Pathway-Based Approaches for Analysis of Genomewide Association Studies

Wang, Kai; Li, Mingyao; Bućan, Maja

doi:10.1086/522374

Cited by 788 publications

(1,035 citation statements)

References 29 publications

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“…On the other hand, SNP based GWAS do not identify all disease risk variants. Many variants conferring a small risk are overlooked and many SNPs falling below the accepted threshold of statistical significance may be relevant when investigated through pathway analyses [43,44]. Another limitation is that not all phenotypes were available in both cohorts, which in the case of the TBS data, introduces some uncertainty as to what extent bone microarchitecture rather than bone density is influenced.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in inflammation associated genes ALOX15 and IL-6 are associated with bone properties in young women and fracture in elderly

Herlin

McGuigan

Luthman

et al. 2015

Bone

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Section: Discussionmentioning

confidence: 99%

Polymorphisms in inflammation associated genes ALOX15 and IL-6 are associated with bone properties in young women and fracture in elderly

Herlin

McGuigan

Luthman

et al. 2015

Bone

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“…increasing the numbers of study participants, collaborative studies and leveraging high-density genomic data using techniques such as imputation 135 and pathway snP analysis [136][137][138][139] will help to accelerate data acquisition to find precise candidate regions or vur-specific genes. Genomic copy-number variation (Cnv) has been shown to be an important pathogenic mechanism in many other disorders in recent years, 140 but no Cnv study in vur has been reported to date.…”

Section: N a T U R E R E V I E W S U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

Genetics of vesicoureteral reflux

et al. 2011

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| Primary vesicoureteral reflux (VUR) is the most common urological anomaly in children, affecting 1-2% of the pediatric population and 30-40% of children presenting with urinary tract infections (UTIs). Refluxassociated nephropathy is a major cause of childhood hypertension and chronic renal failure. The hereditary and familial nature of VUR is well recognized and several studies have reported that siblings of children with VUR have a higher incidence of reflux than the general pediatric population. Familial clustering of VUR implies that genetic factors have an important role in its pathogenesis, but no single major locus or gene for VUR has yet been identified and most researchers now acknowledge that VUR is genetically heterogeneous. Improvements in genome-scan techniques and continuously increasing knowledge of the genetic basis of VUR should help us to further understand its pathogenesis.

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“…However, this is not to say that useful information about disease pathophysiology cannot be attained through analytic approaches that fall short of identifying a comprehensive catalogueue of individual risk variants. Thus, it has been argued that useful insights into complex disorders can be provided by analyses in which evidence is accrued for association at the gene-wide level 9,10 or at the level of pathways derived from sets of genes 11,12 that are in some way functionally interconnected. Rather than focussing on individual SNPs, the analytic approach is based on extracting information from multiple SNPs within genes or within pathways and testing whether en masse, there is some significant excess of association signal in those genes or pathways.…”

Section: Introductionmentioning

confidence: 99%

Permutation-based approaches do not adequately allow for linkage disequilibrium in gene-wide multi-locus association analysis

et al. 2012

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Additional information about risk genes or risk pathways for diseases can be extracted from genome-wide association studies through analyses of groups of markers. The most commonly employed approaches involve combining individual marker data by adding the test statistics, or summing the logarithms of their P-values, and then using permutation testing to derive empirical P-values that allow for the statistical dependence of single-marker tests arising from linkage disequilibrium (LD). In the present study, we use simulated data to show that these approaches fail to reflect the structure of the sampling error, and the effect of this is to give undue weight to correlated markers. We show that the results obtained are internally inconsistent in the presence of strong LD, and are externally inconsistent with the results derived from multi-locus analysis. We also show that the results obtained from regression and multivariate Hotelling T 2 (H-T2) testing, but not those obtained from permutations, are consistent with the theoretically expected distributions, and that the H-T2 test has greater power to detect gene-wide associations in real datasets. Finally, we show that while the results from permutation testing can be made to approximate those from regression and multivariate Hotelling T 2 testing through aggressive LD pruning of markers, this comes at the cost of loss of information. We conclude that when conducting multi-locus analyses of sets of single-nucleotide polymorphisms, regression or multivariate Hotelling T 2 testing, which give equivalent results, are preferable to the other more commonly applied approaches.

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Pathway-Based Approaches for Analysis of Genomewide Association Studies

Cited by 788 publications

References 29 publications

Polymorphisms in inflammation associated genes ALOX15 and IL-6 are associated with bone properties in young women and fracture in elderly

Polymorphisms in inflammation associated genes ALOX15 and IL-6 are associated with bone properties in young women and fracture in elderly

Genetics of vesicoureteral reflux

Permutation-based approaches do not adequately allow for linkage disequilibrium in gene-wide multi-locus association analysis

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