Detecting and Characterizing Pleiotropy: New Methods for Uncovering the Connection Between the Complexity of Genomic Architecture and Multiple Phenotypes- Session Introduction

Tyler, Anna L.; Crawford, Dana C.; Pendergrass, Sarah A.

doi:10.1142/9789814583220_0018

Cited by 7 publications

(5 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to the low Jaccard/Tanimoto coefficients for the HPO terms, the coefficients for the top-level HPO categories were relatively high. This observation supports a modular view of pleiotropy (28). A modular character of gene–trait relationships in particular means that mutations in a certain gene may lead to the development of different, partially overlapping combinations of clinical signs and symptoms with non-random clustering (29).…”

Section: Discussionsupporting

confidence: 85%

Gene- and Disease-Based Expansion of the Knowledge on Inborn Errors of Immunity

et al. 2019

View full text Add to dashboard Cite

The recent report of the International Union of Immunological Societies (IUIS) has provided the categorized list of 354 inborn errors of immunity. We performed a systematic analysis of genes and diseases from the IUIS report with the use of the OMIM, ORPHANET, and HPO resources. To measure phenotypic similarity we applied the Jaccard/Tanimoto (J/T) coefficient for HPO terms and top-level categories. Low J/T coefficients for HPO terms for OMIM or ORPHANET disease pairs associated with the same genes indicated high pleiotropy of these genes. Gene ORGANizer enrichment analysis demonstrated that gene sets related to HPO top-level categories were most often enriched in immune, lymphatic, and corresponding body systems (for example, genes from the category “Cardiovascular” were enriched in cardiovascular system). We presented available data on frequent and very frequent clinical signs and symptoms in inborn errors of immunity. With the use of DisGeNET, we generated the list of 25 IUIS/OMIM diseases with two or more relatively high score gene-disease associations, found for unrelated genes and/or for clusters of genes coding for interacting proteins. Our study showed the enrichment of gene sets related to several IUIS categories with neoplastic and autoimmune diseases from the GWAS Catalog and reported individual genes with phenotypic overlap between inborn errors of immunity and GWAS diseases/traits. We concluded that genetic background may play a role in phenotypic diversity of inborn errors of immunity.

show abstract

Section: Discussionsupporting

confidence: 85%

Gene- and Disease-Based Expansion of the Knowledge on Inborn Errors of Immunity

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Thus, the system can be channelled toward different "predetermined" pathways/attractors. Moreover, some opposing pathways (e.g., proliferation versus death, senescence versus oncogenesis) can be driven, even by the same pleiotropic genes, f.ex., by c-myc and ras [118,119], or by reversible shifts of pou5f1 from full to spliced transcript [120]. In the emergency conditions of the limited resources, this tactic of coupling the opposite effects driven by the same genes, even within the same bi-potential cell undergoing asymmetric division, allows for concentrate growth factors for a few channelled survivors [91,121].…”

Section: Cancer Cell Treatment Resistance Is Ensured By Deterministicmentioning

confidence: 99%

Resolution of Complex Issues in Genome Regulation and Cancer Requires Non-Linear and Network-Based Thermodynamics

Ērenpreisa

Giuliani

2019

IJMS

View full text Add to dashboard Cite

The apparent lack of success in curing cancer that was evidenced in the last four decades of molecular medicine indicates the need for a global re-thinking both its nature and the biological approaches that we are taking in its solution. The reductionist, one gene/one protein method that has served us well until now, and that still dominates in biomedicine, requires complementation with a more systemic/holistic approach, to address the huge problem of cross-talk between more than 20,000 protein-coding genes, about 100,000 protein types, and the multiple layers of biological organization. In this perspective, the relationship between the chromatin network organization and gene expression regulation plays a fundamental role. The elucidation of such a relationship requires a non-linear thermodynamics approach to these biological systems. This change of perspective is a necessary step for developing successful 'tumour-reversion' therapeutic strategies.

show abstract

“…Graph-guided fused lasso (GFlasso) has also been introduced as a method for working with a large number of correlated phenotypes [44] . The CAPE method has been developed to analyze pleiotropy in addition to gene-gene epistatic interactions [45,46]. Other approaches beyond PheWAS include a study assessing the results of multiple studies, taking correlation between a range of metabolic traits and inflammatory markers into account [4].…”

Section: Challenges and Promise For Complex Comprehensive Phenotypic mentioning

confidence: 99%

Phenome-Wide Association Studies: Leveraging Comprehensive Phenotypic and Genotypic Data for Discovery

Pendergrass

Ritchie

2015

Curr Genet Med Rep

View full text Add to dashboard Cite

With the large volume of clinical and epidemiological data being collected, increasingly linked to extensive genotypic data, coupled with expanding high-performance computational resources, there are considerable opportunities for comprehensively exploring the networks of connections that exist between the phenome and the genome. These networks can be identified through Phenome-Wide Association Studies (PheWAS) where the association between a collection of genetic variants, or in some cases a particular clinical lab variable, and a wide and diverse range of phenotypes, diagnoses, traits, and/or outcomes are evaluated. This is a departure from the more familiar genome-wide association study (GWAS) approach, which has been used to identify single nucleotide polymorphisms (SNPs) associated with one outcome or a very limited phenotypic domain. In addition to highlighting novel connections between multiple phenotypes and elucidating more of the phenotype-genotype landscape, PheWAS can generate new hypotheses for further exploration, and can also be used to narrow the search space for research using comprehensive data collections. The complex results of PheWAS also have the potential for uncovering new mechanistic insights. We review here how the PheWAS approach has been used with data from epidemiological studies, clinical trials, and de-identified electronic health record data. We also review methodologies for the analyses underlying PheWAS, and emerging methods developed for evaluating the comprehensive results of PheWAS including genotype-phenotype networks. This review also highlights PheWAS as an important tool for identifying new biomarkers, elucidating the genetic architecture of complex traits, and uncovering pleiotropy. There are many directions and new methodologies for the future of PheWAS analyses, from the phenotypic data to the genetic data, and herein we also discuss some of these important future PheWAS developments.

show abstract

Detecting and Characterizing Pleiotropy: New Methods for Uncovering the Connection Between the Complexity of Genomic Architecture and Multiple Phenotypes- Session Introduction

Cited by 7 publications

References 14 publications

Gene- and Disease-Based Expansion of the Knowledge on Inborn Errors of Immunity

Gene- and Disease-Based Expansion of the Knowledge on Inborn Errors of Immunity

Resolution of Complex Issues in Genome Regulation and Cancer Requires Non-Linear and Network-Based Thermodynamics

Phenome-Wide Association Studies: Leveraging Comprehensive Phenotypic and Genotypic Data for Discovery

Contact Info

Product

Resources

About