GWAS (Genotyping)
Summary
A Genome Wide Association Study (GWAS) examines genetic variation across a given genome for the purpose of identifying genetic associations with observable traits. Until recently, restricted genotyping and analytical capacities limited genetic epidemiological studies to a priori selected candidate genes. We currently use GWAS in the study of Non-Hodgkin Lymphoma (NHL), which has led to the identification of a number of potential NHL risk alleles (alternative DNA sequences at the same physical chromosomal location, which may or may not result in different traits). Using this approach, candidate genes are selected based on our current understanding of disease mechanisms; thus, it relies on, and is only as good as, our present knowledge of the biology. Rapid technological advances in high-throughput genotyping (genetic analysis of large numbers of individuals that allow genotypes to be assigned automatically) and bioinformatics the application of information technology to the field of molecular biology) have paved the way for an unprejudiced exploration of the entire genome to identify NHL risk alleles. One advantage to this unbiased approach is that totally unexpected genetic associations may be revealed. The use of pooled DNA provides a means to efficiently screen single nucleotide polymorphisms (SNPs) and prioritize them for further study. In a NHL case-control study (2,000 cases and 2,000 controls) based in the San Francisco Bay Area, we performed genome-wide genotyping on pooled DNA to screen for NHL susceptibility markers that are being further investigated by individual genotyping. This comprehensive study will define important genetic mechanisms in the etiology of lymphoma and associations described will likely yield clues to potentially important environmental factors.
Updates
Association studies designed to identify the genetic determinants underlying complex disease increasingly require sustainable high-quality DNA resources for large-scale single-nucleotide polymorphism (SNP) genotyping. Recent studies have shown that genomic DNA (gDNA) suitable for SNP genotyping can be obtained from buccal cells and from dried blood spots on Guthrie cards. We conclude that highly multiplexed Illumina genotyping may be done on gDNA and wgaDNA obtained from whole blood, buccal samples, dried blood spots on Guthrie cards, and possibly even urine samples, with minimal misclassification.
Selected Publications
Skibola CF, Bracci PM, Halperin E, Conde L, Craig DW, Agana L, Iyadurai K, Becker N, Brooks-Wilson A, Curry JD, Spinelli JJ, Holly EA, Riby J, Zhang L, Nieters A, Smith MT, Brown KM (2009) Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma. Nat Genet, Aug;41(8):873-5. PMID: 19620980 [Abstract] [Full Text]
Paynter RA, Skibola DR, Skibola CF, Buffler PA, Wiemels JL, Smith MT (2006) Accuracy of multiplexed Illumina platform-based single-nucleotide polymorphism genotyping compared between genomic and whole genome amplified DNA collected from multiple sources. Cancer Epidemiol Biomarkers Prev, 15(12):2533-6. PMID 17164381. [Abstract] [Full Text]
Steinmaus CM, Smith AH, Jones RM, Smith MT (2008) Meta-analysis of benzene exposure and non-Hodgkin lymphoma: biases could mask an important association. Occup Environ Med, Jun;65(6):371-8. PMID: 18417556. [Abstract] [Full Text]
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