DNA, the Genome in a Bottle (GIAB) Consortium integrated 19 sequence-resolved variant calling methods, both alignment-and de novo assembly-based, from short-, linked-, and long-read sequencing, as well as optical and electronic mapping. The final benchmark set contains 12745 isolated, sequence-resolved insertion and deletion calls ≥50 base pairs (bp) discovered by at least 2 technologies or 5 callsets, genotyped as heterozygous or homozygous variants by long reads. The Tier 1 benchmark regions, for which any extra calls are putative false positives, cover 2.66 Gbp and 9641 SVs supported by at least one diploid assembly. Support for SVs was assessed using svviz with short-, linked-, and long-read sequence data. In general, there was strong support from multiple technologies for the benchmark SVs, with 90 % of the Tier 1 SVs having support in reads from more than one technology. The Mendelian genotype error rate was 0.3 %, and genotype concordance with manual curation was >98.7 %. We demonstrate the utility of the benchmark set by showing it reliably identifies both false negatives and false positives in high-quality SV callsets from short-, linked-, and long-read sequencing and optical mapping. GIAB is working towards a new version of the benchmark set that will use new technologies and methods such as PacBio Circular Consensus Sequencing and ultralong Oxford Nanopore sequencing to expand to more challenging genome regions and include more challenging SVs such as inversions. We are also developing a robust integration process to make calls on GRCh37 and GRCh38 for all seven GIAB samples.

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“…However, this increase has not been accompanied by the elucidation of disease mechanisms or an increase in the identification of causal variants. To date, support for mechanisms and/or causal variants have been established for two loci (Sekar et al 2016;Song et al 2018). The inability to construct and test mechanisms for schizophrenia largely stems from the inability to separate disease-relevant variants from those in linkage disequilibrium (LD) and from the lack of knowledge about what cells are important for disease risk.…”

Section: Leveraging Mouse Chromatin Data For Heritability Enrichment mentioning

confidence: 99%

“…We acknowledge this may be compounded by a focus on SNPs. Other more complex variation has been shown to be important in schizophrenia loci and cannot yet be fully assayed with this method (Sekar et al 2016;Song et al 2018).…”

Section: G G T C C G C G T T C G C G C C Cmentioning

confidence: 99%

Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia

Hook

McCallion

2018

Preprint

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Genome-wide association studies have implicated thousands of non-coding variants across human phenotypes. However, they cannot directly inform the cellular context in which disease-associated variants act. Here, we use open chromatin profiles from discrete mouse cell populations to address this challenge. We applied stratified linkage disequilibrium score regression and evaluated heritability enrichment in 64 genome-wide association studies, emphasizing schizophrenia. We provide evidence that mouse-derived human open chromatin profiles can serve as powerful proxies for difficult to obtain human cell populations, facilitating the illumination of common disease heritability enrichment across an array of human phenotypes. We demonstrate signatures from discrete subpopulations of cortical excitatory and inhibitory neurons are significantly enriched for schizophrenia heritability with maximal enrichment in discrete cortical layer V excitatory neurons. We also show differences between schizophrenia and bipolar disorder are concentrated in excitatory neurons in layers II-III, IV, V as well as the dentate gyrus. Finally, we use these data to fine-map variants in 177 schizophrenia loci, nominating variants in 104/177 loci, and place them in the cellular context where they may modulate risk.

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Characterization of a human-specific tandem repeat associated with bipolar disorder and schizophrenia

Cited by 17 publications

References 61 publications

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

A robust benchmark for germline structural variant detection

Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia

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