For the meta-analysis of genome-wide association studies, we propose a new method to adjust for the population stratification and a linear mixed approach that combines family-based and unrelated samples. The proposed approach achieves similar power levels as a standard meta-analysis which combines the different test statistics or p values across studies. However, by virtue of its design, the proposed approach is robust against population admixture and stratification, and no adjustments for population admixture and stratification, even in unrelated samples, are required. Using simulation studies, we examine the power of the proposed method and compare it to standard approaches in the meta-analysis of genome-wide association studies. The practical features of the approach are illustrated with a meta-analysis of three genome-wide association studies for Alzheimer’s disease. We identify three single nucleotide polymorphisms showing significant genome-wide association with affection status. Two single nucleotide polymorphisms are novel and will be verified in other populations in our follow-up study.
© 2012 S. Karger AG, Basel
- Genome-wide study
- Population stratification
- Weedon MN, Lango H, Lindgren CM, Wallace C, Evans DM, Mangino M, Freathy RM, Perry JR, Stevens S, Hall AS, Samani NJ, Shields B, Prokopenko I, Farrall M, Dominiczak A, Johnson T, Bergmann S, Beckmann JS, Vollenweider P, Waterworth DM, Mooser V, Palmer CN, Morris AD, Ouwehand WH, Zhao JH, Li S, Loos RJ, Barroso I, Deloukas P, Sandhu MS, Wheeler E, Soranzo N, Inouye M, Wareham NJ, Caulfield M, Munroe PB, Hattersley AT, McCarthy MI, Frayling TM: Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 2008;40:575–583.
- Dai JY, Ruczinski I, LeBlanc M, Kooperberg C: Imputation methods to improve inference in SNP association studies. Genet Epidemiol 2006;30:690–702.
- Marchini J, Howie B, Myers S, McVean G, Donnelly P: A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 2007;39:906–913.
- Servin B, Stephens M: Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genet 2007;3:e114.
- Marchini J, Cardon LR, Phillips MS, Donnelly P: The effects of human population structure on large genetic association studies. Nat Genet 2004;36:512–517.
- Won S, Wilk JB, Mathias RA, O’Donnell CJ, Silverman EK, Barnes K, O’Connor GT, Weiss ST, Lange C: On the analysis of genome-wide association studies in family-based designs: a universal, robust analysis approach and an application to four genome-wide association studies. PLoS Genet 2009;5:e1000741.
- 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.
- Epstein MP, Veal CD, Trembath RC, Barker JN, Li C, Satten GA: Genetic association analysis using data from triads and unrelated subjects. Am J Hum Genet 2005;76:592–608.
- 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.
- Pritchard JK, Stephens M, Donnelly P: Inference of population structure using multilocus genotype data. Genetics 2000;155:945–959.
- Laird NM, Horvath S, Xu X: Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000;19 Suppl 1:S36–S42.
- Laird NM, Lange C: Family-based designs in the age of large-scale gene-association studies. Nat Rev Genet 2006;7:385–394.
- Lange C, Laird NM: On a general class of conditional tests for family-based association studies in genetics: the asymptotic distribution, the conditional power, and optimality considerations. Genet Epidemiol 2002;23:165–180.
- Lange C, Silverman EK, Xu X, Weiss ST, Laird NM: A multivariate family-based association test using generalized estimating equations: FBAT-GEE. Biostatistics 2003;4:195–206.
- Won S, Bertram L, Becker D, Tanzi RE, Lange C: Maximizing the power of genome-wide association studies: a novel class of powerful family-based association tests. Stat Biosci 2009;1:125–143.
- Rabinowitz D, Laird N: A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000;50:211–223.
- Fulker DW, Cherny SS, Sham PC, Hewitt JK: Combined linkage and association sib-pair analysis for quantitative traits. Am J Hum Genet 1999;64:259–267.
- Ionita-Laza I, McQueen MB, Laird NM, Lange C: Genomewide weighted hypothesis testing in family-based association studies, with an application to a 100K scan. Am J Hum Genet 2007;81:607–614.
- Van Steen K, McQueen MB, Herbert A, Raby B, Lyon H, Demeo DL, Murphy A, Su J, Datta S, Rosenow C, Christman M, Silverman EK, Laird NM, Weiss ST, Lange C: Genomic screening and replication using the same data set in family-based association testing. Nat Genet 2005;37:683–691.
- Lee S, Zou F, Wright FA: Convergence and prediction of principal component scores in high-dimensional settings. Ann Stat 2010;38:3605–3629.
- Patterson N, Price AL, Reich D: Population structure and eigenanalysis. PLoS Genet 2006;2:e190.
- Bourgain C, Hoffjan S, Nicolae R, Newman D, Steiner L, Walker K, Reynolds R, Ober C, McPeek MS: Novel case-control test in a founder population identifies p-selectin as an atopy-susceptibility locus. Am J Hum Genet 2003;73:612–626.
- Browning BL, Browning SR: A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 2009;84:210–223.
- Croiseau P, Genin E, Cordell HJ: Dealing with missing data in family-based association studies: a multiple imputation approach. Hum Hered 2007;63:229–238.
- Balding DJ, Nichols RA: A method for quantifying differentiation between populations at multi-allelic loci and its implications for investigating identity and paternity. Genetica 1995;96:3–12.
- Lange C, Lyon H, DeMeo D, Raby B, Silverman EK, Weiss ST: A new powerful non-parametric two-stage approach for testing multiple phenotypes in family-based association studies. Hum Hered 2003;56:10–17.
- Chen WM, Abecasis GR: Family-based association tests for genomewide association scans. Am J Hum Genet 2007;81:913–926.
- Kang HM, Sul JH, Service SK, Zaitlen NA, Kong SY, Freimer NB, Sabatti C, Eskin E: Variance component model to account for sample structure in genome-wide association studies. Nat Genet 2010;42:348–354.
- Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Fiske A, Pedersen NL: Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006;63:168–174.
- Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, Schjeide BM, Hooli B, Divito J, Ionita I, Jiang H, Laird N, Moscarillo T, Ohlsen KL, Elliott K, Wang X, Hu-Lince D, Ryder M, Murphy A, Wagner SL, Blacker D, Becker KD, Tanzi RE: Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am J Hum Genet 2008;83:623–632.
- Grupe A, Abraham R, Li Y, Rowland C, Hollingworth P, Morgan A, Jehu L, Segurado R, Stone D, Schadt E, Karnoub M, Nowotny P, Tacey K, Catanese J, Sninsky J, Brayne C, Rubinsztein D, Gill M, Lawlor B, Lovestone S, Holmans P, O’Donovan M, Morris JC, Thal L, Goate A, Owen MJ, Williams J: Evidence for novel susceptibility genes for late-onset Alzheimer’s disease from a genome-wide association study of putative functional variants. Hum Mol Genet 2007;16:865–873.
- Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, Hosford D, Barnes MR, Briley JD, Borrie M, Coletta N, Delisle R, Dhalla D, Ehm MG, Feldman HH, Fornazzari L, Gauthier S, Goodgame N, Guzman D, Hammond S, Hollingworth P, Hsiung GY, Johnson J, Kelly DD, Keren R, Kertesz A, King KS, Lovestone S, Loy-English I, Matthews PM, Owen MJ, Plumpton M, Pryse-Phillips W, Prinjha RK, Richardson JC, Saunders A, Slater AJ, St George-Hyslop PH, Stinnett SW, Swartz JE, Taylor RL, Wherrett J, Williams J, Yarnall DP, Gibson RA, Irizarry MC, Middleton LT, Roses AD: Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol 2008;65:45–53.
- Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA: GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers. Neuron 2007;54:713–720.
- Fisher RA: Statistical Methods for Research Workers, ed 11. Edinburgh, Oliver & Boyd, 1950.
- Liptak T: On the combination of independent tests. Magyar Tud Akad Mat Kutato Int Kozl 1958;3:171.
- Hoggart CJ, Parra EJ, Shriver MD, Bonilla C, Kittles RA, Clayton DG, McKeigue PM: Control of confounding of genetic associations in stratified populations. Am J Hum Genet 2003;72:1492–1504.
Department of Applied Statistics
Seoul 156-756 (Republic of Korea)
Tel. +82 2 820 5217, E-Mail firstname.lastname@example.org
Received: March 13, 2011
Accepted after revision: July 15, 2011
Published online: January 18, 2012
Number of Print Pages : 12
Number of Figures : 2, Number of Tables : 5, Number of References : 36
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 73, No. 1, Year 2012 (Cover Date: March 2012)
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.