Integrated statistical and pathway approach to next-generation sequencing analysis: a family-based study of hypertension

Genome wide association studies (GWAS) have been used to search for associations between genetic variants and a phenotypic trait of interest. New technologies, such as next-generation sequencing, hold the potential to revolutionize GWAS. However, millions of polymorphisms are identified with next-generation sequencing technology. Consequently, researchers must be careful when performing such a large number of statistical tests, and corrections are typically made to account for multiple testing. Additionally, for typical GWAS, the p value cutoff is set quite low (approximately <10(−8)). As a result of this p value stringency, it is likely that there are many true associations that do not meet this threshold. To account for this we have incorporated a priori biological knowledge to help identify true associations that may not have reached statistical significance. We propose the application of a pipelined series of statistical and bioinformatic methods, to enable the assessment of the association of genetic polymorphisms with a disease phenotype--here, hypertension--as well as the identification of statistically significant pathways of genes that may play a role in the disease process.