Pathways of distinction analysis: A new technique for multi-SNP analysis of GWAS data

Rosemary Braun, Kenneth Buetow

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) have become increasingly common due to advances in technology and have permitted the identification of differences in single nucleotide polymorphism (SNP) alleles that are associated with diseases. However, while typical GWAS analysis techniques treat markers individually, complex diseases (cancers, diabetes, and Alzheimers, amongst others) are unlikely to have a single causative gene. Thus, there is a pressing need for multi-SNP analysis methods that can reveal system-level differences in cases and controls. Here, we present a novel multi-SNP GWAS analysis method called Pathways of Distinction Analysis (PoDA). The method uses GWAS data and known pathway-gene and gene-SNP associations to identify pathways that permit, ideally, the distinction of cases from controls. The technique is based upon the hypothesis that if a pathway is related to disease risk, cases will appear more similar to other cases than to controls (or vice versa) for the SNPs associated with that pathway. By systematically applying the method to all pathways of potential interest, we can identify those for which the hypothesis holds true, i.e., pathways containing SNPs for which the samples exhibit greater within-class similarity than across classes. Importantly, PoDA improves on existing single-SNP and SNP-set enrichment analyses, in that it does not require the SNPs in a pathway to exhibit independent main effects. This permits PoDA to reveal pathways in which epistatic interactions drive risk. In this paper, we detail the PoDA method and apply it to two GWAS: one of breast cancer and the other of liver cancer. The results obtained strongly suggest that there exist pathway-wide genomic differences that contribute to disease susceptibility. PoDA thus provides an analytical tool that is complementary to existing techniques and has the power to enrich our understanding of disease genomics at the systems-level.

Original languageEnglish (US)
Article numbere1002101
JournalPLoS Genetics
Volume7
Issue number6
DOIs
StatePublished - Jun 2011
Externally publishedYes

Fingerprint

Genome-Wide Association Study
single nucleotide polymorphism
Single Nucleotide Polymorphism
polymorphism
genome
cancer
diabetes
neoplasms
methodology
Neoplasms
Liver Neoplasms
gene
genomics
Genes
genes
liver neoplasms
analysis
genome-wide association study
breast neoplasms
Genomics

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Pathways of distinction analysis : A new technique for multi-SNP analysis of GWAS data. / Braun, Rosemary; Buetow, Kenneth.

In: PLoS Genetics, Vol. 7, No. 6, e1002101, 06.2011.

Research output: Contribution to journalArticle

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