Pathway-based joint effects analysis of rare genetic variants using Genetic Analysis Workshop 17 exon sequence data

Abstract

Pathway-based analysis has been recently used in joint tests of association between disease and a group of common genetic variants. Here we explore this idea for the joint effects analysis of rare genetic variants and their association with quantitative traits and disease. We accumulate multiple rare minor alleles in a genetic risk score for each individual in a given pathway; this score is then used to assess association with quantitative phenotypes and disease. We demonstrate that this approach may be better than studying single rare variants or a gene risk score for identifying individuals with significantly greater risk.

Figure 1

Multidimensional scaling analysis of 697 samples from the 1000 Genomes Project. We used 23,173 SNPs in the multidimensional scaling analysis and removed seven outlier samples (one European and six Africans) in the subsequent analysis. Red circles, Europeans; green circles, Asians; black circles, Africans.

Figure 2

Distribution of minor allele counts in case and control subjects. The frequencies of minor alleles in different bins were estimated for the VEGF pathway in the Reactome and BioCarta databases. Red bars, case subjects; blue bars, control subjects.