A sequence of methodological changes due to sequencing

Burkett, Kelly; Greenwood, Celia M.T.

doi:10.1097/aci.0b013e3283648f68

Cited by 9 publications

(5 citation statements)

References 68 publications

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“…Accordingly, IL‐1 blockade shows efficacy in treating AOSD symptoms in refractory cases . Recent advances in sequencing technology are allowing investigators to sequence selected genes to discover low‐frequency variants in patients with complex and genetically matched controls . Thus, we propose that MEFV mutations/polymorphisms may be one of the genetic factors associated with AOSD.…”

Section: Introductionmentioning

confidence: 99%

Increased prevalence of MEFV exon 10 variants in Japanese patients with adult-onset Still's disease

Nonaka

Migita

Jiuchi

et al. 2015

Clinical and Experimental Immunology

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SummaryAutoinflammatory diseases include a large spectrum of monogenic diseases, e.g. familial Mediterranean fever (FMF), as well as complex genetic trait diseases, e.g. adult-onset Still's disease (AOSD). In populations where FMF is common, an increased MEFV mutation rate is found in patients with rheumatic diseases. The aim of this study was to examine MEFV mutations in Japanese patients with AOSD. Genomic DNA was isolated from 49 AOSD patients and 105 healthy controls, and exons 1, 2, 3 and 10 of the MEFV gene genotyped by direct sequencing. MEFV mutation frequencies in AOSD patients were compared with controls. We found no significant difference in overall allele frequencies of MEFV variants between AOSD patients and controls. However, MEFV exon 10 variants (M694I and G632S) were significantly higher in AOSD patients than controls (6·1 versus 0%). In addition, there was no significant difference between MEFV variant carriers and noncarriers with clinical manifestations, but the monocyclic clinical course of the AOSD disease phenotype was observed less frequently in patients without MEFV variants. AOSD patients had significantly higher frequencies of MEFV exon 10 mutations, suggesting that low-frequency variants of MEFV gene may be one of the susceptibility factors of AOSD.

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Section: Introductionmentioning

confidence: 99%

Increased prevalence of MEFV exon 10 variants in Japanese patients with adult-onset Still's disease

Nonaka

Migita

Jiuchi

et al. 2015

Clinical and Experimental Immunology

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“…In set-based analyses, SNPs are assigned to SNP sets by forming linkage disequilibrium (LD) blocks, using sliding windows or on the basis of some meaningful biological criteria (genomic features); e.g., genes or pathways 1 . Many different set-based methods have been proposed, such as burden tests 2 , 3 , variance component score test 4 , the combination of these two types of tests 5 , 6 , and many others 7 .…”

Section: Introductionmentioning

confidence: 99%

Exome-wide rare variant analyses of two bone mineral density phenotypes: the challenges of analyzing rare genetic variation

Sun

Oualkacha

Forgetta

et al. 2018

Sci Rep

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Performance of a recently developed test for association between multivariate phenotypes and sets of genetic variants (MURAT) is demonstrated using measures of bone mineral density (BMD). By combining individual-level whole genome sequenced data from the UK10K study, and imputed genome-wide genetic data on individuals from the Study of Osteoporotic Fractures (SOF) and the Osteoporotic Fractures in Men Study (MrOS), a data set of 8810 individuals was assembled; tests of association were performed between autosomal gene-sets of genetic variants and BMD measured at lumbar spine and femoral neck. Distributions of p-values obtained from analyses of a single BMD phenotype are compared to those from the multivariate tests, across several region definitions and variant weightings. There is evidence of increased power with the multivariate test, although no new loci for BMD were identified. Among 17 genes highlighted either because there were significant p-values in region-based association tests or because they were in well-known BMD genes, 4 windows in 2 genes as well as 6 single SNPs in one of these genes showed association at genome-wide significant thresholds with the multivariate phenotype test but not with the single-phenotype test, Sequence Kernel Association Test (SKAT).

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“…There is a growing literature on methods for analysis of association for a set of rare variants: for example, the burden test, 1 , 2 sequence kernel association test (SKAT), 3 optimal SKAT (SKAT-O), 4 mixed effects score test, 5 and many others. 6 Most of the existing rare-variant association tests can be thought of as univariate tests. That is, they focus on the association between a set of rare variants and a single phenotype.…”

Section: Introductionmentioning

confidence: 99%

A method for analyzing multiple continuous phenotypes in rare variant association studies allowing for flexible correlations in variant effects

et al. 2016

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For region-based sequencing data, power to detect genetic associations can be improved through analysis of multiple related phenotypes. With this motivation, we propose a novel test to detect association simultaneously between a set of rare variants, such as those obtained by sequencing in a small genomic region, and multiple continuous phenotypes. We allow arbitrary correlations among the phenotypes and build on a linear mixed model by assuming the effects of the variants follow a multivariate normal distribution with a zero mean and a specific covariance matrix structure. In order to account for the unknown correlation parameter in the covariance matrix of the variant effects, a data-adaptive variance component test based on score-type statistics is derived. As our approach can calculate the P-value analytically, the proposed test procedure is computationally efficient. Broad simulations and an application to the UK10K project show that our proposed multivariate test is generally more powerful than univariate tests, especially when there are pleiotropic effects or highly correlated phenotypes.

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A sequence of methodological changes due to sequencing

Cited by 9 publications

References 68 publications

Increased prevalence of MEFV exon 10 variants in Japanese patients with adult-onset Still's disease

Increased prevalence of MEFV exon 10 variants in Japanese patients with adult-onset Still's disease

Exome-wide rare variant analyses of two bone mineral density phenotypes: the challenges of analyzing rare genetic variation

A method for analyzing multiple continuous phenotypes in rare variant association studies allowing for flexible correlations in variant effects

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