Pathway analysis by randomization incorporating structure—PARIS: an update

Butkiewicz, Mariusz; Bailey, Jessica N. Cooke; Frase, Alex T.; Dudek, Scott M.; Yaspan, Brian L.; Ritchie, Marylyn D.; Pendergrass, Sarah A.; Haines, Jonathan L.

doi:10.1093/bioinformatics/btw130

Cited by 10 publications

(14 citation statements)

References 6 publications

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“…We submitted the P values from SNPs within 50 kB of the start and end sites of these genes to PARIS (v2.4). 23 We have previously described PARIS 23 , 24 and used a prior version of this software to assess the estrogen metabolism pathway gene variants in relation to POAG. 15 PARIS derives a P value for association between a given gene variant set and outcome of interest using a permutation procedure.…”

Section: Methodsmentioning

confidence: 99%

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Bailey

Gharahkhani

Kang

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeSex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk.MethodsWe used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]).ResultsIn the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations.ConclusionsCollectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

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Section: Methodsmentioning

confidence: 99%

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Bailey

Gharahkhani

Kang

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…Finer sub-classifications of phenotypes allow one to focus on pathways and convergence of specific phenotypes onto those pathways. One such pathway enrichment tool, PARIS, allows for pathway analysis by randomization incorporating structure [9]. Pathway analysis aggregates single variants results into a single score, allowing modest association signals to collectively reach significance, essentially increasing the signal to noise ratio.…”

Section: Qars and Other Locimentioning

confidence: 99%

“…It is pertinent to ask whether the identified loci point to genes involved in common processes, active at specific cell types at the stages of development. We conducted a pathway enrichment analysis of the set of highly significant results (SNPs in the identified region as discussed) using tools such PARIS [9] and DAVID with primary results shown in Table 1. Interestingly, the significant pathways include axon guidance, circadian rhythm, addiction related pathways and vitamin B metabolism among others.…”

Section: Functional Significance Of the Region For Asdmentioning

confidence: 99%

Modifiers of Severity in Autism Spectrum Disorder

pS¹,

Smieszekp²

2019

J Genet Genome Res

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Autism Spectrum Disorder (ASD) comprises a complex of neurodevelopmental disorders primarily characterized by deficits in verbal communication, impaired social interaction and repetitive behaviors. The complex genetic architecture of ASD encompasses profound clinical heterogeneity, which poses huge challenges in understanding its pathophysiology. We conducted a large scale association analysis of the MSSNG whole genome sequencing data to elucidate potential modifiers of ASD severity. Using linear regression, we have directly tested the association between 6,198,166 SNPs and Vineland Adaptive Behavior Scale Scores a standardized metric for measuring severity across multiple ASD spectra.

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“…Theoretically, this method could be applied to any algorithm that allows the use of custom gene sets. As another example, PARIS (Butkiewicz et al., ; Yaspan et al., ) contains functionality for assessing the contribution of SNPs within each individual gene as they relate to the significance of a pathway as a whole.…”

Section: Commentarymentioning

confidence: 99%

Strategies for Pathway Analysis Using GWAS and WGS Data

White

Yaspan²,

Veatch

et al. 2018

CP Human Genetics

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Single allele study designs, commonly used in genome-wide association studies (GWAS) as well as the more recently developed whole genome sequencing (WGS) studies, are a standard approach for investigating the relationship of common variation within the human genome to a given phenotype of interest. However, single-allele association results published for many GWAS studies represent only the tip of the iceberg for the information that can be extracted from these datasets. The primary analysis strategy for GWAS entails association analysis in which only the single nucleotide polymorphisms (SNPs) with the strongest p-values are declared statistically significant due to issues arising from multiple testing and type I errors. Factors such as locus heterogeneity, epistasis, and multiple genes conferring small effects contribute to the complexity of the genetic models underlying phenotype expression. Thus, many biologically meaningful associations having lower effect sizes at individual genes are overlooked, making it difficult to separate true associations from a sea of false-positive associations. Organizing these individual SNPs into biologically meaningful groups to look at the overall effects of minor perturbations to genes and pathways is desirable. This pathway-based approach provides researchers with insight into the functional foundations of the phenotype being studied and allows testing of various genetic scenarios.

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Pathway analysis by randomization incorporating structure—PARIS: an update

Cited by 10 publications

References 6 publications

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Modifiers of Severity in Autism Spectrum Disorder

Strategies for Pathway Analysis Using GWAS and WGS Data

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