Christopher A Haiman

Publications (180)1878.73 Total impact

• Article: Genome-wide association study of age at menarche in African-American women.

  Ellen W Demerath, Ching-Ti Liu, Nora Franceschini, Gary Chen, Julie R Palmer, Erin N Smith, Christina T L Chen, Christine B Ambrosone, Alice M Arnold, Elisa V Bandera, [......], B Gwen Windham, Melissa Wellons, Sarah S Murray, Michael Nalls, Aleksandar Rajkovic, Joel Hirschhorn, L Adrienne Cupples, Charles Kooperberg, Joanne M Murabito, Christopher A Haiman
  [show abstract] [hide abstract]
  ABSTRACT: African American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single nucleotide polymorphisms (SNPs) in a total of 18,089 AA women in 15 cohort studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2,850 women (Stage 2). First, while no SNP passed the pre-specified p< 5 x 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Second, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.
  Human Molecular Genetics 04/2013; · 7.64 Impact Factor
• Source

  Available from: Irene Konstantopoulou

  Article: Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

  Montserrat Garcia-Closas, Fergus J Couch, Sara Lindstrom, Kyriaki Michailidou, Marjanka K Schmidt, Mark N Brook, Nick Orr, Suhn Kyong Rhie, Elio Riboli, Heather S Feigelson, [......], Alison M Dunning, Mark E Sherman, Georgia Chenevix-Trench, Stephen J Chanock, Per Hall, Paul D P Pharoah, Celine Vachon, Douglas F Easton, Christopher A Haiman, Peter Kraft
  [show abstract] [hide abstract]
  ABSTRACT: Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
  Nature Genetics 03/2013; 45(4):392-398. · 35.53 Impact Factor
• Source

  Available from: Jiajun Shi

  Article: Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls.

  Wei Zheng, Ben Zhang, Qiuyin Cai, Hyuna Sung, Kyriaki Michailidou, Jiajun Shi, Ji-Yeob Choi, Jirong Long, Joe Dennis, Manjeet K Humphreys, [......], Aiko Sueta, Mi Kyung Kim, Ui Soon Khoo, Motoki Iwasaki, Paul D P Pharoah, Wanqing Wen, Per Hall, Xiao-Ou Shu, Douglas F Easton, Daehee Kang
  [show abstract] [hide abstract]
  ABSTRACT: In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ∼10% of excess familial risk of breast cancer in Asian populations.
  Human Molecular Genetics 03/2013; · 7.64 Impact Factor
• Article: Large-scale genotyping identifies 41 new loci associated with breast cancer risk.

  Kyriaki Michailidou, Per Hall, Anna Gonzalez-Neira, Maya Ghoussaini, Joe Dennis, Roger L Milne, Marjanka K Schmidt, Jenny Chang-Claude, Stig E Bojesen, Manjeet K Bolla, [......], Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Jacques Simard, Montse Garcia-Closas, Paul D P Pharoah, Georgia Chenevix-Trench, Alison M Dunning, Javier Benitez, Douglas F Easton
  [show abstract] [hide abstract]
  ABSTRACT: Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
  Nature Genetics 03/2013; 45(4):353-361. · 35.53 Impact Factor
• Source

  Available from: Robert A Vierkant

  Article: Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

  Stig E Bojesen, Karen A Pooley, Sharon E Johnatty, Jonathan Beesley, Kyriaki Michailidou, Jonathan P Tyrer, Stacey L Edwards, Hilda A Pickett, Howard C Shen, Chanel E Smart, [......], Simon A Gayther, Paul D P Pharoah, Roger R Reddel, Ellen L Goode, Mark H Greene, Douglas F Easton, Andrew Berchuck, Antonis C Antoniou, Georgia Chenevix-Trench, Alison M Dunning
  [show abstract] [hide abstract]
  ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
  Nature Genetics 03/2013; 45(4):371-384. · 35.53 Impact Factor
• Article: Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression.

  Zsofia Kote-Jarai, Edward J Saunders, Daniel A Leongamornlert, Malgorzata Tymrakiewicz, Tokhir Dadaev, Sarah Jugurnauth-Little, Helen Ross-Adams, Ali Amin Al Olama, Sara Benlloch, Silvia Halim, [......], Ed Dicks, Caroline Baynes, Don Conroy, Stig E Bojesen, Rudolf Kaaks, Daniel Vincent, François Bacot, Daniel C Tessier, Douglas F Easton, Rosalind A Eeles
  [show abstract] [hide abstract]
  ABSTRACT: Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.
  Human Molecular Genetics 03/2013; · 7.64 Impact Factor
• Article: Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.

  Rosalind A Eeles, Ali Amin Al Olama, Sara Benlloch, Edward J Saunders, Daniel A Leongamornlert, Malgorzata Tymrakiewicz, Maya Ghoussaini, Craig Luccarini, Joe Dennis, Sarah Jugurnauth-Little, [......], Sofia Maia, Paula Paulo, Ethan Lange, Kathleen A Cooney, Antonis C Antoniou, Daniel Vincent, François Bacot, Daniel C Tessier, Zsofia Kote-Jarai, Douglas F Easton
  [show abstract] [hide abstract]
  ABSTRACT: Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.
  Nature Genetics 03/2013; 45(4):385-391. · 35.53 Impact Factor
• Article: Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers.

  Juliet D French, Maya Ghoussaini, Stacey L Edwards, Kerstin B Meyer, Kyriaki Michailidou, Shahana Ahmed, Sofia Khan, Mel J Maranian, Martin O'Reilly, Kristine M Hillman, [......], Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J Schoemaker, Bruce A J Ponder, Heli Nevanlinna, Melissa A Brown, Georgia Chenevix-Trench, Douglas F Easton, Alison M Dunning
  [show abstract] [hide abstract]
  ABSTRACT: Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
  The American Journal of Human Genetics 03/2013; · 10.60 Impact Factor
• Article: Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk.

  Mia M Gaudet, Karoline B Kuchenbaecker, Joseph Vijai, Robert J Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M Dunning, Andrew Lee, Joe Dennis, [......], Guillermo Pita, M Rosario Alonso, Per Hall, Fergus J Couch, Jacques Simard, David Altshuler, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, Kenneth Offit
  [show abstract] [hide abstract]
  ABSTRACT: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
  PLoS Genetics 03/2013; 9(3):e1003173. · 8.69 Impact Factor
• Article: Trans-ethnic fine-mapping of lipid Loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.

  Ying Wu, Lindsay L Waite, Anne U Jackson, Wayne H-H Sheu, Steven Buyske, Devin Absher, Donna K Arnett, Eric Boerwinkle, Lori L Bonnycastle, Cara L Carty, [......], Tzung-Dau Wang, Michael Boehnke, Christopher A Haiman, Yii-Der I Chen, Charles Kooperberg, Themistocles L Assimes, Dana C Crawford, Chao A Hsiung, Kari E North, Karen L Mohlke
  [show abstract] [hide abstract]
  ABSTRACT: Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
  PLoS Genetics 03/2013; 9(3):e1003379. · 8.69 Impact Factor
• Article: Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population.

  Christopher A Haiman, Ying Han, Ye Feng, Lucy Xia, Chris Hsu, Xin Sheng, Loreall C Pooler, Yesha Patel, Laurence N Kolonel, Erin Carter, Karen Park, Loic Le Marchand, David Van Den Berg, Brian E Henderson, Daniel O Stram
  [show abstract] [hide abstract]
  ABSTRACT: Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls. In breast cancer, the strongest associations included either SNPs in or gene burden scores for genes LDLRAD1, SLC19A1, FGFBP3, CASP5, MMAB, SLC16A6, and INS-IGF2. In prostate cancer, one of the most associated SNPs was in the gene GPRC6A (rs2274911, Pro91Ser, OR = 0.88, P = 1.3×10(-5)) near to a known risk locus for prostate cancer; other suggestive associations were noted in genes such as F13A1, ANXA4, MANSC1, and GP6. For both breast and prostate cancer, several of the most significant associations involving SNPs or gene burden scores (sum of minor alleles) were noted in genes previously reported to be associated with a cancer-related phenotype. However, only one of the associations (rs145889899 in LDLRAD1, p = 2.5×10(-7) only seen in African Americans) for overall breast or prostate cancer risk was statistically significant after correcting for multiple comparisons. In addition to breast and prostate cancer, other cancer-related traits were examined (body mass index, PSA level, and alcohol drinking) with a number of known and potentially novel associations described. In general, these findings do not support there being many protein coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. Very large sample sizes will be required to better define the role of rare and less penetrant coding variation in prostate and breast cancer disease genetics.
  PLoS Genetics 03/2013; 9(3):e1003419. · 8.69 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
• Article: Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study.

  Megan D Fesinmeyer, Kari E North, Unhee Lim, Petra Buzková, Dana C Crawford, Jeffrey Haessler, Myron D Gross, Jay H Fowke, Robert Goodloe, Shelley-Ann Love, [......], Ross L Prentice, Lawrence N Kolonel, Joann E Manson, James Pankow, Lucia A Hindorff, Nora Franceschini, Lynne R Wilkens, Christopher A Haiman, Loic Marchand, Ulrike Peters
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND: Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored. METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE)' Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses. RESULTS: We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (beta = 0.018, p = 0.002), vs. current smokers (beta = 0.001, p = 0.95, pinteraction = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (beta = 0.017, p = 3.5x10-5), vs. former/never smokers (beta = 0.006, p = 0.05, pinteraction = 0.08). CONCLUSIONS: These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results.Clinical Trial Registration: NCT00000611.
  BMC Medical Genetics 01/2013; 14(1):6. · 2.33 Impact Factor
• Article: The Influence of Obesity-Related Single Nucleotide Polymorphisms on BMI Across the Life Course: The PAGE Study.

  Mariaelisa Graff, Penny Gordon-Larsen, Unhee Lim, Jay H Fowke, Shelly-Ann Love, Megan Fesinmeyer, Lynne R Wilkens, Shawyntee Vertilus, Marilyn D Ritchie, Ross L Prentice, [......], Nora Franceschini, Christopher S Carlson, Steven Buyske, Petra Buzková, Lucia A Hindorff, Tara C Matise, Dana C Crawford, Christopher A Haiman, Ulrike Peters, Kari E North
  [show abstract] [hide abstract]
  ABSTRACT: Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture of Genomics and Epidemiology Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26-49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m(2), respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.
  Diabetes 01/2013; · 8.29 Impact Factor
• Article: Genetic Variation and Reproductive Timing: African American Women from the Population Architecture Using Genomics and Epidemiology (PAGE) Study.

  Kylee L Spencer, Jennifer Malinowski, Cara L Carty, Nora Franceschini, Lindsay Fernández-Rhodes, Alicia Young, Iona Cheng, Marylyn D Ritchie, Christopher A Haiman, Lynne Wilkens, Chunyuanwu, Tara C Matise, Christopher S Carlson, Kathleen Brennan, Amy Park, Aleksandar Rajkovic, Lucia A Hindorff, Steven Buyske, Dana C Crawford
  [show abstract] [hide abstract]
  ABSTRACT: Age at menarche (AM) and age at natural menopause (ANM) define the boundaries of the reproductive lifespan in women. Their timing is associated with various diseases, including cancer and cardiovascular disease. Genome-wide association studies have identified several genetic variants associated with either AM or ANM in populations of largely European or Asian descent women. The extent to which these associations generalize to diverse populations remains unknown. Therefore, we sought to replicate previously reported AM and ANM findings and to identify novel AM and ANM variants using the Metabochip (n = 161,098 SNPs) in 4,159 and 1,860 African American women, respectively, in the Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study. We replicated or generalized one previously identified variant for AM, rs1361108/CENPW, and two variants for ANM, rs897798/BRSK1 and rs769450/APOE, to our African American cohort. Overall, generalization of the majority of previously-identified variants for AM and ANM, including LIN28B and MCM8, was not observed in this African American sample. We identified three novel loci associated with ANM that reached significance after multiple testing correction (LDLR rs189596789, p = 5×10(-08); KCNQ1 rs79972789, p = 1.9×10(-07); COL4A3BP rs181686584, p = 2.9×10(-07)). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, p = 1.6×10(-06)). While most associations were identified in either AM or ANM, we did identify genes suggestively associated with both: PHACTR1 and ARHGAP42. The lack of generalization coupled with the potentially novel associations identified here emphasize the need for additional genetic discovery efforts for AM and ANM in diverse populations.
  PLoS ONE 01/2013; 8(2):e55258. · 4.09 Impact Factor
• Article: Global patterns of prostate cancer incidence, aggressiveness, and mortality in men of african descent.

  Timothy R Rebbeck, Susan S Devesa, Bao-Li Chang, Clareann H Bunker, Iona Cheng, Kathleen Cooney, Rosalind Eeles, Pedro Fernandez, Veda N Giri, Serigne M Gueye, [......], Robin A Roberts, Benjamin A Rybicki, Janet L Stanford, Sara Strom, Ian M Thompson, John Witte, Jianfeng Xu, Edward Yeboah, Ann W Hsing, Charnita M Zeigler-Johnson
  [show abstract] [hide abstract]
  ABSTRACT: Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.
  Prostate cancer. 01/2013; 2013:560857.
• Source

  Available from: Shuo Jiao

  Article: A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study.

  Ulrike Peters, Kari E North, Praveen Sethupathy, Steve Buyske, Jeff Haessler, Shuo Jiao, Megan D Fesinmeyer, Rebecca D Jackson, Lew H Kuller, Aleksandar Rajkovic, [......], C Charles Gu, Denise Houston, Petra Buzkova, Marylyn Ritchie, Tara C Matise, Loic Le Marchand, Lucia A Hindorff, Dana C Crawford, Christopher A Haiman, Charles Kooperberg
  [show abstract] [hide abstract]
  ABSTRACT: Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3×10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.
  PLoS Genetics 01/2013; 9(1):e1003171. · 8.69 Impact Factor
• Article: Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network.

  Sarah A Pendergrass, Kristin Brown-Gentry, Scott Dudek, Alex Frase, Eric S Torstenson, Robert Goodloe, Jose Luis Ambite, Christy L Avery, Steve Buyske, Petra Bůžková, [......], Yi Lin, Tara C Matise, Kristine R Monroe, Larry Moreland, Sungshim L Park, Alex Reiner, Robert Wallace, Lynn R Wilkens, Dana C Crawford, Marylyn D Ritchie
  [show abstract] [hide abstract]
  ABSTRACT: Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype-phenotype associations, 26 represented phenotypes closely related to previously known genotype-phenotype associations, and 33 represented potentially novel genotype-phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits.
  PLoS Genetics 01/2013; 9(1):e1003087. · 8.69 Impact Factor
• Article: One thousand genomes imputation in the national cancer institute breast and prostate cancer cohort consortium aggressive prostate cancer genome-wide association study.

  Mitchell J Machiela, Constance Chen, Liming Liang, W Ryan Diver, Victoria L Stevens, Konstantinos K Tsilidis, Christopher A Haiman, Stephen J Chanock, David J Hunter, Peter Kraft
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND: Genotype imputation substantially increases available markers for analysis in genome-wide association studies (GWAS) by leveraging linkage disequilibrium from a reference panel. We sought to (i) investigate the performance of imputation from the August 2010 release of the 1000 Genomes Project (1000GP) in an existing GWAS of prostate cancer, (ii) look for novel associations with prostate cancer risk, (iii) fine-map known prostate cancer susceptibility regions using an approximate Bayesian framework and stepwise regression, and (iv) compare power and efficiency of imputation and de novo sequencing. METHODS: We used 2,782 aggressive prostate cancer cases and 4,458 controls from the NCI Breast and Prostate Cancer Cohort Consortium aggressive prostate cancer GWAS to infer 5.8 million well-imputed autosomal single nucleotide polymorphisms (SNPs). RESULTS: Imputation quality, as measured by correlation between imputed and true allele counts, was higher among common variants than rare variants. We found no novel prostate cancer associations among a subset of 1.2 million well-imputed low-frequency variants. At a genome-wide sequencing cost of $2,500, imputation from SNP arrays is a more powerful strategy than sequencing for detecting disease associations of SNPs with minor allele frequencies (MAF) above 1%. CONCLUSIONS: 1000GP imputation provided dense coverage of previously identified prostate cancer susceptibility regions, highlighting its potential as an inexpensive first-pass approach to fine mapping in regions such as 5p15 and 8q24. Our study shows 1000GP imputation can accurately identify low-frequency variants and stresses the importance of large sample size when studying these variants. Prostate © 2012 Wiley Periodicals, Inc.
  The Prostate 12/2012; · 3.48 Impact Factor
• Article: Levels of Beta-Microseminoprotein in Blood and Risk of Prostate Cancer in Multiple Populations.

  Christopher A Haiman, Daniel O Stram, Andrew J Vickers, Lynne R Wilkens, Katharina Braun, Camilla Valtonen-André, Mari Peltola, Kim Pettersson, Kevin M Waters, Loic Le Marchand, Laurence N Kolonel, Brian E Henderson, Hans Lilja
  [show abstract] [hide abstract]
  ABSTRACT: BackgroundA common genetic variant (rs10993994) in the 5' region of the gene encoding β-microseminoprotein (MSP) is associated with circulating levels of MSP and prostate cancer risk. Whether MSP levels are predictive of prostate cancer risk has not been evaluated.Methods We investigated the prospective relationship between circulating plasma levels of MSP and prostate cancer risk in a nested case-control study of 1503 case subjects and 1503 control subjects among black, Latino, Japanese, Native Hawaiian, and white men from the Multiethnic Cohort study. We also examined the ability of MSP to serve as a biomarker for discriminating prostate cancer case subjects from control subjects. All statistical tests are two-sided.ResultsIn all racial and ethnic groups, men with lower MSP levels were at greater risk of developing prostate cancer (odds ratio = 1.02 per one unit decrease in MSP, P < .001 in the prostate-specific antigen [PSA]-adjusted analysis). Compared with men in the highest decile of MSP, the multivariable PSA-adjusted odds ratio was 3.64 (95% confidence interval = 2.41 to 5.49) for men in the lowest decile. The positive association with lower MSP levels was observed consistently across racial and ethnic populations, by disease stage and Gleason score, for men with both high and low levels of PSA and across all genotype classes of rs10993994. However, we did not detect strong evidence of MSP levels in improving prostate cancer prediction beyond that of PSA.Conclusions Regardless of race and ethnicity or rs10993994 genotype, men with low blood levels of MSP have increased risk of prostate cancer.
  CancerSpectrum Knowledge Environment 12/2012; · 14.07 Impact Factor