Grant Number:	7RC1CA144910-02 Interpret this number
Primary Investigator:	Kazazian, Haig
Organization:	Johns Hopkins University
Project Title:	Augmenting Gwas with Retrotransposon Polymorphisms
Fiscal Year:	2010

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-CA-101: Augmenting Genome-Wide Association Studies. Genome-wide association studies (GWAS) are typically carried out to uncover potential correlations between SNP genotypes and disease phenotypes. Often, cancer or neoplastic conditions have been the subject of these studies, and they have provided useful insights into the genetic determinants of cancer etiology. While SNPs are the most common form of genetic variation, there are other forms such as copy number variation (CNV) and retrotransposon insertion polymorphisms (RIPs). Recently, GWAS incorporating CNV data have been completed with positive results, but to date no GWAS experiments have used RIPs as the genotypic marker despite the fact that active human families of retrotransposon (LINE-1, Alu, and SVA) are collectively responsible for over 60 disease-causing mutations. The reason for this omission of an important source of genomic variation has been largely technical: no large-scale detection method has enabled the cataloguing of RIPs. Recently, we have developed a robust method for the detection of human-specific LINE-1 (L1) insertions on a genome- wide scale using a hemi-specific PCR method to amplify L1 3' flanking regions in a manner amenable to next-generation sequencing on Illumina's Genome Analyzer platform. Subsequent analysis of the sequencing results reproducibly provides the location of human-specific L1 insertion locations. This technique can be readily extended to other forms of retrotransposon-induced variation including the Alu and SVA families of retroposons simply by interchanging the hemi- specific primer sequences. Once a significant amount of RIP-induced variation has been catalogued across several distinct populations, we will use these sites to design a genotyping array using Illumina's iSelect custom Infinium assay system. Using this array of RIP markers, we will then carry out a GWAS for prostate cancer on ~1000 cases and ~1000 controls. We fully expect to identify 4,000 or more RIP markers for this assay that will serve as an augmentation to GWAS studies in which RIPs have not yet been considered. Genome Wide Association Studies (GWAS) have proven their utility in identifying genomic variants associated with risk for many diseases. To date, SNPs and CNVs have been used as the variant markers in these studies, omitting a major contributor to Human variation: retrotransposon insertion polymorphisms (RIPs). We propose to use a technique we have developed which identifies RIPs on a genome-wide scale to collect a large number of RIP markers for a genotyping array and then conduct a GWAS on prostate cancer in a proof-of-concept attempt to identify new markers associated with the disease.





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