The functional false discovery rate with applications to genomics

Chen, Xiongzhi; Robinson, David G.; Storey, J. Douglas

doi:10.1093/biostatistics/kxz010

Cited by 36 publications

(20 citation statements)

References 36 publications

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“…The q value is a useful algorithm to correct for multiple testing given that with traditional FDR cannot be defined when there are no positive results. A recent update to this algorithm using an additional informative variable approach is available for processes such eQTL mapping or RNA-seq data where an additional variable such as read depth can enhance the overall amount of information available to calculate these q values [ 46 ]. The remaining genes (the general pool) were still examined to avoid ignoring potentially important surprise findings; however, their q values [ 45 ] were calculated independently from those of the candidate pool.…”

Section: Methodsmentioning

confidence: 99%

mRNA expression analysis of the hippocampus in a vervet monkey model of fetal alcohol spectrum disorder

Gillis

Palmour

2022

J Neurodevelop Disord

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Background Fetal alcohol spectrum disorders (FASD) are common, yet preventable developmental disorders that stem from prenatal exposure to alcohol. This exposure leads to a wide array of behavioural and physical problems with a complex and poorly defined biological basis. Molecular investigations to date predominantly use rodent animal models, but because of genetic, developmental and social behavioral similarity, primate models are more relevant. We previously reported reduced cortical and hippocampal neuron levels in an Old World monkey (Chlorocebus sabaeus) model with ethanol exposure targeted to the period of rapid synaptogenesis and report here an initial molecular study of this model. The goal of this study was to evaluate mRNA expression of the hippocampus at two different behavioural stages (5 months, 2 years) corresponding to human infancy and early childhood. Methods Offspring of alcohol-preferring or control dams drank a maximum of 3.5 g ethanol per kg body weight or calorically matched sucrose solution 4 days per week during the last 2 months of gestation. Total mRNA expression was measured with the Affymetrix GeneChip Rhesus Macaque Genome Array in a 2 × 2 study design that interrogated two independent variables, age at sacrifice, and alcohol consumption during gestation. Results and discussion Statistical analysis identified a preferential downregulation of expression when interrogating the factor ‘alcohol’ with a balanced effect of upregulation vs. downregulation for the independent variable ‘age’. Functional exploration of both independent variables shows that the alcohol consumption factor generates broad functional annotation clusters that likely implicate a role for epigenetics in the observed differential expression, while the variable age reliably produced functional annotation clusters predominantly related to development. Furthermore, our data reveals a novel connection between EFNB1 and the FASDs; this is highly plausible both due to the role of EFNB1 in neuronal development as well as its central role in craniofrontal nasal syndrome (CFNS). Fold changes for key genes were subsequently confirmed via qRT-PCR. Conclusion Prenatal alcohol exposure leads to global downregulation in mRNA expression. The cellular interference model of EFNB1 provides a potential clue regarding how genetically susceptible individuals may develop the phenotypic triad generally associated with classic fetal alcohol syndrome.

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Section: Methodsmentioning

confidence: 99%

mRNA expression analysis of the hippocampus in a vervet monkey model of fetal alcohol spectrum disorder

Gillis

Palmour

2022

J Neurodevelop Disord

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“…Kaplan-Meier curve and log-rank test were conducted for survival analysis using GraphPad Prism v.5.0 (GraphPad Software, Inc.). The aberrantly expressed lncRNAs were explored according to Benjamini-Hochberg method ( 29 ). P<0.05 was considered to indicate a statistically significant difference.…”

Section: Methodsmentioning

confidence: 99%

lncRNA KTN1‑AS1 promotes glioma cell proliferation and invasion by negatively regulating miR‑505‑3p

Tang

Feng

et al. 2020

Oncol Rep

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Glioblastoma (GBM) is one of the most prevalent and aggressive central nervous tumors with high mobility and mortality. The prognosis of patients with GBM is poor. It is therefore essential to explore the therapeutic strategies for the treatment of GBM. Previous studies have demonstrated that the long non-coding RNA (lncRNA) Kinectin 1-Antisense RNA 1 (KTN1-AS1) can participate in the development of several types of cancer. However, the underlying mechanism of KTN1-AS1 in GBM remains unknown. The present study aimed to determine the potential role of KTN1-AS1 in GBM. In this study, reverse transcription quantitative PCR analysis was conducted and the results demonstrated that KTN1-AS1 was upregulated in GBM tissues and cell lines compared with normal tissues and astrocytes (NHA). Furthermore, KTN1-AS1 knockdown decreased the viability and invasive ability of glioma cells in vitro and in vivo . In addition, high level of KTN1-AS1 was correlated with poor prognosis in TCGA GBM database. Furthermore, microRNA-505-3p (miR-505-3p) was a promising target of KTN1-AS1, and the suppressing effects of miR-505-3p on cell proliferation and invasive ability was reversed by downregulating KTN1-AS1. Taken together, the results from the present provided novel insights into the roles of KTN1-AS1 in GBM, and suggested that the KTN1-AS1/miR-505-3p axis may be considered as a novel therapeutic target for the treatment of patients with GBM.

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“…We test m features, and for each feature i , we let X i be a factor with values in {0,1} expressing whether the feature was significantly differential in experiment 1 ( X i = 1), or not ( X i = 0). We are interested in whether the variable X = ( X 1 , …, X m ) is an informative covariate for experiment 2, using terminology from recent work in covariate-powered multiple hypothesis testing 42,43 .…”

Section: Methodsmentioning

confidence: 99%

“…= 0). We are interested in whether the variable = ( " , … , # ) is an informative covariate for experiment 2, using terminology from recent work in covariate-powered multiple hypothesis testing 42,43 .…”

Section: Testing For Statistically Significant Overlap Between Two LImentioning

confidence: 99%

Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

Luperchio

Boukas

Zhang

et al. 2020

Preprint

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The Mendelian Disorders of the Epigenetic Machinery (MDEMs) have emerged as a class of Mendelian disorders caused by loss-of-function variants in epigenetic regulators. Although each MDEM has a different causative gene, they exhibit several overlapping disease manifestations. Here, we hypothesize that this phenotypic convergence is a consequence of common abnormalities at the epigenomic level, which directly or indirectly lead to downstream convergence at the transcriptomic level. This implies that identifying abnormalities shared across multiple MDEMs could pinpoint locations where epigenetic variation is causally related to disease phenotypes. To test our hypothesis, we perform a comprehensive interrogation of chromatin (ATAC-Seq) and expression (RNA-Seq) states in B cells from mouse models of three MDEMs (Kabuki types 1&2 and Rubinstein-Taybi syndromes). We build on recent work in covariate-powered multiple testing to develop a new approach for the overlap analysis, which enables us to find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often leads to disruption of downstream gene expression, and identify a total of 463 loci and 249 genes commonly disrupted across the three MDEMs. As an example of how widespread dysregulation leads to specific phenotypes, we show that subtle expression alterations of multiple, directly relevant genes, collectively contribute to IgA deficiency in KS1 and RT. In contrast, we predict that KS2 does not have IgA deficiency, and confirm this pattern in mice. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.

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The functional false discovery rate with applications to genomics

Cited by 36 publications

References 36 publications

mRNA expression analysis of the hippocampus in a vervet monkey model of fetal alcohol spectrum disorder

mRNA expression analysis of the hippocampus in a vervet monkey model of fetal alcohol spectrum disorder

lncRNA KTN1‑AS1 promotes glioma cell proliferation and invasion by negatively regulating miR‑505‑3p

Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

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