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A genome-wide scan for breast cancer risk haplotypes among African American women.

Song C, Chen GK, Millikan RC, Ambrosone CB, John EM, Bernstein L, Zheng W, Hu JJ, Ziegler RG, Nyante S, Bandera EV, Ingles SA, Press MF, Deming SL, Rodriguez-Gil JL, Chanock SJ, Wan P, Sheng X, Pooler LC, Van Den Berg DJ, Le Marchand L, Kolonel LN, Henderson BE, Haiman CA, Stram DO - PLoS ONE (2013)

Bottom Line: Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects.We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data.It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.

View Article: PubMed Central - PubMed

Affiliation: Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.

ABSTRACT
Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.

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Comparison of the permutation minimum p-values to theoretical beta distributions. (A). Quantile-Quantile plot comparing the minimum p-values from 1,000 permutations on chromosome 22 data to beta(1,7426). (B). Quantile-Quantile plot comparing the minimum p-values to beta(1,7823).
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pone-0057298-g001: Comparison of the permutation minimum p-values to theoretical beta distributions. (A). Quantile-Quantile plot comparing the minimum p-values from 1,000 permutations on chromosome 22 data to beta(1,7426). (B). Quantile-Quantile plot comparing the minimum p-values to beta(1,7823).

Mentions: The minimum p-values from the 1,000 permutations of chromosome 22 data containing 15,649 genotyped SNPs ranged between 1.54×10−7 and 9.44×10−4 with the fifth percentile being 5.58×10−6. So the permutation-based effective number of tests for chromosome 22 was simply . The maximum likelihood estimates of the beta distribution parameters were and ; or if was constrained at 1. Although the hypothesis of equality was nominally rejected in the former two-parameter case (p<0.01), was close to 1 and the QQ plot comparing it to the Beta(1,7426) distribution showed the majority of the data points fell on the diagonal line, suggesting the lack of fit was not severe (Figure 1A). When setting and experimenting with different’s, i.e., goodness-of-fit tests based on empirical distribution functions (EDF) statistics (Kolmogorov-Smirnov, Cramer-von Mises and Anderson-Darling statistics) did not reject the hypothesis at the 0.10 significance level, implying that the minimum p-values followed the designated beta distributions satisfactorily (Table 1). The range of the effective numbers of tests, 7,400–8,300, included half the number of total sliding windows (). The corresponding significance level under this approximation was , benchmarking to the 5.7 percentile of the minimum p-values from 1,000 permutations. The QQ plot for those minimum p-values compared to Beta (1,7823) distribution indicated the fit was reasonably good (Figure 1B) and none of the goodness-of-fit tests were rejected (p>0.25). We proceeded with the effective number of independent tests equal to half of the total number of overlapping haplotype blocks as a quick reference to spotting potentially significant haplotype effects. The genome-wide significance level was therefore derived as in contrast to the Bonferroni corrected genome-wide significance level .


A genome-wide scan for breast cancer risk haplotypes among African American women.

Song C, Chen GK, Millikan RC, Ambrosone CB, John EM, Bernstein L, Zheng W, Hu JJ, Ziegler RG, Nyante S, Bandera EV, Ingles SA, Press MF, Deming SL, Rodriguez-Gil JL, Chanock SJ, Wan P, Sheng X, Pooler LC, Van Den Berg DJ, Le Marchand L, Kolonel LN, Henderson BE, Haiman CA, Stram DO - PLoS ONE (2013)

Comparison of the permutation minimum p-values to theoretical beta distributions. (A). Quantile-Quantile plot comparing the minimum p-values from 1,000 permutations on chromosome 22 data to beta(1,7426). (B). Quantile-Quantile plot comparing the minimum p-values to beta(1,7823).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585353&req=5

pone-0057298-g001: Comparison of the permutation minimum p-values to theoretical beta distributions. (A). Quantile-Quantile plot comparing the minimum p-values from 1,000 permutations on chromosome 22 data to beta(1,7426). (B). Quantile-Quantile plot comparing the minimum p-values to beta(1,7823).
Mentions: The minimum p-values from the 1,000 permutations of chromosome 22 data containing 15,649 genotyped SNPs ranged between 1.54×10−7 and 9.44×10−4 with the fifth percentile being 5.58×10−6. So the permutation-based effective number of tests for chromosome 22 was simply . The maximum likelihood estimates of the beta distribution parameters were and ; or if was constrained at 1. Although the hypothesis of equality was nominally rejected in the former two-parameter case (p<0.01), was close to 1 and the QQ plot comparing it to the Beta(1,7426) distribution showed the majority of the data points fell on the diagonal line, suggesting the lack of fit was not severe (Figure 1A). When setting and experimenting with different’s, i.e., goodness-of-fit tests based on empirical distribution functions (EDF) statistics (Kolmogorov-Smirnov, Cramer-von Mises and Anderson-Darling statistics) did not reject the hypothesis at the 0.10 significance level, implying that the minimum p-values followed the designated beta distributions satisfactorily (Table 1). The range of the effective numbers of tests, 7,400–8,300, included half the number of total sliding windows (). The corresponding significance level under this approximation was , benchmarking to the 5.7 percentile of the minimum p-values from 1,000 permutations. The QQ plot for those minimum p-values compared to Beta (1,7823) distribution indicated the fit was reasonably good (Figure 1B) and none of the goodness-of-fit tests were rejected (p>0.25). We proceeded with the effective number of independent tests equal to half of the total number of overlapping haplotype blocks as a quick reference to spotting potentially significant haplotype effects. The genome-wide significance level was therefore derived as in contrast to the Bonferroni corrected genome-wide significance level .

Bottom Line: Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects.We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data.It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.

View Article: PubMed Central - PubMed

Affiliation: Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.

ABSTRACT
Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.

Show MeSH
Related in: MedlinePlus