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From single-SNP to wide-locus: genome-wide association studies identifying functionally related genes and intragenic regions in small sample studies.

ABSTRACT: Genome-wide association studies (GWAS) have had limited success when applied to complex diseases. Analyzing SNPs individually requires several large studies to integrate the often divergent results. In the presence of epistasis, multivariate approaches based on the linear model (including stepwise logistic regression) often have low sensitivity and generate an abundance of artifacts.Recent advances in distributed and parallel processing spurred methodological advances in nonparametric statistics. U-statistics for structured multivariate data (µStat) are not confounded by unrealistic assumptions (e.g., linearity, independence).By incorporating knowledge about relationships between SNPs, µGWAS (GWAS based on µStat) can identify clusters of genes around biologically relevant pathways and pinpoint functionally relevant regions within these genes.With this computational biostatistics approach increasing power and guarding against artifacts, personalized medicine and comparative effectiveness will advance while subgroup analyses of Phase III trials can now suggest risk factors for adverse events and novel directions for drug development.

SUBMITTER: Wittkowski KM

PROVIDER: S-EPMC3643309 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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From single-SNP to wide-locus: genome-wide association studies identifying functionally related genes and intragenic regions in small sample studies.

Wittkowski Knut M KM Sonakya Vikas V Song Tingting T Seybold Martin P MP Keddache Mehdi M Durner Martina M

Pharmacogenomics 20130301 4

<h4>Background</h4>Genome-wide association studies (GWAS) have had limited success when applied to complex diseases. Analyzing SNPs individually requires several large studies to integrate the often divergent results. In the presence of epistasis, multivariate approaches based on the linear model (including stepwise logistic regression) often have low sensitivity and generate an abundance of artifacts.<h4>Methods</h4>Recent advances in distributed and parallel processing spurred methodological a ...[more]

PMID: 23438886

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Project description:BACKGROUND: Recently we have witnessed a surge of interest in using genome-wide association studies (GWAS) to discover the genetic basis of complex diseases. Many genetic variations, mostly in the form of single nucleotide polymorphisms (SNPs), have been identified in a wide spectrum of diseases, including diabetes, cancer, and psychiatric diseases. A common theme arising from these studies is that the genetic variations discovered by GWAS can only explain a small fraction of the genetic risks associated with the complex diseases. New strategies and statistical approaches are needed to address this lack of explanation. One such approach is the pathway analysis, which considers the genetic variations underlying a biological pathway, rather than separately as in the traditional GWAS studies. A critical challenge in the pathway analysis is how to combine evidences of association over multiple SNPs within a gene and multiple genes within a pathway. Most current methods choose the most significant SNP from each gene as a representative, ignoring the joint action of multiple SNPs within a gene. This approach leads to preferential identification of genes with a greater number of SNPs. RESULTS: We describe a SNP-based pathway enrichment method for GWAS studies. The method consists of the following two main steps: 1) for a given pathway, using an adaptive truncated product statistic to identify all representative (potentially more than one) SNPs of each gene, calculating the average number of representative SNPs for the genes, then re-selecting the representative SNPs of genes in the pathway based on this number; and 2) ranking all selected SNPs by the significance of their statistical association with a trait of interest, and testing if the set of SNPs from a particular pathway is significantly enriched with high ranks using a weighted Kolmogorov-Smirnov test. We applied our method to two large genetically distinct GWAS data sets of schizophrenia, one from European-American (EA) and the other from African-American (AA). In the EA data set, we found 22 pathways with nominal P-value less than or equal to 0.001 and corresponding false discovery rate (FDR) less than 5%. In the AA data set, we found 11 pathways by controlling the same nominal P-value and FDR threshold. Interestingly, 8 of these pathways overlap with those found in the EA sample. We have implemented our method in a JAVA software package, called SNP Set Enrichment Analysis (SSEA), which contains a user-friendly interface and is freely available at http://cbcl.ics.uci.edu/SSEA. CONCLUSIONS: The SNP-based pathway enrichment method described here offers a new alternative approach for analysing GWAS data. By applying it to schizophrenia GWAS studies, we show that our method is able to identify statistically significant pathways, and importantly, pathways that can be replicated in large genetically distinct samples.

Dataset Information

From single-SNP to wide-locus: genome-wide association studies identifying functionally related genes and intragenic regions in small sample studies.

Publications

From single-SNP to wide-locus: genome-wide association studies identifying functionally related genes and intragenic regions in small sample studies.

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