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A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

Al Olama AA, Kote-Jarai Z, Berndt SI, Conti DV, Schumacher F, Han Y, Benlloch S, Hazelett DJ, Wang Z, Saunders E, Leongamornlert D, Lindstrom S, Jugurnauth-Little S, Dadaev T, Tymrakiewicz M, Stram DO, Rand K, Wan P, Stram A, Sheng X, Pooler LC, Park K, Xia L, Tyrer J, Kolonel LN, Le Marchand L, Hoover RN, Machiela MJ, Yeager M, Burdette L, Chung CC, Hutchinson A, Yu K, Goh C, Ahmed M, Govindasami K, Guy M, Tammela TL, Auvinen A, Wahlfors T, Schleutker J, Visakorpi T, Leinonen KA, Xu J, Aly M, Donovan J, Travis RC, Key TJ, Siddiq A, Canzian F, Khaw KT, Takahashi A, Kubo M, Pharoah P, Pashayan N, Weischer M, Nordestgaard BG, Nielsen SF, Klarskov P, Røder MA, Iversen P, Thibodeau SN, McDonnell SK, Schaid DJ, Stanford JL, Kolb S, Holt S, Knudsen B, Coll AH, Gapstur SM, Diver WR, Stevens VL, Maier C, Luedeke M, Herkommer K, Rinckleb AE, Strom SS, Pettaway C, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, Cannon-Albright L, Cybulski C, Wokołorczyk D, Kluźniak W, Park J, Sellers T, Lin HY, Isaacs WB, Partin AW, Brenner H, Dieffenbach AK, Stegmaier C, Chen C, Giovannucci EL, Ma J, Stampfer M, Penney KL, Mucci L, John EM, Ingles SA, Kittles RA, Murphy AB, Pandha H, Michael A, Kierzek AM, Blot W, Signorello LB, Zheng W, Albanes D, Virtamo J, Weinstein S, Nemesure B, Carpten J, Leske C, Wu SY, Hennis A, Kibel AS, Rybicki BA, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Zheng SL, Batra J, Clements J, Spurdle A, Teixeira MR, Paulo P, Maia S, Slavov C, Kaneva R, Mitev V, Witte JS, Casey G, Gillanders EM, Seminara D, Riboli E, Hamdy FC, Coetzee GA, Li Q, Freedman ML, Hunter DJ, Muir K, Gronberg H, Neal DE, Southey M, Giles GG, Severi G, Breast and Prostate Cancer Cohort Consortium (BPC3)PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) ConsortiumCOGS (Collaborative Oncological Gene-environment Study) ConsortiumGAME-ON/ELLIPSE ConsortiumCook MB, Nakagawa H, Wiklund F, Kraft P, Chanock SJ, Henderson BE, Easton DF, Eeles RA, Haiman CA - Nat. Genet. (2014)

Bottom Line: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry.Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer.These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

View Article: PubMed Central - PubMed

Affiliation: 1] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [2].

ABSTRACT
Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

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Related in: MedlinePlus

Manhattan Plot of genotyped and imputed results from the European ancestry meta-analysis of overall prostate cancer risk. All SNPs within 500kb of known GWAS SNPs are omitted. The green line represents P=5×10-8. This figure shows all new variants with P<5×10-8, regardless of the confirmation results (one signal on chr1, one on chr4, one on chr17, and 2 on chr X were not confirmed). Many of the new signals are in close proximity to one another on the same chromosome (see Supplementary Table 6).
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Figure 1: Manhattan Plot of genotyped and imputed results from the European ancestry meta-analysis of overall prostate cancer risk. All SNPs within 500kb of known GWAS SNPs are omitted. The green line represents P=5×10-8. This figure shows all new variants with P<5×10-8, regardless of the confirmation results (one signal on chr1, one on chr4, one on chr17, and 2 on chr X were not confirmed). Many of the new signals are in close proximity to one another on the same chromosome (see Supplementary Table 6).

Mentions: In the meta-analysis of the European ancestry studies,20 novel signals in18 regions ±500 kb outside of previously associated loci were observed to be associated with prostate cancer risk at P<5×10-8 (Figure 1; Supplementary Figure 2 Supplementary Figure 3). The most significant associations in each region were observed with imputed variants and we were able to confirm the imputed genotypes for 15 variants which had high imputation information scores (r2 range, 0.76-1) through direct genotyping or sequencing across multiple studies (Table 1;Online Methods,Supplementary Tables 5-8). Two of the variants were located within 370kb of each other on chromosome Xq13and are independent signals based on conditional analyses (rs6625711, P=6.1×10-10 and rs4844289, P=2.0×10-8; r2<0.01 in EUR 1KGP; Supplementary Table 9). All 15 variants were common, with minor allele frequencies (MAFs) ≥0.09, in the European ancestry population, and all but three (rs80130819/12q13, rs76939039/10q11 and rs17694493/9p21) were also common (MAF≥0.05) in African, Japanese and Latino populations. Evidence of heterogeneity in the per-allele OR was noted with 4 variants (Phet=0.01-8.4×10-6; rs17599629/1q21, rs115306967/6p21, rs17694493/9p21 and rs6625711/Xq13). Four of the 15 variants (rs10009409/4q13, rs4713266/6p24, rs80130819/12q13 and rs2807031/Xp11) had directional effects that were consistent with men of European ancestry and were nominally statistically significant (P<0.05) in at least one other population (Table 1) and for 3 SNPs, combining data across populations strengthened the statistical significance of the association (Table 1). In this large European ancestry sample we also confirmed the reported signal at 22q13 with variant rs58133635 (P=5.8×10-9; r2=0.74 with rs9623117 in 1KGP European ancestry populations (EUR); Supplemental Figure 2; Supplementary Figure 3).15


A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

Al Olama AA, Kote-Jarai Z, Berndt SI, Conti DV, Schumacher F, Han Y, Benlloch S, Hazelett DJ, Wang Z, Saunders E, Leongamornlert D, Lindstrom S, Jugurnauth-Little S, Dadaev T, Tymrakiewicz M, Stram DO, Rand K, Wan P, Stram A, Sheng X, Pooler LC, Park K, Xia L, Tyrer J, Kolonel LN, Le Marchand L, Hoover RN, Machiela MJ, Yeager M, Burdette L, Chung CC, Hutchinson A, Yu K, Goh C, Ahmed M, Govindasami K, Guy M, Tammela TL, Auvinen A, Wahlfors T, Schleutker J, Visakorpi T, Leinonen KA, Xu J, Aly M, Donovan J, Travis RC, Key TJ, Siddiq A, Canzian F, Khaw KT, Takahashi A, Kubo M, Pharoah P, Pashayan N, Weischer M, Nordestgaard BG, Nielsen SF, Klarskov P, Røder MA, Iversen P, Thibodeau SN, McDonnell SK, Schaid DJ, Stanford JL, Kolb S, Holt S, Knudsen B, Coll AH, Gapstur SM, Diver WR, Stevens VL, Maier C, Luedeke M, Herkommer K, Rinckleb AE, Strom SS, Pettaway C, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, Cannon-Albright L, Cybulski C, Wokołorczyk D, Kluźniak W, Park J, Sellers T, Lin HY, Isaacs WB, Partin AW, Brenner H, Dieffenbach AK, Stegmaier C, Chen C, Giovannucci EL, Ma J, Stampfer M, Penney KL, Mucci L, John EM, Ingles SA, Kittles RA, Murphy AB, Pandha H, Michael A, Kierzek AM, Blot W, Signorello LB, Zheng W, Albanes D, Virtamo J, Weinstein S, Nemesure B, Carpten J, Leske C, Wu SY, Hennis A, Kibel AS, Rybicki BA, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Zheng SL, Batra J, Clements J, Spurdle A, Teixeira MR, Paulo P, Maia S, Slavov C, Kaneva R, Mitev V, Witte JS, Casey G, Gillanders EM, Seminara D, Riboli E, Hamdy FC, Coetzee GA, Li Q, Freedman ML, Hunter DJ, Muir K, Gronberg H, Neal DE, Southey M, Giles GG, Severi G, Breast and Prostate Cancer Cohort Consortium (BPC3)PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) ConsortiumCOGS (Collaborative Oncological Gene-environment Study) ConsortiumGAME-ON/ELLIPSE ConsortiumCook MB, Nakagawa H, Wiklund F, Kraft P, Chanock SJ, Henderson BE, Easton DF, Eeles RA, Haiman CA - Nat. Genet. (2014)

Manhattan Plot of genotyped and imputed results from the European ancestry meta-analysis of overall prostate cancer risk. All SNPs within 500kb of known GWAS SNPs are omitted. The green line represents P=5×10-8. This figure shows all new variants with P<5×10-8, regardless of the confirmation results (one signal on chr1, one on chr4, one on chr17, and 2 on chr X were not confirmed). Many of the new signals are in close proximity to one another on the same chromosome (see Supplementary Table 6).
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Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383163&req=5

Figure 1: Manhattan Plot of genotyped and imputed results from the European ancestry meta-analysis of overall prostate cancer risk. All SNPs within 500kb of known GWAS SNPs are omitted. The green line represents P=5×10-8. This figure shows all new variants with P<5×10-8, regardless of the confirmation results (one signal on chr1, one on chr4, one on chr17, and 2 on chr X were not confirmed). Many of the new signals are in close proximity to one another on the same chromosome (see Supplementary Table 6).
Mentions: In the meta-analysis of the European ancestry studies,20 novel signals in18 regions ±500 kb outside of previously associated loci were observed to be associated with prostate cancer risk at P<5×10-8 (Figure 1; Supplementary Figure 2 Supplementary Figure 3). The most significant associations in each region were observed with imputed variants and we were able to confirm the imputed genotypes for 15 variants which had high imputation information scores (r2 range, 0.76-1) through direct genotyping or sequencing across multiple studies (Table 1;Online Methods,Supplementary Tables 5-8). Two of the variants were located within 370kb of each other on chromosome Xq13and are independent signals based on conditional analyses (rs6625711, P=6.1×10-10 and rs4844289, P=2.0×10-8; r2<0.01 in EUR 1KGP; Supplementary Table 9). All 15 variants were common, with minor allele frequencies (MAFs) ≥0.09, in the European ancestry population, and all but three (rs80130819/12q13, rs76939039/10q11 and rs17694493/9p21) were also common (MAF≥0.05) in African, Japanese and Latino populations. Evidence of heterogeneity in the per-allele OR was noted with 4 variants (Phet=0.01-8.4×10-6; rs17599629/1q21, rs115306967/6p21, rs17694493/9p21 and rs6625711/Xq13). Four of the 15 variants (rs10009409/4q13, rs4713266/6p24, rs80130819/12q13 and rs2807031/Xp11) had directional effects that were consistent with men of European ancestry and were nominally statistically significant (P<0.05) in at least one other population (Table 1) and for 3 SNPs, combining data across populations strengthened the statistical significance of the association (Table 1). In this large European ancestry sample we also confirmed the reported signal at 22q13 with variant rs58133635 (P=5.8×10-9; r2=0.74 with rs9623117 in 1KGP European ancestry populations (EUR); Supplemental Figure 2; Supplementary Figure 3).15

Bottom Line: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry.Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer.These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

View Article: PubMed Central - PubMed

Affiliation: 1] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [2].

ABSTRACT
Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

Show MeSH
Related in: MedlinePlus