Dataset Information

Application of systems biology approach identifies and validates GRB2 as a risk gene for schizophrenia in the Irish Case Control Study of Schizophrenia (ICCSS) sample.

ABSTRACT: Recently, we prioritized 160 schizophrenia candidate genes (SZGenes) by integrating multiple lines of evidence and subsequently identified twenty-four pathways in which these 160 genes are overrepresented. Among them, four neurotransmitter-related pathways were top ranked. In this study, we extended our previous pathway analysis by applying a systems biology approach to identifying candidate genes for schizophrenia. We constructed protein-protein interaction subnetworks for four neurotransmitter-related pathways and merged them to obtain a general neurotransmitter network, from which five candidate genes stood out. We tested the association of four genes (GRB2, HSPA5, YWHAG, and YWHAZ) in the Irish Case-Control Study of Schizophrenia (ICCSS) sample (1021 cases and 626 controls). Interestingly, six of the seven tested SNPs in GRB2 showed significant signal, two of which (rs7207618 and rs9912608) remained significant after permutation test or Bonferroni correction, suggesting that GRB2 might be a risk gene for schizophrenia in Irish population. To our knowledge, this is the first report of GRB2 being significantly associated with schizophrenia in a specific population. Our results suggest that the systems biology approach is promising for identification of candidate genes and understanding the etiology of complex diseases.

SUBMITTER: Sun J

PROVIDER: S-EPMC3031722 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Application of systems biology approach identifies and validates GRB2 as a risk gene for schizophrenia in the Irish Case Control Study of Schizophrenia (ICCSS) sample.

Sun Jingchun J Wan Chunling C Jia Peilin P Fanous Ayman H AH Kendler Kenneth S KS Riley Brien P BP Zhao Zhongming Z

Schizophrenia research 20101230 2-3

Recently, we prioritized 160 schizophrenia candidate genes (SZGenes) by integrating multiple lines of evidence and subsequently identified twenty-four pathways in which these 160 genes are overrepresented. Among them, four neurotransmitter-related pathways were top ranked. In this study, we extended our previous pathway analysis by applying a systems biology approach to identifying candidate genes for schizophrenia. We constructed protein-protein interaction subnetworks for four neurotransmitter ...[more]

PMID: 21195589

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Project description:Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This sine qua non of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different "omics," clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. Moreover, first trimester maternal blood from preterm preeclamptic patients in vitro dysregulated trophoblastic gene expression. Placental transcriptomics of women with preterm preeclampsia identified distinct gene modules associated with maternal or fetal disease. Placental "virtual" liquid biopsy showed that the dysregulation of these disease gene modules originates during the first trimester. In vitro experiments on hub transcription factors of these gene modules demonstrated that DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, while BCL6 and ARNT2 up-regulation sensitizes the trophoblast to ischemia, hallmarks of preterm preeclampsia. In summary, our data suggest that there are distinct maternal and placental disease pathways, and their interaction influences the clinical presentation of preeclampsia. The activation of maternal disease pathways can be detected in all phenotypes of preeclampsia earlier and upstream of placental dysfunction, not only downstream as described before, and distinct placental disease pathways are superimposed on these maternal pathways. This is a paradigm shift, which, in agreement with epidemiological studies, warrants for the central pathologic role of preexisting maternal diseases or perturbed maternal-fetal-placental immune interactions in preeclampsia. The description of these novel pathways in the "molecular phase" of preeclampsia and the identification of their hub molecules may enable timely molecular characterization of patients with distinct preeclampsia phenotypes.

Project description:ObjectiveThe transcription factor networks that drive parotid salivary gland progenitor cells to terminally differentiate, remain largely unknown and are vital to understanding the regeneration process.MethodologyA systems biology approach was taken to measure mRNA and microRNA expression in vivo across acinar cell terminal differentiation in the rat parotid salivary gland. Laser capture microdissection (LCM) was used to specifically isolate acinar cell RNA at times spanning the month-long period of parotid differentiation.ResultsClustering of microarray measurements suggests that expression occurs in four stages. mRNA expression patterns suggest a novel role for Pparg which is transiently increased during mid postnatal differentiation in concert with several target gene mRNAs. 79 microRNAs are significantly differentially expressed across time. Profiles of statistically significant changes of mRNA expression, combined with reciprocal correlations of microRNAs and their target mRNAs, suggest a putative network involving Klf4, a differentiation inhibiting transcription factor, which decreases as several targeting microRNAs increase late in differentiation. The network suggests a molecular switch (involving Prdm1, Sox11, Pax5, miR-200a, and miR-30a) progressively decreases repression of Xbp1 gene transcription, in concert with decreased translational repression by miR-214. The transcription factor Xbp1 mRNA is initially low, increases progressively, and may be maintained by a positive feedback loop with Atf6. Transfection studies show that Xbp1 activates the Mist1 promoter [corrected]. In addition, Xbp1 and Mist1 each activate the parotid secretory protein (Psp) gene, which encodes an abundant salivary protein, and is a marker of terminal differentiation.ConclusionThis study identifies novel expression patterns of Pparg, Klf4, and Sox11 during parotid acinar cell differentiation, as well as numerous differentially expressed microRNAs. Network analysis identifies a novel stemness arm, a genetic switch involving transcription factors and microRNAs, and transition to an Xbp1 driven differentiation network. This proposed network suggests key regulatory interactions in parotid gland terminal differentiation.

Dataset Information

Application of systems biology approach identifies and validates GRB2 as a risk gene for schizophrenia in the Irish Case Control Study of Schizophrenia (ICCSS) sample.

Publications

Application of systems biology approach identifies and validates GRB2 as a risk gene for schizophrenia in the Irish Case Control Study of Schizophrenia (ICCSS) sample.

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