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  • Genetics Society of America (GSA)  (1)
  • The American Association of Immunologists (AAI)  (1)
  • 1
    Publication Date: 2018-10-05
    Description: The genetic etiology of many complex diseases is highly heterogeneous. A complex disease can be caused by multiple mutations within the same gene or mutations in multiple genes at various genomic loci. Although these disease-susceptibility mutations can be collectively common in the population, they are often individually rare or even private to certain families. Family-based studies are powerful for detecting rare variants enriched in families, which is an important feature for sequencing studies due to the heterogeneous nature of rare variants. In addition, family designs can provide robust protection against population stratification. Nevertheless, statistical methods for analyzing family-based sequencing data are underdeveloped, especially those accounting for heterogeneous etiology of complex diseases. In this article, we introduce a random field framework for detecting gene-phenotype associations in family-based sequencing studies, referred to as family-based genetic random field (FGRF). Similar to existing family-based association tests, FGRF could utilize within-family and between-family information separately or jointly to test an association. We demonstrate that FGRF has comparable statistical power with existing methods when there is no genetic heterogeneity, but can improve statistical power when there is genetic heterogeneity across families. The proposed method also shares the same advantages with the conventional family-based association tests ( e.g. , being robust to population stratification). Finally, we applied the proposed method to a sequencing data from the Minnesota Twin Family Study, and revealed several genes, including SAMD14 , potentially associated with alcohol dependence.
    Print ISSN: 0016-6731
    Topics: Biology
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  • 2
    Publication Date: 2018-06-19
    Description: Enterovirus 71 (EV71) induces significantly elevated levels of cytokines and chemokines, leading to local or systemic inflammation and severe complications. As shown in our previous study, microRNA (miR) 302c regulates influenza A virus–induced IFN expression by targeting NF-B-inducing kinase. However, little is known about the role of the miR-302 cluster in EV71-mediated proinflammatory responses. In this study, we found that the miR-302 cluster controls EV71-induced cytokine expression. Further studies demonstrated that karyopherin α2 (KPNA2) is a direct target of the miR-302 cluster. Interestingly, we also found that EV71 infection upregulates KPNA2 expression by downregulating miR-302 cluster expression. Upon investigating the mechanisms behind this event, we found that KPNA2 intracellularly associates with JNK1/JNK2 and p38, leading to translocation of those transcription factors from the cytosol into the nucleus. In EV71-infected patients, miR-302 cluster expression was downregulated and KPNA2 expression was upregulated compared with controls, and their expression levels were closely correlated. Taken together, our work establishes a link between the miR-302/ KPNA2 axis and EV71-induced cytokine expression and represents a promising target for future antiviral therapy.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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