Epistasis Blog

From the Computational Genetics Laboratory at Dartmouth Medical School (www.epistasis.org)

Tuesday, June 28, 2011

Pathway of distinction analysis

A very nice paper on pathway analysis of genetic association data. I like this paper because it doesn't make any assumptions about there being main effects.

Braun R, Buetow K. Pathways of Distinction Analysis: A New Technique for Multi-SNP Analysis of GWAS Data. PLoS Genet. 2011 Jun;7(6):e1002101. [PubMed]

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.

Monday, June 27, 2011

Molecular mechanisms of epistasis

This is an interesting new paper that discusses how molecular interactions might give rise to epistasis. The connection between biological and statistical epistasis is a very important question.

Lehner B. Molecular mechanisms of epistasis within and between genes. Trends Genet. 2011 [PubMed]

Abstract

'Disease-causing' mutations do not cause disease in all individuals. One possible important reason for this is that the outcome of a mutation can depend upon other genetic variants in a genome. These epistatic interactions between mutations occur both within and between molecules, and studies in model organisms show that they are extremely prevalent. However, epistatic interactions are still poorly understood at the molecular level, and consequently difficult to predict de novo. Here I provide an overview of our current understanding of the molecular mechanisms that can cause epistasis, and areas where more research is needed. A more complete understanding of epistasis will be vital for making accurate predictions about the phenotypes of individuals.

Saturday, June 04, 2011

Two Epistasis Papers in Science

There are two papers on epistasis in the June 3rd issue of Science.

Khan AI, Dinh DM, Schneider D, Lenski RE, Cooper TF. Negative epistasis between beneficial mutations in an evolving bacterial population. Science. 2011 Jun 3;332(6034):1193-6. PubMed PMID: 21636772. [PubMed]

Chou HH, Chiu HC, Delaney NF, Segrè D, Marx CJ. Diminishing returns epistasis among beneficial mutations decelerates adaptation. Science. 2011 Jun 3;332(6034):1190-2. PubMed PMID: 21636771. [PubMed]