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. 2012 Oct 12:3:203.
doi: 10.3389/fgene.2012.00203. eCollection 2012.

Leveraging ethnic group incidence variation to investigate genetic susceptibility to glioma: a novel candidate SNP approach

Daniel I Jacobs  1 , Kyle M Walsh, Margaret Wrensch, John Wiencke, Robert Jenkins, Richard S Houlston, Melissa Bondy, Matthias Simon, Marc Sanson, Konstantinos Gousias, Johannes Schramm, Marianne Labussière, Anna Luisa Di Stefano, H-Erich Wichmann, Martina Müller-Nurasyid, Stefan Schreiber, Andre Franke, Susanne Moebus, Lewin Eisele, Andrew T Dewan, Robert Dubrow
Affiliations

Leveraging ethnic group incidence variation to investigate genetic susceptibility to glioma: a novel candidate SNP approach

Daniel I Jacobs et al. Front Genet. .

Abstract

Objectives: Using a novel candidate SNP approach, we aimed to identify a possible genetic basis for the higher glioma incidence in Whites relative to East Asians and African-Americans.

Methods: We hypothesized that genetic regions containing SNPs with extreme differences in allele frequencies across ethnicities are most likely to harbor susceptibility variants. We used International HapMap Project data to identify 3,961 candidate SNPs with the largest allele frequency differences in Whites compared to East Asians and Africans and tested these SNPs for association with glioma risk in a set of White cases and controls. Top SNPs identified in the discovery dataset were tested for association with glioma in five independent replication datasets.

Results: No SNP achieved statistical significance in either the discovery or replication datasets after accounting for multiple testing or conducting meta-analysis. However, the most strongly associated SNP, rs879471, was found to be in linkage disequilibrium with a previously identified risk SNP, rs6010620, in RTEL1. We estimate rs6010620 to account for a glioma incidence rate ratio of 1.34 for Whites relative to East Asians.

Conclusion: We explored genetic susceptibility to glioma using a novel candidate SNP method which may be applicable to other diseases with appropriate epidemiologic patterns.

Keywords: admixture; ancestry informative markers; brain cancer; candidate SNP association study; ethnicity; glioma; race.

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Figures

Figure 1
Figure 1
White/East Asian incidence rate ratios for varying allele distributions and genotypic relative risks. Plots were generated by calculating incidence rate ratios (IRRs) according to varying genotypic relative risks (GRR) and ethnic group allele frequencies. For example, suppose the GRR for glioma for persons with one B allele is 2.00, and the GRR for persons with two B alleles is 3.00 (relative to those homozygous for the A allele). If the frequency of allele A in Whites is 0.20 (p = 0.2), the proportions of AA (p2), AB (2pq), and BB (q2) genotypes are 0.04, 0.32, and 0.64, respectively, assuming Hardy Weinberg equilibrium. To calculate a normalized incidence rate, the genotype proportion is multiplied by the associated GRR risk: 0.04 (1.00) + 0.32 (2.00) + 0.64 (3.00) = 2.60. Given an East Asian allele A frequency of 0.80, the East Asian normalized incidence rate is 0.64 (1.00) + 0.32 (2.00) + 0.04 (3.00) = 1.40. The White/East Asian IRR is 1.86 (2.60/1.40) in this scenario. The same calculations apply for White/African IRRs.
Figure 2
Figure 2
Flow diagram of candidate SNP selection from HapMap.
Figure 3
Figure 3
White vs. African and White vs. East Asian allele frequency differences and selected candidate SNPs. Each SNP is plotted by its allele frequency difference between Whites and Africans vs. its allele frequency difference between Whites and East Asians. Green SNPs in the upper-right and lower-left quadrants represent those with mean allele frequency differences of 0.40 to <0.60 (Moderate), red SNPs represent those with mean allele frequency differences of 0.60 to <0.70 (High), and black SNPs represent those with mean allele frequency differences ≥0.70 (Highest). Orange SNPs around the perimeter represent those in which the allele frequency difference was at least 0.70 in one comparison, but less than 0.40 in the other (Highest/Low).
Figure 4
Figure 4
Manhattan plot for 3,961 tested candidate SNPs.
See this image and copyright information in PMC

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References

    1. Altshuler D. M., Gibbs R. A., Peltonen L., Dermitzakis E., Schaffner S. F., Yu F., et al. (2010). Integrating common and rare genetic variation in diverse human populations. Nature 467, 52–5810.1038/nature09298 - DOI - PMC - PubMed
    1. Barrett J. C., Fry B., Maller J., Daly M. J. (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–26510.1093/bioinformatics/bti464 - DOI - PubMed
    1. Blankenberg D., Kuster G. V., Coraor N., Ananda G., Lazarus R., Mangan M., et al. (2001). Galaxy: a web-based genome analysis tool for experimentalists. Curr. Protoc. Mol. Biol. 89, 1–21 - PMC - PubMed
    1. Bondy M. L., Scheurer M. E., Malmer B., Barnholtz-Sloan J. S., Davis F. G., Il’Yasova D., et al. (2008). Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer 113, 1953–196810.1002/cncr.23741 - DOI - PMC - PubMed
    1. Cardis E., Deltour I., Vrijheid M., Combalot E., Moissonnier M., Tardy H., et al. (2010). Brain tumour risk in relation to mobile telephone use: results of the INTERPHONE international case–control study. Int. J. Epidemiol. 39, 675–69410.1093/ije/dyq079 - DOI - PubMed