Dataset Information

Multi-SNP mediation intersection-union test.

ABSTRACT: SUMMARY:Tens of thousands of reproducibly identified GWAS (Genome-Wide Association Studies) variants, with the vast majority falling in non-coding regions resulting in no eventual protein products, call urgently for mechanistic interpretations. Although numerous methods exist, there are few, if any methods, for simultaneously testing the mediation effects of multiple correlated SNPs via some mediator (e.g. the expression of a gene in the neighborhood) on phenotypic outcome. We propose multi-SNP mediation intersection-union test (SMUT) to fill in this methodological gap. Our extensive simulations demonstrate the validity of SMUT as well as substantial, up to 92%, power gains over alternative methods. In addition, SMUT confirmed known mediators in a real dataset of Finns for plasma adiponectin level, which were missed by many alternative methods. We believe SMUT will become a useful tool to generate mechanistic hypotheses underlying GWAS variants, facilitating functional follow-up. AVAILABILITY AND IMPLEMENTATION:The R package SMUT is publicly available from CRAN at https://CRAN.R-project.org/package=SMUT. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

SUBMITTER: Zhong W

PROVIDER: S-EPMC6853702 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Multi-SNP mediation intersection-union test.

Zhong Wujuan W Spracklen Cassandra N CN Mohlke Karen L KL Zheng Xiaojing X Fine Jason J Li Yun Y

Bioinformatics (Oxford, England) 20191101 22

<h4>Summary</h4>Tens of thousands of reproducibly identified GWAS (Genome-Wide Association Studies) variants, with the vast majority falling in non-coding regions resulting in no eventual protein products, call urgently for mechanistic interpretations. Although numerous methods exist, there are few, if any methods, for simultaneously testing the mediation effects of multiple correlated SNPs via some mediator (e.g. the expression of a gene in the neighborhood) on phenotypic outcome. We propose mu ...[more]

PMID: 31099385

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Project description:BackgroundApproximately twice as many females as males are diagnosed with posttraumatic stress disorder (PTSD). However, little is known about why females report more PTSD symptoms than males. Prior studies have generally focused on few potential mediators at a time and have often used methods that were not ideally suited to test for mediation effects. Prior research has identified a number of individual risk factors that may contribute to sex differences in PTSD severity, although these cannot fully account for the increased symptom levels in females when examined individually.ObjectiveThe present study is the first to systematically test the hypothesis that a combination of pre-, peri-, and posttraumatic risk factors more prevalent in females can account for sex differences in PTSD severity.MethodThe study was a quasi-prospective questionnaire survey assessing PTSD and related variables in 73.3% of all Danish bank employees exposed to bank robbery during the period from April 2010 to April 2011. Participants filled out questionnaires 1 week (T1, N=450) and 6 months after the robbery (T2, N=368; 61.1% females). Mediation was examined using an analysis designed specifically to test a multiple mediator model.ResultsFemales reported more PTSD symptoms than males and higher levels of neuroticism, depression, physical anxiety sensitivity, peritraumatic fear, horror, and helplessness (the A2 criterion), tonic immobility, panic, dissociation, negative posttraumatic cognitions about self and the world, and feeling let down. These variables were included in the model as potential mediators. The combination of risk factors significantly mediated the association between sex and PTSD severity, accounting for 83% of the association.ConclusionThe findings suggest that females report more PTSD symptoms because they experience higher levels of associated risk factors. The results are relevant to other trauma populations and to other trauma-related psychiatric disorders more prevalent in females, such as depression and anxiety.

Dataset Information

Multi-SNP mediation intersection-union test.

Publications

Multi-SNP mediation intersection-union test.

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