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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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Related in: MedlinePlus

Two known breast cancer risk regions 10p15 and 14q24 exhibit putative haplotype effects.(A) 5.67–6.17 Mb region at 10p15; (B) 67.84–68.34 Mb region at 14q24. Black circles denote individual haplotypes, the sizes of which are proportional to their haplotype frequencies. Red dots denote genotyped SNPs within the same region. Blue dot shows the most significant SNP. Cyan dot denotes the known breast cancer risk SNP identified by previous GWAS.
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pone-0057298-g004: Two known breast cancer risk regions 10p15 and 14q24 exhibit putative haplotype effects.(A) 5.67–6.17 Mb region at 10p15; (B) 67.84–68.34 Mb region at 14q24. Black circles denote individual haplotypes, the sizes of which are proportional to their haplotype frequencies. Red dots denote genotyped SNPs within the same region. Blue dot shows the most significant SNP. Cyan dot denotes the known breast cancer risk SNP identified by previous GWAS.

Mentions: As noted by Chen et al [23], the endeavor to replicate the significance of the known GWAS hits using the AABC data was largely unsuccessful, implying the risk loci for breast cancer found in other GWAS, predominantly of European ancestries, may not be the same as in African Americans. For four of the known GWAS SNPs the associations in our African American breast cancer data had a nominally significant p-value less than 0.05 (Table S4), namely rs13387042 at 2q35 (OR = 0.89; 95% CI = 0.82–0.97; p = 0.00713), rs865686 at 9q31 (OR = 0.92; 95% CI = 0.85–0.99; p = 0.0287), rs2981582 at 10q26 (OR = 1.11; 95% CI = 1.03–1.19; p = 0.0087), and rs2363956 at 19p13 (OR = 0.88; 95% CI = 0.82–0.95; p = 8.1×10−4). They are all common variants of modest effects in this study with minor allele frequency between 0.07 and 0.49. Across these 21 regions with known breast cancer risk, 10p15 and 14q24 showed potential haplotype effects with the global test p-value less than 1.0×10−4, albeit not genome-wide significant. When scrutinizing all possible inferred individual haplotypes of 2–10 SNPs long in the vicinity of the known markers, a 3-SNP haplotype at 10p15, CTC (Position: 5705780–5712025; frequency = 0.22) constituted by rs17141741, rs2386661 and rs4414128 was three orders of magnitude more significant than the most significant individual SNP contained in the haplotype, rs4414128 (unadjusted haplotype p-value = 5×10−6 vs. best SNP p-value = 7.08×10−3) (Table 3). This haplotype was associated with a 20% reduced risk per copy for breast cancer relative to the women not carrying it. The haplotype-specific effect was almost unchanged after adjustment for both the best contained SNP (rs4414128) and the index marker (rs2380205) (adjusted haplotype OR = 0.81, 95% CI = 0.72–0.91, p = 2.16×10−4). The haplotype signal was two or three orders of magnitude more significant than any of the remaining individual SNPs adjacent to that haplotype, as shown from the leftmost haplotype signal peak in Figure 4A. When further compared to the 1 KGP imputed SNPs in the same region, this CTC haplotype was still independent of the imputed SNPs (Figure 5A). The imputed SNPs residing within close proximity had similar significance levels to that of the genotyped SNPs (Figure 4A vs. Figure 5A), which emphasized that haplotype effect was unlikely to be explained by SNP imputation either. Another 3 SNP haplotype GAG (Position: 6042374–6043841; frequency = 0.60) was stronger than any genotyped SNPs. However, we found an imputed SNP (rs3181152; risk allele: G; frequency: 0.45; p = 4.72×10−5) that fell on this haplotype and was an even stronger predictor of risk. The analysis of individual haplotype effects also identified a new region at 14q24 containing the known hit rs999737, where the most significant haplotype was CGCAGC (Position: 68033499–68045127; frequency = 0.05) with the unadjusted haplotype p-value over three orders of magnitude less than that of the best contained SNP, rs10132579 (unadjusted haplotype p = 1.69×10−6 vs. best SNP p = 9.55×10−3) (Figure 4B). It was also noted that this haplotype effect was stable after additional adjustment for rs10132579 and rs999737 (unadjusted OR = 0.60, 95% CI = 0.48–0.74 and the adjusted OR = 0.60 with 95% CI = 0.47–0.77), suggesting approximately a 40% decreased breast cancer risk per copy was associated with this CGCAGC haplotype among the carriers. Taking local ancestry into account did not change the results for either the CTC haplotype on 10p15 or the CGCAGC haplotype on 14q25 (Table S5). There were numerous other individual haplotypes with unadjusted significance between 10−6 and 10−5 on 8q24 and 19p13. However, these top haplotype effects were indistinguishable from the top SNPs. Once adjusted for the best SNP contained, these haplotypes became insignificant (p>0.05) (Figures S4 A–D).


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)

Two known breast cancer risk regions 10p15 and 14q24 exhibit putative haplotype effects.(A) 5.67–6.17 Mb region at 10p15; (B) 67.84–68.34 Mb region at 14q24. Black circles denote individual haplotypes, the sizes of which are proportional to their haplotype frequencies. Red dots denote genotyped SNPs within the same region. Blue dot shows the most significant SNP. Cyan dot denotes the known breast cancer risk SNP identified by previous GWAS.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585353&req=5

pone-0057298-g004: Two known breast cancer risk regions 10p15 and 14q24 exhibit putative haplotype effects.(A) 5.67–6.17 Mb region at 10p15; (B) 67.84–68.34 Mb region at 14q24. Black circles denote individual haplotypes, the sizes of which are proportional to their haplotype frequencies. Red dots denote genotyped SNPs within the same region. Blue dot shows the most significant SNP. Cyan dot denotes the known breast cancer risk SNP identified by previous GWAS.
Mentions: As noted by Chen et al [23], the endeavor to replicate the significance of the known GWAS hits using the AABC data was largely unsuccessful, implying the risk loci for breast cancer found in other GWAS, predominantly of European ancestries, may not be the same as in African Americans. For four of the known GWAS SNPs the associations in our African American breast cancer data had a nominally significant p-value less than 0.05 (Table S4), namely rs13387042 at 2q35 (OR = 0.89; 95% CI = 0.82–0.97; p = 0.00713), rs865686 at 9q31 (OR = 0.92; 95% CI = 0.85–0.99; p = 0.0287), rs2981582 at 10q26 (OR = 1.11; 95% CI = 1.03–1.19; p = 0.0087), and rs2363956 at 19p13 (OR = 0.88; 95% CI = 0.82–0.95; p = 8.1×10−4). They are all common variants of modest effects in this study with minor allele frequency between 0.07 and 0.49. Across these 21 regions with known breast cancer risk, 10p15 and 14q24 showed potential haplotype effects with the global test p-value less than 1.0×10−4, albeit not genome-wide significant. When scrutinizing all possible inferred individual haplotypes of 2–10 SNPs long in the vicinity of the known markers, a 3-SNP haplotype at 10p15, CTC (Position: 5705780–5712025; frequency = 0.22) constituted by rs17141741, rs2386661 and rs4414128 was three orders of magnitude more significant than the most significant individual SNP contained in the haplotype, rs4414128 (unadjusted haplotype p-value = 5×10−6 vs. best SNP p-value = 7.08×10−3) (Table 3). This haplotype was associated with a 20% reduced risk per copy for breast cancer relative to the women not carrying it. The haplotype-specific effect was almost unchanged after adjustment for both the best contained SNP (rs4414128) and the index marker (rs2380205) (adjusted haplotype OR = 0.81, 95% CI = 0.72–0.91, p = 2.16×10−4). The haplotype signal was two or three orders of magnitude more significant than any of the remaining individual SNPs adjacent to that haplotype, as shown from the leftmost haplotype signal peak in Figure 4A. When further compared to the 1 KGP imputed SNPs in the same region, this CTC haplotype was still independent of the imputed SNPs (Figure 5A). The imputed SNPs residing within close proximity had similar significance levels to that of the genotyped SNPs (Figure 4A vs. Figure 5A), which emphasized that haplotype effect was unlikely to be explained by SNP imputation either. Another 3 SNP haplotype GAG (Position: 6042374–6043841; frequency = 0.60) was stronger than any genotyped SNPs. However, we found an imputed SNP (rs3181152; risk allele: G; frequency: 0.45; p = 4.72×10−5) that fell on this haplotype and was an even stronger predictor of risk. The analysis of individual haplotype effects also identified a new region at 14q24 containing the known hit rs999737, where the most significant haplotype was CGCAGC (Position: 68033499–68045127; frequency = 0.05) with the unadjusted haplotype p-value over three orders of magnitude less than that of the best contained SNP, rs10132579 (unadjusted haplotype p = 1.69×10−6 vs. best SNP p = 9.55×10−3) (Figure 4B). It was also noted that this haplotype effect was stable after additional adjustment for rs10132579 and rs999737 (unadjusted OR = 0.60, 95% CI = 0.48–0.74 and the adjusted OR = 0.60 with 95% CI = 0.47–0.77), suggesting approximately a 40% decreased breast cancer risk per copy was associated with this CGCAGC haplotype among the carriers. Taking local ancestry into account did not change the results for either the CTC haplotype on 10p15 or the CGCAGC haplotype on 14q25 (Table S5). There were numerous other individual haplotypes with unadjusted significance between 10−6 and 10−5 on 8q24 and 19p13. However, these top haplotype effects were indistinguishable from the top SNPs. Once adjusted for the best SNP contained, these haplotypes became insignificant (p>0.05) (Figures S4 A–D).

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