Fredrick R Schumacher

Publications (45)436.18 Total impact

• Article: Meta-analysis identifies four new loci associated with testicular germ cell tumor.

  Charles C Chung, Peter A Kanetsky, Zhaoming Wang, Michelle A T Hildebrandt, Roelof Koster, Rolf I Skotheim, Christian P Kratz, Clare Turnbull, Victoria K Cortessis, Anne C Bakken, [......], Eila C Skinner, Duncan C Thomas, Xifeng Wu, Meredith Yeager, Fredrick R Schumacher, Mark H Greene, Stephen M Schwartz, Katherine A McGlynn, Stephen J Chanock, Katherine L Nathanson
  [show abstract] [hide abstract]
  ABSTRACT: We conducted a meta-analysis to identify new susceptibility loci for testicular germ cell tumor (TGCT). In the discovery phase, we analyzed 931 affected individuals and 1,975 controls from 3 genome-wide association studies (GWAS). We conducted replication in 6 independent sample sets comprising 3,211 affected individuals and 7,591 controls. In the combined analysis, risk of TGCT was significantly associated with markers at four previously unreported loci: 4q22.2 in HPGDS (per-allele odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.12-1.26; P = 1.11 × 10(-8)), 7p22.3 in MAD1L1 (OR = 1.21, 95% CI = 1.14-1.29; P = 5.59 × 10(-9)), 16q22.3 in RFWD3 (OR = 1.26, 95% CI = 1.18-1.34; P = 5.15 × 10(-12)) and 17q22 (rs9905704: OR = 1.27, 95% CI = 1.18-1.33; P = 4.32 × 10(-13) and rs7221274: OR = 1.20, 95% CI = 1.12-1.28; P = 4.04 × 10(-9)), a locus that includes TEX14, RAD51C and PPM1E. These new TGCT susceptibility loci contain biologically plausible genes encoding proteins important for male germ cell development, chromosomal segregation and the DNA damage response.
  Nature Genetics 05/2013; · 35.53 Impact Factor
• Article: Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23.

  Fredrick R Schumacher, Zhaoming Wang, Rolf I Skotheim, Roelof Koster, Charles C Chung, Michelle A T Hildebrandt, Christian P Kratz, Anne C Bakken, D Timothy Bishop, Michael B Cook, [......], Kimberly D Siegmund, Eila C Skinner, Clare Turnbull, David J Van Den Berg, Xifeng Wu, Meredith Yeager, Katherine L Nathanson, Stephen J Chanock, Victoria K Cortessis, Katherine A McGlynn
  [show abstract] [hide abstract]
  ABSTRACT: Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCT). A previous GWAS study reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWAS including a total of 940 TGCT cases and 1,559 controls for 122 single nucleotide polymorphisms (SNP) on chromosome 1q23 and followed up the most significant SNPs in an additional 2,202 TGCT cases and 2,386 controls from four case-control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined=6.0x10-9). Additional support is provided from an independent familial study of TGCT where a significant over transmission for rs3790665 with TGCT risk was observed (PFBAT=2.3x10-3). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk.
  Human Molecular Genetics 03/2013; · 7.64 Impact Factor
• Article: Insulin-like growth factor pathway genes and blood concentrations, dietary protein, and risk of prostate cancer in the NCI breast and prostate cancer cohort consortium (BPC3).

  Konstantinos K Tsilidis, Ruth C Travis, Paul N Appleby, Naomi E Allen, Sara Lindström, Demetrius Albanes, Regina G Ziegler, Marjorie L McCullough, Afshan Siddiq, Aurelio Barricarte, [......], Loic Le Marchand, Kim Overvad, Silvia Polidoro, Elio Riboli, Fredrick R Schumacher, Victoria L Stevens, Dimitrios Trichopoulos, Jarmo Virtamo, Walter C Willett, Timothy J Key
  [show abstract] [hide abstract]
  ABSTRACT: It has been hypothesized that a high intake of dairy protein may increase prostate cancer risk by increasing the production of insulin-like growth factor 1 (IGF-1). Several single nucleotide polymorphisms (SNPs) have been weakly associated with circulating concentrations of IGF-1 and IGF binding protein 3 (IGFBP-3), but none of these SNPs was associated with risk of prostate cancer. We examined whether an association between 16 SNPs associated with circulating IGF-1 or IGFBP-3 concentrations and prostate cancer exists within subgroups defined by dietary protein intake in 5,253 cases and 4,963 controls of European ancestry within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). The BPC3 includes nested case-control studies within large North-American and European cohorts. Per allele odds ratios for prostate cancer for the SNPs were compared across tertiles of protein intake, which was expressed as the percentage of energy derived from total, animal, dairy or plant protein sources, using conditional logistic regression models. Total, animal, dairy and plant protein intakes were significantly positively associated with blood IGF-1 (P<0.01), but not with IGFBP-3 concentrations (P>0.10) or with risk of prostate cancer (P>0.20). After adjusting for multiple testing, the SNP-prostate cancer associations did not differ by intakes of protein, although two interactions by intake of plant protein were of marginal statistical significance (SSTR5 (somatostatin receptor 5) -rs197056 [uncorrected P for interaction, 0.001]; SSTR5-rs197057 [uncorrected P for interaction, 0.002]). We found no strong evidence that the associations between 16 IGF pathway SNPs and prostate cancer differed by intakes of dietary protein. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 01/2013; · 5.44 Impact Factor
• Source

  Available from: Shuo Jiao

  Article: Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-Analysis.

  Ulrike Peters, Shuo Jiao, Fredrick R Schumacher, Carolyn M Hutter, Aaron K Aragaki, John A Baron, Sonja I Berndt, Stéphane Bézieau, Hermann Brenner, Katja Butterbach, [......], Darin Taverna, Stephen N Thibodeau, Cornelia M Ulrich, Emily White, Yongbing Xiang, Brent W Zanke, Yi-Xin Zeng, Ben Zhang, Wei Zheng, Li Hsu
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND & AIMS: Heritable factors contribute to development of colorectal cancer (CRC). Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS: We conducted a genome-wide association study (GWAS) that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS: Based on the combined analysis we identified a locus that reached the conventional genome-wide significance level at <5.0 x 10-8: an intergenic region on chromosome 2q32.3, close toNABP1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR]=1.15 per risk allele;P =3.7 x 10-8). We also found evidence for 3 additional loci with P values <5.0 x 10-7: a locus within theLAMC1gene on chromosome 1q25.3 (rs10911251; OR=1.10 per risk allele;P =9.5 x 10-8), a locus within theCCND2gene on chromosome 12p13.32 (rs3217810 per risk allele; OR=0.84;P =5.9 x 10-8), and a locus in theTBX3gene on chromosome 12q24.21 (rs59336, OR=0.91 per risk allele;P =3.7 x 10-7). CONCLUSIONS: In a large GWAS, we associated polymorphisms close toNABP (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms inLAMC1 (this is the second gene in the laminin family to be associated with CRCs),CCND2 (which encodes for cyclin D2), andTBX3 (which encodes a T-box transcription factor and is a target of Wnt signaling to -catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
  Gastroenterology 12/2012; · 11.68 Impact Factor
• Article: A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease.

  Ali Amin Al Olama, Zsofia Kote-Jarai, Fredrick R Schumacher, Fredrik Wiklund, Sonja I Berndt, Sara Benlloch, Graham G Giles, Gianluca Severi, David E Neal, Freddie C Hamdy, [......], Shintaro Narita, Guang-Wen Cao, Chavdar Slavov, Vanio Mitev, Stephen Chanock, Henrik Gronberg, Christopher A Haiman, Peter Kraft, Douglas F Easton, Rosalind A Eeles
  [show abstract] [hide abstract]
  ABSTRACT: Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four genome-wide association studies (GWAS) including 5,953 cases of aggressive PrCa and 11,463 controls (men without PrCa). We computed association tests for ~2.6M SNPs and followed up the most significant SNPs by genotyping 49,121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa (OR=1.12 (95% CI 1.03-1.21), P=1.4x10(-8)). This report describes a genetic variant which is associated with aggressive prostate cancer, which is a type of prostate cancer associated with a poorer prognosis.
  Human Molecular Genetics 10/2012; · 7.64 Impact Factor
• Article: A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11.

  Afshan Siddiq, Fergus J Couch, Gary K Chen, Sara Lindström, Diana Eccles, Robert C Millikan, Kyriaki Michailidou, Daniel O Stram, Lars Beckmann, Suhn Kyong Rhie, [......], Elad Ziv, Heli Nevanlinna, Douglas F Easton, David J Hunter, Brian E Henderson, Stephen J Chanock, Montserrat Garcia-Closas, Peter Kraft, Christopher A Haiman, Celine M Vachon
  [show abstract] [hide abstract]
  ABSTRACT: Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
  Human Molecular Genetics 09/2012; · 7.64 Impact Factor
• Article: Interactions between genome-wide significant genetic variants and circulating concentrations of insulin-like growth factor 1, sex hormones, and binding proteins in relation to prostate cancer risk in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.

  Konstantinos K Tsilidis, Ruth C Travis, Paul N Appleby, Naomi E Allen, Sara Lindstrom, Fredrick R Schumacher, David Cox, Ann W Hsing, Jing Ma, Gianluca Severi, [......], Edward Giovannucci, David J Hunter, Peter Kraft, Meir J Stampfer, Graham G Giles, Gerald L Andriole, Sonja I Berndt, Stephen J Chanock, Richard B Hayes, Timothy J Key
  [show abstract] [hide abstract]
  ABSTRACT: Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. There is limited information on the mechanistic basis of these associations, particularly about whether they interact with circulating concentrations of growth factors and sex hormones, which may be important in prostate cancer etiology. Using conditional logistic regression, the authors compared per-allele odds ratios for prostate cancer for 39 GWAS-identified SNPs across thirds (tertile groups) of circulating concentrations of insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), testosterone, androstenedione, androstanediol glucuronide, estradiol, and sex hormone-binding globulin (SHBG) for 3,043 cases and 3,478 controls in the Breast and Prostate Cancer Cohort Consortium. After allowing for multiple testing, none of the SNPs examined were significantly associated with growth factor or hormone concentrations, and the SNP-prostate cancer associations did not differ by these concentrations, although 4 interactions were marginally significant (MSMB-rs10993994 with androstenedione (uncorrected P = 0.008); CTBP2-rs4962416 with IGFBP-3 (uncorrected P = 0.003); 11q13.2-rs12418451 with IGF-1 (uncorrected P = 0.006); and 11q13.2-rs10896449 with SHBG (uncorrected P = 0.005)). The authors found no strong evidence that associations between GWAS-identified SNPs and prostate cancer are modified by circulating concentrations of IGF-1, sex hormones, or their major binding proteins.
  American journal of epidemiology 03/2012; 175(9):926-35. · 5.59 Impact Factor
• Article: Common genetic variants in prostate cancer risk prediction--results from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3).

  Sara Lindström, Fredrick R Schumacher, David Cox, Ruth C Travis, Demetrius Albanes, Naomi E Allen, Gerald Andriole, Sonja I Berndt, Heiner Boeing, H Bas Bueno-de-Mesquita, [......], Dimitrios Trichopoulos, Jarmo Virtamo, Stephanie J Weinstein, Walter C Willett, Meredith Yeager, Richard B Hayes, Gianluca Severi, Christopher A Haiman, Stephen J Chanock, Peter Kraft
  [show abstract] [hide abstract]
  ABSTRACT: One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent single-nucleotide polymorphism markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer, and age. We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data. The best risk model (C-statistic = 0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P = 0.009), with highest accuracy in men younger than 60 years (C-statistic = 0.679). The absolute ten-year risk for 50-year-old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile). Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from prostate-specific antigen screening. Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited.
  Cancer Epidemiology Biomarkers &amp Prevention 03/2012; 21(3):437-44. · 4.12 Impact Factor
• Article: Genetic variants associated with predisposition to prostate cancer and potential clinical implications.

  C L Goh, F R Schumacher, D Easton, K Muir, B Henderson, Z Kote-Jarai, R A Eeles
  [show abstract] [hide abstract]
  ABSTRACT: Prostate cancer is the commonest cancer in the developed world. There is an inherited component to this disease as shown in familial and twin studies. However, the discovery of these variants has been difficult. The emergence of genome-wide association studies has led to the identification of over 46 susceptibility loci. Their clinical utility to predict risk, response to treatment, or treatment toxicity, remains undefined. Large consortia are needed to achieve adequate statistical power to answer these genetic-clinical and genetic-epidemiological questions. International collaborations are currently underway to link genetic with clinical/epidemiological data to develop risk prediction models, which could direct screening and treatment programs.
  Journal of Internal Medicine 02/2012; 271(4):353-65. · 5.48 Impact Factor
• Article: Incorporating prior biologic information for high-dimensional rare variant association studies.

  Melanie A Quintana, Fredrick R Schumacher, Graham Casey, Jonine L Bernstein, Li Li, David V Conti
  [show abstract] [hide abstract]
  ABSTRACT: Background: Given the increasing scale of rare variant association studies, we introduce a method for high-dimensional studies that integrates multiple sources of data as well as allows for multiple region-specific risk indices. Methods: Our method builds upon the previous Bayesian risk index by integrating external biological variant-specific covariates to help guide the selection of associated variants and regions. Our extension also incorporates a second level of uncertainty as to which regions are associated with the outcome of interest. Results: Using a set of study-based simulations, we show that our approach leads to an increase in power to detect true associations in comparison to several commonly used alternatives. Additionally, the method provides multi-level inference at the pathway, region and variant levels. Conclusion: To demonstrate the flexibility of the method to incorporate various types of information and the applicability to high-dimensional data, we apply our method to a single region within a candidate gene study of second primary breast cancer and to multiple regions within a candidate pathway study of colon cancer.
  Human Heredity 01/2012; 74(3-4):184-95. · 1.79 Impact Factor
• Source

  Available from: Petra Buzková

  Article: Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.

  Steven Buyske, Ying Wu, Cara L Carty, Iona Cheng, Themistocles L Assimes, Logan Dumitrescu, Lucia A Hindorff, Sabrina Mitchell, Jose Luis Ambite, Eric Boerwinkle, [......], Carlos Rodriguez, Fredrick R Schumacher, Benjamin F Voight, Alicia Young, Teri A Manolio, Karen L Mohlke, Christopher A Haiman, Ulrike Peters, Dana C Crawford, Kari E North
  [show abstract] [hide abstract]
  ABSTRACT: The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
  PLoS ONE 01/2012; 7(4):e35651. · 4.09 Impact Factor
• Article: A genome-wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32.

  Wendy Cozen, Dalin Li, Timothy Best, David J Van Den Berg, Pierre-Antoine Gourraud, Victoria K Cortessis, Andrew D Skol, Thomas M Mack, Sally L Glaser, Lawrence M Weiss, [......], Amie E Hwang, Susan L Slager, Zachary S Fredericksen, Louise C Strong, Thomas M Habermann, Brian K Link, James R Cerhan, Leslie L Robison, David V Conti, Kenan Onel
  [show abstract] [hide abstract]
  ABSTRACT: Nodular sclerosing Hodgkin lymphoma (NSHL) is a distinct, highly heritable Hodgkin lymphoma subtype. We undertook a genome-wide meta-analysis of 393 European-origin adolescent/young adult NSHL patients and 3315 controls using the Illumina Human610-Quad Beadchip and Affymetrix Genome-Wide Human SNP Array 6.0. We identified 3 single nucleotide polymorphisms (SNPs) on chromosome 6p21.32 that were significantly associated with NSHL risk: rs9268542 (P = 5.35 × 10(-10)), rs204999 (P = 1.44 × 10(-9)), and rs2858870 (P = 1.69 × 10(-8)). We also confirmed a previously reported association in the same region, rs6903608 (P = 3.52 × 10(-10)). rs204999 and rs2858870 were weakly correlated (r(2) = 0.257), and the remaining pairs of SNPs were not correlated (r(2) < 0.1). In an independent set of 113 NSHL cases and 214 controls, 2 SNPs were significantly associated with NSHL and a third showed a comparable odds ratio (OR). These SNPs are found on 2 haplotypes associated with NSHL risk (rs204999-rs9268528-rs9268542-rs6903608-rs2858870; AGGCT, OR = 1.7, P = 1.71 × 10(-6); GAATC, OR = 0.4, P = 1.16 × 10(-4)). All individuals with the GAATC haplotype also carried the HLA class II DRB1*0701 allele. In a separate analysis, the DRB1*0701 allele was associated with a decreased risk of NSHL (OR = 0.5, 95% confidence interval = 0.4, 0.7). These data support the importance of the HLA class II region in NSHL etiology.
  Blood 11/2011; 119(2):469-75. · 9.90 Impact Factor
• Article: Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium.

  Daniele Campa, Rudolf Kaaks, Loïc Le Marchand, Christopher A Haiman, Ruth C Travis, Christine D Berg, Julie E Buring, Stephen J Chanock, W Ryan Diver, Lucie Dostal, [......], Fredrick R Schumacher, Guri Skeie, Daniel O Stram, Michael J Thun, Dimitrios Trichopoulos, Shumin Zhang, Regina G Ziegler, David J Hunter, Sara Lindström, Federico Canzian
  [show abstract] [hide abstract]
  ABSTRACT: Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer. To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 × 10(-4)) was done. Case-case comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided. We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 × 10(-3) -3.96 × 10(-19)). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028). This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.
  CancerSpectrum Knowledge Environment 08/2011; 103(16):1252-63. · 14.07 Impact Factor
• Article: Genome-wide association study identifies new prostate cancer susceptibility loci.

  Fredrick R Schumacher, Sonja I Berndt, Afshan Siddiq, Kevin B Jacobs, Zhaoming Wang, Sara Lindstrom, Victoria L Stevens, Constance Chen, Alison M Mondul, Ruth C Travis, [......], Laurence N Kolonel, Brian E Henderson, Demetrius Albanes, Richard B Hayes, Heather Spencer Feigelson, Elio Riboli, David J Hunter, Stephen J Chanock, Christopher A Haiman, Peter Kraft
  [show abstract] [hide abstract]
  ABSTRACT: Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P= 0.72 and P= 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.
  Human Molecular Genetics 07/2011; 20(19):3867-75. · 7.64 Impact Factor
• Article: Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer.

  Charles C Chung, Julia Ciampa, Meredith Yeager, Kevin B Jacobs, Sonja I Berndt, Richard B Hayes, Jesus Gonzalez-Bosquet, Peter Kraft, Sholom Wacholder, Nick Orr, [......], Kristian Hveem, Inger Njolstad, Daniela S Gerhard, Margaret Tucker, Robert N Hoover, Joseph F Fraumeni, David J Hunter, Gilles Thomas, Nilanjan Chatterjee, Stephen J Chanock
  [show abstract] [hide abstract]
  ABSTRACT: Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10(-8)) with rs10896449 the most significant (P= 7.94 × 10(-19)). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 × 10(-5), adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r(2)= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 × 10(-3), adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r(2)= 0.17; rs10896449-rs10896438, r(2)= 0.10; rs12793759-rs10896438, r(2)= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ∼123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.
  Human Molecular Genetics 07/2011; 20(14):2869-78. · 7.64 Impact Factor
• Source

  Available from: Shuo Jiao

  Article: Meta-analysis of new genome-wide association studies of colorectal cancer risk.

  Ulrike Peters, Carolyn M Hutter, Li Hsu, Fredrick R Schumacher, David V Conti, Christopher S Carlson, Christopher K Edlund, Robert W Haile, Steven Gallinger, Brent W Zanke, [......], John L Hopper, Mark A Jenkins, Loic Le Marchand, Noralane M Lindor, Polly A Newcomb, Daniela Seminara, Thomas J Hudson, David J Duggan, John D Potter, Graham Casey
  [show abstract] [hide abstract]
  ABSTRACT: Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.
  Human Genetics 07/2011; 131(2):217-34. · 5.07 Impact Factor
• Article: Large-scale fine mapping of the HNF1B locus and prostate cancer risk.

  Sonja I Berndt, Joshua Sampson, Meredith Yeager, Kevin B Jacobs, Zhaoming Wang, Amy Hutchinson, Charles Chung, Nick Orr, Sholom Wacholder, Nilanjan Chatterjee, [......], Kristian Hveem, Inger Njølstad, Daniela S Gerhard, Margaret Tucker, Richard B Hayes, Robert N Hoover, Joseph F Fraumeni, David J Hunter, Gilles Thomas, Stephen J Chanock
  [show abstract] [hide abstract]
  ABSTRACT: Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10(-8) with the most significant association with rs4430796 (P = 1.62 × 10(-24)). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r(2)= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10(-23)) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10(-8)); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10(-10)), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.
  Human Molecular Genetics 06/2011; 20(16):3322-9. · 7.64 Impact Factor
• Source

  Available from: Jean Maccluer

  Article: Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study.

  Logan Dumitrescu, Cara L Carty, Kira Taylor, Fredrick R Schumacher, Lucia A Hindorff, José L Ambite, Garnet Anderson, Lyle G Best, Kristin Brown-Gentry, Petra Bůžková, [......], Sarah A Pendergrass, Miguel Quibrera, Ralph V Shohet, Lynne R Wilkens, Christopher A Haiman, Loïc Le Marchand, Steven Buyske, Charles Kooperberg, Kari E North, Dana C Crawford
  [show abstract] [hide abstract]
  ABSTRACT: For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.
  PLoS Genetics 06/2011; 7(6):e1002138. · 8.69 Impact Factor
• Conference Proceeding: Fine-mapping of Type 2 Diabetes Risk Loci in African Americans using the Metabochip: The PAGE Study

  Fredrick R Schumacher, Kari E North, Jeff Haessler, Kylee L Spencer, Nora Franceschini, Kristine R Monroe, Barbara V Howard, Rebecca D Jackson, Linda W H Kao, Laurence N Kolonel, [......], Lewis H Kuller, Lynne R Wilkens, Lucia A Hindorff, José Luis Ambite, Loic Le Marchand, Dana C Crawford, Steven Buyske, James S Pankow, Ulrike Peters, Christopher A Haiman
  American Diabetes Association 71st Scientific Sessions; 06/2011
• Article: Type 2 diabetes risk variants and colorectal cancer risk: the Multiethnic Cohort and PAGE studies.

  Iona Cheng, Christian P Caberto, Annette Lum-Jones, Ann Seifried, Lynne R Wilkens, Fredrick R Schumacher, Kristine R Monroe, Unhee Lim, Maarit Tiirikainen, Laurence N Kolonel, Brian E Henderson, Daniel O Stram, Christopher A Haiman, Loïc Le Marchand
  [show abstract] [hide abstract]
  ABSTRACT: Diabetes has been positively associated with the risk of colorectal cancer. This study investigated whether recently established risk variants for diabetes also have effects on colorectal cancer. 19 single nucleotide repeats (SNPs) associated with type 2 diabetes in genome-wide association studies were tested in a case-control study of 2011 colorectal cancer cases and 6049 controls nested in the Multiethnic Cohort study as part of the Population Architecture using Genomics and Epidemiology (PAGE) initiative. ORs and 95% CIs were estimated by unconditional logistic regression to evaluate the association between SNPs and colorectal cancer risk, adjusting for age, sex and race/ethnicity. Permutation testing was conducted to correct for multiple hypothesis testing. Four type 2 diabetes SNPs were associated with colorectal cancer risk: rs7578597 (THADA), rs864745 (JAZF1), rs5219 (KCNJ11) and rs7961581 (TSPAN8, LGR5). The strongest association was for the rs7578597 (THADA) Thr1187Ala missense polymorphism (P(trend)=0.004 adjusted for multiple testing), with the high risk allele for colorectal cancer being the low risk allele for diabetes. Similar patterns of associations were seen with further adjustment for diabetes status and body mass index. The association of diabetes status with colorectal cancer risk was somewhat weakened after adjustment for these SNPs. The findings suggest that diabetes risk variants also influence colorectal cancer susceptibility, possibly through mechanisms different from those for diabetes.
  Gut 05/2011; 60(12):1703-11. · 10.11 Impact Factor