Dataset Information

Genome-wide association study of rheumatoid arthritis by a score test based on wavelet transformation.

ABSTRACT: BACKGROUND:We have conducted a genome-wide association study on the Genetic Analysis Workshop (GAW) 16 rheumatoid arthritis data using a multilocus score test based on wavelet transform proposed recently by the authors. The wavelet-based test automatically adjusts for the amount of noise suppressed from the data. The power of the test is also increased by using the genetic information contained in the spatial ordering of single-nucleotide polymorphisms on a chromosome. RESULTS:After adjusting for the effect of population stratification, the test identified some previously discovered rheumatoid arthritis susceptibility loci (HLA-DRB1 and rs3761847) as well as some loci (rs2076530 and rs3130340) known to have association with sarcoidosis and bone mineral density. It was previously reported that patients with rheumatoid arthritis have elevated prevalence of sarcoidosis and have reduced bone mass. CONCLUSION:This new test provides a useful tool in genome-wide association studies.

SUBMITTER: Jiang R

PROVIDER: S-EPMC2795982 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Genome-wide association study of rheumatoid arthritis by a score test based on wavelet transformation.

Jiang Renfang R Dong Jianping J Dai Yilin Y

BMC proceedings 20091215

<h4>Background</h4>We have conducted a genome-wide association study on the Genetic Analysis Workshop (GAW) 16 rheumatoid arthritis data using a multilocus score test based on wavelet transform proposed recently by the authors. The wavelet-based test automatically adjusts for the amount of noise suppressed from the data. The power of the test is also increased by using the genetic information contained in the spatial ordering of single-nucleotide polymorphisms on a chromosome.<h4>Results</h4>Aft ...[more]

PMID: 20018075

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Project description:GWAS owe their popularity to the expectation that they will make a major impact on diagnosis, prognosis and management of disease by uncovering genetics underlying clinical phenotypes. The dominant paradigm in GWAS data analysis so far consists of extensive reliance on methods that emphasize contribution of individual SNPs to statistical association with phenotypes. Multivariate methods, however, can extract more information by considering associations of multiple SNPs simultaneously. Recent advances in other genomics domains pinpoint multivariate causal graph-based inference as a promising principled analysis framework for high-throughput data. Designed to discover biomarkers in the local causal pathway of the phenotype, these methods lead to accurate and highly parsimonious multivariate predictive models. In this paper, we investigate the applicability of causal graph-based method TIE* to analysis of GWAS data. To test the utility of TIE*, we focus on anti-CCP positive rheumatoid arthritis (RA) GWAS datasets, where there is a general consensus in the community about the major genetic determinants of the disease.Application of TIE* to the North American Rheumatoid Arthritis Cohort (NARAC) GWAS data results in six SNPs, mostly from the MHC locus. Using these SNPs we develop two predictive models that can classify cases and disease-free controls with an accuracy of 0.81 area under the ROC curve, as verified in independent testing data from the same cohort. The predictive performance of these models generalizes reasonably well to Swedish subjects from the closely related but not identical Epidemiological Investigation of Rheumatoid Arthritis (EIRA) cohort with 0.71-0.78 area under the ROC curve. Moreover, the SNPs identified by the TIE* method render many other previously known SNP associations conditionally independent of the phenotype.Our experiments demonstrate that application of TIE* captures maximum amount of genetic information about RA in the data and recapitulates the major consensus findings about the genetic factors of this disease. In addition, TIE* yields reproducible markers and signatures of RA. This suggests that principled multivariate causal and predictive framework for GWAS analysis empowers the community with a new tool for high-quality and more efficient discovery.This article was reviewed by Prof. Anthony Almudevar, Dr. Eugene V. Koonin, and Prof. Marianthi Markatou.

Project description:ObjectiveRheumatoid arthritis (RA) is a complex autoimmune disease. Using a gene-based association research strategy, the present study aims to detect unknown susceptibility to RA and to address the ethnic differences in genetic susceptibility to RA between European and Asian populations.MethodsGene-based association analyses were performed with KGG 2.5 by using publicly available large RA datasets (14,361 RA cases and 43,923 controls of European subjects, 4,873 RA cases and 17,642 controls of Asian Subjects). For the newly identified RA-associated genes, gene set enrichment analyses and protein-protein interactions analyses were carried out with DAVID and STRING version 10.0, respectively. Differential expression verification was conducted using 4 GEO datasets. The expression levels of three selected 'highly verified' genes were measured by ELISA among our in-house RA cases and controls.ResultsA total of 221 RA-associated genes were newly identified by gene-based association study, including 71'overlapped', 76 'European-specific' and 74 'Asian-specific' genes. Among them, 105 genes had significant differential expressions between RA patients and health controls at least in one dataset, especially for 20 genes including 11 'overlapped' (ABCF1, FLOT1, HLA-F, IER3, TUBB, ZKSCAN4, BTN3A3, HSP90AB1, CUTA, BRD2, HLA-DMA), 5 'European-specific' (PHTF1, RPS18, BAK1, TNFRSF14, SUOX) and 4 'Asian-specific' (RNASET2, HFE, BTN2A2, MAPK13) genes whose differential expressions were significant at least in three datasets. The protein expressions of two selected genes FLOT1 (P value = 1.70E-02) and HLA-DMA (P value = 4.70E-02) in plasma were significantly different in our in-house samples.ConclusionOur study identified 221 novel RA-associated genes and especially highlighted the importance of 20 candidate genes on RA. The results addressed ethnic genetic background differences for RA susceptibility between European and Asian populations and detected a long list of overlapped or ethnic specific RA genes. The study not only greatly increases our understanding of genetic susceptibility to RA, but also provides important insights into the ethno-genetic homogeneity and heterogeneity of RA in both ethnicities.

Dataset Information

Genome-wide association study of rheumatoid arthritis by a score test based on wavelet transformation.

Publications

Genome-wide association study of rheumatoid arthritis by a score test based on wavelet transformation.

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