Exome sequencing supports a de novo mutational paradigm for schizophrenia

Xu, Bin; Roos, J.L.; Dexheimer, Phillip; Boone, Braden; Plummer, Brooks; Levy, Shawn; Gogos, Joseph A.; Karayiorgou, Maria

doi:10.1038/ng.902

Cited by 426 publications

(365 citation statements)

References 35 publications

Supporting

Mentioning

324

Contrasting

Unclassified

Order By: Relevance

“…4,22,26,39 Vissers et al 4 showed that de novo point mutations could be linked to disease in 7 out of 10 patients with intellectual disability, indicating that these mutations may explain the large majority of the genetic burden. These remarkable findings in intellectual disability have recently been replicated in sporadic forms of autism 39 and schizophrenia, 5 indicating that de novo mutations may explain a considerable proportion of the sporadic forms of common neurodevelopmental disorders. 4,40 Note that, as for the other strategies, variants prioritized in this way are more likely to be causative for disease, but de novo occurrence in itself is not sufficient evidence, and follow-up studies are required to identify recurrence or functional proof of pathogenicity.…”

Section: Gene Identification Strategies For Exome Sequencing C Gilissmentioning

confidence: 90%

Disease gene identification strategies for exome sequencing

et al. 2012

View full text Add to dashboard Cite

Section: Gene Identification Strategies For Exome Sequencing C Gilissmentioning

confidence: 90%

Disease gene identification strategies for exome sequencing

et al. 2012

View full text Add to dashboard Cite

“…Gbx2 is a homeobox transcriptional factor that has been shown to regulate various aspects of neural stem cell differentiation (44) and may contribute to the reported effects of GCs on differentiation of distinct neuroprogenitors (11)(12)(13). No role for phospholipase C-related protein (Plcl2) in neurodevelopment or GC action has been reported, although Plcl2 was identified in exome sequencing analysis as one of 40 genes with protein coding sequence variations in schizophrenia patients (45).…”

Section: Discussionmentioning

confidence: 99%

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Peffer

Chandran

Luthra

et al. 2014

Molecular and Cellular Biology

View full text Add to dashboard Cite

While glucocorticoids (GCs) are used clinically to treat many conditions, their neonatal and prenatal usage is increasingly controversial due to reports of delayed adverse outcomes, especially their effects on brain development. Such alterations may reflect the impact of GCs on neural progenitor/stem cell (NPSC) function. We previously demonstrated that the lipid raft protein caveolin-1 (Cav-1) was required for rapid GC signaling in embryonic mouse NPSCs operating through plasma membranebound glucocorticoid receptors (GRs). We show here that genomic GR signaling in NPSCs requires Cav-1. Loss of Cav-1 impacts the transcriptional response of many GR target genes (e.g., the serum-and glucocorticoid-regulated kinase 1 gene) that are likely to mediate the antiproliferative effects of GCs. Microarray analysis of wild-type C57 or Cav-1-deficient NPSCs identified approximately 100 genes that are differentially regulated by GC treatment. These changes in hormone responsiveness in Cav-1 knockout NPSCs are associated with the loss of GC-regulated phosphorylation of GR at serine 211 but not at serine 226. Chromatin recruitment of total GR to regulatory regions of target genes such as Fkbp-5, RhoJ, and Sgk-1, as well as p211-GR recruitment to Sgk-1, are compromised in Cav-1 knockout NPSCs. Cav-1 is therefore a multifunctional regulator of GR in NPSCs influencing both rapid and genomic action of the receptor to impact cell proliferation.

show abstract

“…9 Since that publication, the study has generated exome sequence data for most participants. 21 The National Human Genome Research Institute's Institutional Review Board approved this study.…”

Section: Methodsmentioning

confidence: 99%

Intentions to receive individual results from whole-genome sequencing among participants in the ClinSeq study

et al. 2012

View full text Add to dashboard Cite

Genome sequencing has been rapidly integrated into clinical research and is currently marketed to health-care practitioners and consumers alike. The volume of sequencing data generated for a single individual and the wide range of findings from wholegenome sequencing raise critical questions about the return of results and their potential value for end-users. We conducted a mixed-methods study of 311 sequential participants in the NIH ClinSeq study to assess general preferences and specific attitudes toward learning results. We tested how these variables predicted intentions to receive results within four categories of findings ranging from medically actionable to variants of unknown significance. Two hundred and ninety-four participants indicated a preference to learn their genome sequencing results. Most often, participants cited disease prevention as their reason, including intention to change their lifestyle behaviors. Participants held positive attitudes, strongly perceived social norms and strong intentions to learn results, although there were significant mean differences among four categories of findings (Po0.01). Attitudes and social norms for medically actionable and carrier results were most similar and rated the highest. Participants distinguished among the types and quality of information they may receive, despite strong intentions to learn all results presented. These intentions were motivated by confidence in their ability to use the information to prevent future disease and a belief in the value of even uninterpretable information. It behooves investigators to facilitate participants' desire to learn a range of information from genomic sequencing while promoting realistic expectations for its clinical and personal utility.

show abstract

Exome sequencing supports a de novo mutational paradigm for schizophrenia

Cited by 426 publications

References 35 publications

Disease gene identification strategies for exome sequencing

Disease gene identification strategies for exome sequencing

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Intentions to receive individual results from whole-genome sequencing among participants in the ClinSeq study

Contact Info

Product

Resources

About