- Genome-wide association studies
- Additional controls
- Population stratification
- Pancreatic cancer
Though genome-wide association studies (GWAS) have identified numerous susceptibility loci for common diseases, their use is limited due to the expense of genotyping large cohorts of individuals. One potential solution is to use ‘additional controls’, or genotype data from control individuals deposited in public repositories. While this approach has been used by several groups, the genetically heterogeneous nature of the population of the United States makes this approach potentially problematic. We empirically investigated the utility of this approach in a US-based GWAS. In a small GWAS of pancreatic cancer in New York, we observed clear population structure differences relative to controls from the database of Genotypes and Phenotypes (dbGaP). When we conduct the GWAS using these additional controls, we find large inflation of the test statistic that is properly corrected by using eigenvectors from principal components analysis as covariates. To deal with errors introduced due to different sources, we propose simultaneously genotyping a small number of controls along with cases and then comparing this group to the additional controls. We show that removing SNPs that show differences between these control groups reduces false-positive findings. Thus, through an empirical approach, this report provides practical guidance for using additional controls from publicly available datasets.
Copyright © 2011 S. Karger AG, Basel
- WTCCC: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661–678.
- Crowther-Swanepoel D, Qureshi M, Dyer MJ, Matutes E, Dearden C, Catovsky D, Houlston RS: Genetic variation in cxcr4 and risk of chronic lymphocytic leukemia. Blood 2009;114:4843–4846.
- Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B, Simon M, Marie Y, Boisselier B, Delattre JY, Hoang-Xuan K, El Hallani S, Idbaih A, Zelenika D, Andersson U, Henriksson R, Bergenheim AT, Feychting M, Lonn S, Ahlbom A, Schramm J, Linnebank M, Hemminki K, Kumar R, Hepworth SJ, Price A, Armstrong G, Liu Y, Gu X, Yu R, Lau C, Schoemaker M, Muir K, Swerdlow A, Lathrop M, Bondy M, Houlston RS: Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet 2009;41:899–904.
- Di Bernardo MC, Crowther-Swanepoel D, Broderick P, Webb E, Sellick G, Wild R, Sullivan K, Vijayakrishnan J, Wang Y, Pittman AM, Sunter NJ, Hall AG, Dyer MJ, Matutes E, Dearden C, Mainou-Fowler T, Jackson GH, Summerfield G, Harris RJ, Pettitt AR, Hillmen P, Allsup DJ, Bailey JR, Pratt G, Pepper C, Fegan C, Allan JM, Catovsky D, Houlston RS: A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat Genet 2008;40:1204–1210.
- Kilpivaara O, Mukherjee S, Schram AM, Wadleigh M, Mullally A, Ebert BL, Bass A, Marubayashi S, Heguy A, Garcia-Manero G, Kantarjian H, Offit K, Stone RM, Gilliland DG, Klein RJ, Levine RL: A germline jak2 snp is associated with predisposition to the development of jak2(v617f)-positive myeloproliferative neoplasms. Nat Genet 2009;41:455–459.
- Zhuang JJ, Zondervan K, Nyberg F, Harbron C, Jawaid A, Cardon LR, Barratt BJ, Morris AP: Optimizing the power of genome-wide association studies by using publicly available reference samples to expand the control group. Genet Epidemiol 2010;34:319–326.
- Price AL, Butler J, Patterson N, Capelli C, Pascali VL, Scarnicci F, Ruiz-Linares A, Groop L, Saetta AA, Korkolopoulou P, Seligsohn U, Waliszewska A, Schirmer C, Ardlie K, Ramos A, Nemesh J, Arbeitman L, Goldstein DB, Reich D, Hirschhorn JN: Discerning the ancestry of European Americans in genetic association studies. PLoS Genet 2008;4:e236.
- Tian C, Kosoy R, Nassir R, Lee A, Villoslada P, Klareskog L, Hammarström L, Garchon HJ, Pulver AE, Ransom M, Gregersen PK, Seldin MF: European population genetic substructure: further definition of ancestry informative markers for distinguishing among diverse European ethnic groups. Mol Med 2009;15:371–383.
- Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006;38:904–909.
- Li Q, Yu K: Improved correction for population stratification in genome-wide association studies by identifying hidden population structures. Genet Epidemiol 2008;32:215–226.
- Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, Fuchs CS, Petersen GM, Arslan AA, Bueno-de-Mesquita HB, Gross M, Helzlsouer K, Jacobs EJ, LaCroix A, Zheng W, Albanes D, Bamlet W, Berg CD, Berrino F, Bingham S, Buring JE, Bracci PM, Canzian F, Clavel-Chapelon F, Clipp S, Cotterchio M, de Andrade M, Duell EJ, Fox JW Jr, Gallinger S, Gaziano JM, Giovannucci EL, Goggins M, Gonzalez CA, Hallmans G, Hankinson SE, Hassan M, Holly EA, Hunter DJ, Hutchinson A, Jackson R, Jacobs KB, Jenab M, Kaaks R, Klein AP, Kooperberg C, Kurtz RC, Li D, Lynch SM, Mandelson M, McWilliams RR, Mendelsohn JB, Michaud DS, Olson SH, Overvad K, Patel AV, Peeters PH, Rajkovic A, Riboli E, Risch HA, Shu XO, Thomas G, Tobias GS, Trichopoulos D, Van Den Eeden SK, Virtamo J, Wactawski-Wende J, Wolpin BM, Yu H, Yu K, Zeleniuch-Jacquotte A, Chanock SJ, Hartge P, Hoover RN: Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 2009;41:986–990.
- Petersen GM, Amundadottir L, Fuchs CS, Kraft P, Stolzenberg-Solomon RZ, Jacobs KB, Arslan AA, Bueno-de-Mesquita HB, Gallinger S, Gross M, Helzlsouer K, Holly EA, Jacobs EJ, Klein AP, LaCroix A, Li D, Mandelson MT, Olson SH, Risch HA, Zheng W, Albanes D, Bamlet WR, Berg CD, Boutron-Ruault MC, Buring JE, Bracci PM, Canzian F, Clipp S, Cotterchio M, de Andrade M, Duell EJ, Gaziano JM, Giovannucci EL, Goggins M, Hallmans G, Hankinson SE, Hassan M, Howard B, Hunter DJ, Hutchinson A, Jenab M, Kaaks R, Kooperberg C, Krogh V, Kurtz RC, Lynch SM, McWilliams RR, Mendelsohn JB, Michaud DS, Parikh H, Patel AV, Peeters PH, Rajkovic A, Riboli E, Rodriguez L, Seminara D, Shu XO, Thomas G, Tjonneland A, Tobias GS, Trichopoulos D, Van Den Eeden SK, Virtamo J, Wactawski-Wende J, Wang Z, Wolpin BM, Yu H, Yu K, Zeleniuch-Jacquotte A, Fraumeni JF Jr, Hoover RN, Hartge P, Chanock SJ: A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet 2010;42:224–228.
- Klein RJ: Power analysis for genome-wide association studies. BMC Genet2007;8:58.
- Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: Plink: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81:559–575.
- Tian C, Plenge RM, Ransom M, Lee A, Villoslada P, Selmi C, Klareskog L, Pulver AE, Qi L, Gregersen PK, Seldin MF: Analysis and application of European genetic substructure using 300 K SNP information. PLoS Genet 2008;4:e4.
- Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A, Indap A, King KS, Bergmann S, Nelson MR, Stephens M, Bustamante CD: Genes mirror geography within Europe. Nature 2008;456:98–101.
- Paschou P, Drineas P, Lewis J, Nievergelt CM, Nickerson DA, Smith JD, Ridker PM, Chasman DI, Krauss RM, Ziv E: Tracing sub-structure in the European American population with PCA-informative markers. PLoS Genet 2008;4:e1000114.
- Devlin B, Roeder K: Genomic control for association studies. Biometrics 1999;55:997–1004.
- Pluzhnikov A, Below JE, Konkashbaev A, Tikhomirov A, Kistner-Griffin E, Roe CA, Nicolae DL, Cox NJ: Spoiling the whole bunch: quality control aimed at preserving the integrity of high-throughput genotyping. Am J Hum Genet 2010;87:123–128.
- Kimmel G, Jordan MI, Halperin E, Shamir R, Karp RM: A randomization test for controlling population stratification in whole-genome association studies. Am J Hum Genet 2007;81:895–905.
- Epstein MP, Allen AS, Satten GA: A simple and improved correction for population stratification in case-control studies. Am J Hum Genet 2007;80:921–930.
- Lee S, Sullivan PF, Zou F, Wright FA: Comment on a simple and improved correction for population stratification. Am J Hum Genet 2008;82:524–526; author reply 526–528.
- Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O’Donovan M, Owen MJ, Williams J: Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 2009;41:1088–1093.
- Wang H, Thomas DC, Pe’er I, Stram DO: Optimal two-stage genotyping designs for genome-wide association scans. Genet Epidemiol 2006;30:356–368.
- Ohashi J, Clark AG: Application of the stepwise focusing method to optimize the cost-effectiveness of genome-wide association studies with limited research budgets for genotyping and phenotyping. Ann Hum Genet 2005;69:323–328.
- Skol AD, Scott LJ, Abecasis GR, Boehnke M: Optimal designs for two-stage genome-wide association studies. Genet Epidemiol 2007;31:776–788.
- Satagopan JM, Elston RC: Optimal two-stage genotyping in population-based association studies. Genet Epidemiol 2003;25:149–157.
- Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A, Wang J, Yu K, Chatterjee N, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover RN, Thomas G, Chanock SJ: A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 2007;39:870–874.
- Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, Wacholder S, Minichiello MJ, Fearnhead P, Yu K, Chatterjee N, Wang Z, Welch R, Staats BJ, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cancel-Tassin G, Cussenot O, Valeri A, Andriole GL, Gelmann EP, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover R, Hunter DJ, Chanock SJ, Thomas G: Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007;39:645–649.
- Landi MT, Chatterjee N, Yu K, Goldin LR, Goldstein AM, Rotunno M, Mirabello L, Jacobs K, Wheeler W, Yeager M, Bergen AW, Li Q, Consonni D, Pesatori AC, Wacholder S, Thun M, Diver R, Oken M, Virtamo J, Albanes D, Wang Z, Burdette L, Doheny KF, Pugh EW, Laurie C, Brennan P, Hung R, Gaborieau V, McKay JD, Lathrop M, McLaughlin J, Wang Y, Tsao MS, Spitz MR, Wang Y, Krokan H, Vatten L, Skorpen F, Arnesen E, Benhamou S, Bouchard C, Metsapalu A, Vooder T, Nelis M, Valk K, Field JK, Chen C, Goodman G, Sulem P, Thorleifsson G, Rafnar T, Eisen T, Sauter W, Rosenberger A, Bickeboller H, Risch A, Chang-Claude J, Wichmann HE, Stefansson K, Houlston R, Amos CI, Fraumeni JF Jr, Savage SA, Bertazzi PA, Tucker MA, Chanock S, Caporaso NE: A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet 2009;85:679–691.
Robert J. Klein
Program in Cancer Biology and Genetics
Memorial Sloan-Kettering Cancer Center
1275 York Ave., Box 337, New York, NY 10065 (USA)
Tel. +1 646 888 2525, E-Mail email@example.com
Received: January 11, 2011
Accepted after revision: May 31, 2011
Published online: August 17, 2011
Number of Print Pages : 14
Number of Figures : 4, Number of Tables : 6, Number of References : 30
Additional supplementary material is available online - Number of Parts : 4
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 72, No. 1, Year 2011 (Cover Date: September 2011)
Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)
For additional information: http://www.karger.com/HHE
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.