Meta-Analysis of Genome-Wide Association Studies
Abstract
INTRODUCTION: Individual genome-wide association studies have only limited power to find novel loci underlying complex traits and common diseases. With relatively modest sample and effect sizes, a true association between genotype and phenotype may never meet genome-wide statistical significance (P < 5 × 10-8) in a single study. Through meta-analysis, novel susceptibility loci can be discovered by effectively summing the statistical evidence of individually underpowered studies. Most genetic discoveries for complex traits are now made through meta-analysis collaborations, which so far have been restricted to single-locus analyses, testing for main effects at a single polymorphism at a time. A key benefit of this approach is that individual-level genotype (and phenotype) data do not need to be exchanged between research groups. In this article, we focus on meta-analysis at individual single-nucleotide polymorphisms (SNPs), paying particular attention to how imputation uncertainty can be incorporated into the association analysis and subsequent meta-analysis. Probably the most important aspect of genome-wide association meta-analysis is harmonization of the study results. As studies differ in design, sample collection, genotyping platforms, and association analysis methods, it is important that the association results (per SNP) of each study can be formatted, exchanged, and analyzed in such a way that the statistical evidence can be combined appropriately and that no valuable information is lost. Without minimizing the importance of having a clear phenotype definition (and corresponding measurements), we will assume that investigators representing the various studies have made sensible agreements about phenotype definitions, necessary sample exclusions, and appropriate covariate modeling.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
There have been multiple meta-analysis consortia in psychiatric genetics, of which the Psychiatric Genomics Consortium is the largest and most encompassing.
“there have been multiple meta-analysis 146,147 consortia in psychiatric genetics, of which the Psychiatric Genomics Consortium (http://pgc.unc.edu) is the largest and most encompassing. 123,148,149”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [148]
Cites
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
Self-citationAn integrated encyclopedia of DNA elements in the human genome
The ENCODE Project Consortium (2012) · Nature · doi:10.1038/nature11247 · Cited by 18,072 · see citing works
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194 · see citing works
(2004) · The Lancet · doi:10.1016/s0140-6736(03)15268-3 · Cited by 12,717 · see citing works
A map of human genome variation from population-scale sequencing.
The 1000 Genomes Project Consortium (2010) · Nature · doi:10.1038/nature09534 · Cited by 7,877 · see citing works
A haplotype map of the human genome
The International HapMap Consortium (2005) · Nature · doi:10.1038/nature04226 · Cited by 5,858 · see citing works
The combination of estimates from different experiments
Cochran, W. G. (1954) · Biometrics · doi:10.2307/3001666 · Cited by 5,380 · see citing works
Frayling, T. M., Timpson, N. J., Weedon, M. N., Zeggini, E., Freathy, R. M., Lindgren, C. M., Perry, J. R. B., Elliott, K. S., Lango, H., Rayner, N. W., et al. (2007) · Science · doi:10.1126/science.1141634 · Cited by 4,531 · see citing works
A second generation human haplotype map of over 3.1 million SNPs
The International HapMap Consortium (2007) · Nature · doi:10.1038/nature06258 · Cited by 4,438 · see citing works
Global estimates of visual impairment: 2010
Pascolini, D., & Mariotti, S. P. (2011) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2011-300539 · Cited by 3,773 · see citing works
Genomic Control for Association Studies
Devlin, B., & Roeder, K. (1999) · Biometrics · doi:10.1111/j.0006-341x.1999.00997.x · Cited by 3,162 · see citing works
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
MAGIC, Speliotes, E. K., on behalf of Procardis Consortium, Willer, C. J., Berndt, S. I., Monda, K. L., Thorleifsson, G., Jackson, A. U., Allen, H. L., Lindgren, C. M., et al. (2010) · Nature Genetics · doi:10.1038/ng.686 · Cited by 2,912 · see citing works
Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
Saxena, R., Voight, B. F., Lyssenko, V., Burtt, N. P., de Bakker, P. I. W., Chen, H., Roix, J. J., Kathiresan, S., Hirschhorn, J. N., Daly, M. J., et al. (2007) · Science · doi:10.1126/science.1142358 · Cited by 2,843 · see citing works
Self-citationA new multipoint method for genome-wide association studies by imputation of genotypes
Marchini, J., Howie, B., Myers, S., McVean, G., & Donnelly, P. (2007) · Nature Genetics · doi:10.1038/ng2088 · Cited by 2,609 · see citing works
Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease
the NIDDK IBD Genetics Consortium, Barrett, J. C., the Belgian-French IBD Consortium, the Wellcome Trust Case Control Consortium, Hansoul, S., Nicolae, D. L., Cho, J. H., Duerr, R. H., Rioux, J. D., Brant, S. R., et al. (2008) · Nature Genetics · doi:10.1038/ng.175 · Cited by 2,593 · see citing works
Self-citationWard, L. D., & Kellis, M. (2012) · Nucleic Acids Research · doi:10.1093/nar/gkr917 · Cited by 2,229 · see citing works
Wellcome Trust Case Control Consortium, Zeggini, E., Scott, L. J., Saxena, R., Voight, B. F., Marchini, J. L., Hu, T., de Bakker, P. I., Abecasis, G. R., Almgren, P., et al. (2008) · Nature Genetics · doi:10.1038/ng.120 · Cited by 1,864 · see citing works
Self-citationBrowning, B. L., & Browning, S. R. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.01.005 · Cited by 1,640 · see citing works
Common variants at 30 loci contribute to polygenic dyslipidemia
Kathiresan, S., Willer, C. J., Peloso, G. M., Demissie, S., Musunuru, K., Schadt, E. E., Kaplan, L., Bennett, D., Li, Y., Tanaka, T., et al. (2009) · Nature Genetics · doi:10.1038/ng.291 · Cited by 1,364 · see citing works
Self-citationCommon variants near MC4R are associated with fat mass, weight and risk of obesity
The Prostate, L., Loos, R. J. F., KORA, Study, N. H., Initiative, D. G., Study, T. S., The Wellcome Trust Case Control Consortium, FUSION, Lindgren, C. M., Li, S., et al. (2008) · Nature Genetics · doi:10.1038/ng.140 · Cited by 1,325 · see citing works
Wellcome Trust Case Control Consortium, Ferreira, M. A. R., O'Donovan, M. C., Meng, Y. A., Jones, I. R., Ruderfer, D. M., Jones, L., Fan, J., Kirov, G., Perlis, R. H., et al. (2008) · Nature Genetics · doi:10.1038/ng.209 · Cited by 1,237 · see citing works
Self-citationGenome-wide association study identifies eight loci associated with blood pressure
Wellcome Trust Case Control Consortium, Newton-Cheh, C., Johnson, T., Gateva, V., Tobin, M. D., Bochud, M., Coin, L., Najjar, S. S., Zhao, J. H., Heath, S. C., et al. (2009) · Nature Genetics · doi:10.1038/ng.361 · Cited by 1,215 · see citing works
Population genomics of human gene expression
Stranger, B. E., Nica, A. C., Forrest, M. S., Dimas, A. S., Bird, C., Beazley, C., Ingle, C., Dunning, M., Flicek, P., Koller, D., et al. (2007) · Nature Genetics · doi:10.1038/ng2142 · Cited by 1,132 · see citing works
Cho, Y. S., Go, M. J., Kim, Y. J., Heo, J. Y., Oh, J. H., Ban, H., Yoon, D., Lee, M. H., Kim, D. J., Park, M., et al. (2009) · Nature Genetics · doi:10.1038/ng.357 · Cited by 1,015 · see citing works
Transcriptome genetics using second generation sequencing in a Caucasian population
Montgomery, S. B., Sammeth, M., Gutierrez-Arcelus, M., Lach, R. P., Ingle, C., Nisbett, J., Guigo, R., & Dermitzakis, E. T. (2010) · Nature · doi:10.1038/nature08903 · Cited by 797 · see citing works
Xu, Z., & Taylor, J. A. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp290 · Cited by 753 · see citing works
Han, B., & Eskin, E. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.04.014 · Cited by 680 · see citing works
Meyre, D., Delplanque, J., Chèvre, J.-C., Lecœur, C., Lobbens, S., Gallina, S., Durand, E., Vatin, V., Degraeve, F., Cavalcanti-Proença, C., et al. (2009) · Nature Genetics · doi:10.1038/ng.301 · Cited by 648 · see citing works
Genetics and Beyond – The Transcriptome of Human Monocytes and Disease Susceptibility
Zeller, T., Wild, P. S., Szymczak, S., Rotival, M., Schillert, A., Castagné, R., Maouche, S., Germain, M., Lackner, K. J., Rossmann, H., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010693 · Cited by 584 · see citing works
Kato, N., Takeuchi, F., Tabara, Y., Kelly, T. N., Go, M. J., Sim, X., Tay, W. T., Chen, C.-H., Zhang, Y., Yamamoto, K., et al. (2011) · Nature Genetics · doi:10.1038/ng.834 · Cited by 563 · see citing works
Practical aspects of imputation-driven meta-analysis of genome-wide association studies
de Bakker, P. I. W., Ferreira, M. A. R., Jia, X., Neale, B. M., Raychaudhuri, S., & Voight, B. F. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn288 · Cited by 531 · see citing works
Self-citationImputation-Based Analysis of Association Studies: Candidate Regions and Quantitative Traits
Servin, B., & Stephens, M. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030114 · Cited by 520 · see citing works
Genome-wide association study of hematological and biochemical traits in a Japanese population
Kamatani, Y., Matsuda, K., Okada, Y., Kubo, M., Hosono, N., Daigo, Y., Nakamura, Y., & Kamatani, N. (2010) · Nature Genetics · doi:10.1038/ng.531 · Cited by 501 · see citing works
Segrè, A. V., DIAGRAM Consortium, MAGIC investigators, Groop, L., Mootha, V. K., Daly, M. J., & Altshuler, D. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001058 · Cited by 463 · see citing works
Self-citationRaychaudhuri, S., Plenge, R. M., Rossin, E. J., Ng, A., Purcell, S., Sklar, P. B., Scolnick, E. M., Xavier, R. J., Altshuler, D., & Daly, M. J. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000534 · Cited by 422 · see citing works
Self-citationCommon variants at ten loci influence QT interval duration in the QTGEN Study
Newton‐Cheh, C., Eijgelsheim, M., Rice, K. M., de Bakker, P. I. W., Yin, X., Estrada, K., Bis, J. C., Marciante, K. D., Rivadeneira, F., Noseworthy, P. A., et al. (2009) · Nature Genetics · doi:10.1038/ng.364 · Cited by 412 · see citing works
GATES: A Rapid and Powerful Gene-Based Association Test Using Extended Simes Procedure
Li, M., Gui, H., Kwan, J. S. H., & Sham, P. C. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.01.019 · Cited by 378 · see citing works
Scherag, A., Christian Dina, C., Hinney, A., Vatin, V., Scherag, S., Vogel, C. I. G., Müller, T. D., Grallert, H., Wichmann, H. ‐., Balkau, B., et al. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1000916 · Cited by 327 · see citing works
Assessment of Cataracts from Photographs in the Beaver Dam Eye Study
Klein, B. E. K., Klein, R., Linton, K. L. P., Magli, Y. L., & Neider, M. W. (1990) · Ophthalmology · doi:10.1016/s0161-6420(90)32391-6 · Cited by 326 · see citing works
Lavanya, R., Jeganathan, V. S. E., Zheng, Y., Raju, P., Cheung, N., Tai, E. S., Wang, J. J., Lamoureux, E. L., Mitchell, P. L. R., Young, T. L., et al. (2009) · Ophthalmic Epidemiology · doi:10.3109/09286580903144738 · Cited by 320 · see citing works
The epidemiology of age related eye diseases in Asia
Wong, T. Y. (2006) · British Journal of Ophthalmology · doi:10.1136/bjo.2005.083733 · Cited by 301 · see citing works
Kim, Y. J., Go, M. J., Hu, C., Hong, C. B., Kim, Y. K., Lee, J. Y., Hwang, J., Oh, J. H., Kim, D. J., Kim, N. H., et al. (2011) · Nature Genetics · doi:10.1038/ng.939 · Cited by 293 · see citing works
Transethnic meta‐analysis of genomewide association studies
Morris, A. P. (2011) · Genetic Epidemiology · doi:10.1002/gepi.20630 · Cited by 287 · see citing works
Evaluating and improving power in whole-genome association studies using fixed marker sets
Pe’er, I., de Bakker, P. I. W., Maller, J., Yelensky, R., Altshuler, D., & Daly, M. J. (2006) · Nature Genetics · doi:10.1038/ng1816 · Cited by 275 · see citing works
Self-citation(2001) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(00)00732-7 · Cited by 240 · see citing works
Jonas, J. B., Xu, L., & Wang, Y. X. (2009) · Acta Ophthalmologica · doi:10.1111/j.1755-3768.2008.01385.x · Cited by 227 · see citing works
Pras, E., Frydman, M., Levy‐Nissenbaum, E., et al. (2000) · PubMed · Cited by 191 · see citing works
Mackay, D. S., Andley, U. P., & Shiels, A. (2003) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5201046 · Cited by 175 · see citing works
Practical Issues in Imputation-Based Association Mapping
Guan, Y., & Stephens, M. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000279 · Cited by 171 · see citing works
Genome-wide association study of coronary artery disease in the Japanese
Takeuchi, F., Yokota, M., Yamamoto, K., Nakashima, E., Katsuya, T., Asano, H., Isono, M., Nabika, T., Sugiyama, T., Fujioka, A., et al. (2011) · European Journal of Human Genetics · doi:10.1038/ejhg.2011.184 · Cited by 163 · see citing works
Epidemiologic study of age-related cataracts among an elderly chinese population in Shih-Pai, Taiwan
Tsai, S.-Y., Hsu, W., Cheng, C., et al. (2003) · Ophthalmology · doi:10.1016/s0161-6420(03)00243-4 · Cited by 144 · see citing works
CHMP4B, a Novel Gene for Autosomal Dominant Cataracts Linked to Chromosome 20q
Shiels, A., Bennett, T. M., Knopf, H. L. S., Yamada, K., Yoshiura, K.-I., Niikawa, N., Shim, S., & Hanson, P. I. (2007) · The American Journal of Human Genetics · doi:10.1086/519980 · Cited by 122 · see citing works
Identification of Two Proteins Associated with Mammalian ATP Synthase
Meyer, B., Wittig, I., Trifilieff, É., Karas, M., & Schägger, H. (2007) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m700097-mcp200 · Cited by 112 · see citing works
Rees, M. I., Watts, P., Fenton, I., et al. (2000) · Human Genetics · doi:10.1007/s004390051029 · Cited by 99 · see citing works
Bowman lecture. The conquest of cataract: a global challenge.
Kupfer, C. (1985) · PubMed · Cited by 98 · see citing works
Effects of α-Crystallin on Lens Cell Function and Cataract Pathology
Andley, U. P. (2009) · Current Molecular Medicine · doi:10.2174/156652409789105598 · Cited by 94 · see citing works
Smoking, Socioeconomic Factors, and Age-Related Cataract
Wu, R. (2010) · Archives of Ophthalmology · doi:10.1001/archophthalmol.2010.147 · Cited by 89 · see citing works
Genetic Variation in KCNQ1 Associates With Fasting Glucose andβ-Cell Function
Tan, J. T., Nurbaya, S., Gardner, D. S.-L., Ye, S., Tai, E. S., & Ng, D. P. K. (2009) · Diabetes · doi:10.2337/db08-1138 · Cited by 82 · see citing works
Effects of smoking on ocular health
Galor, A., & Lee, D. J. (2011) · Current Opinion in Ophthalmology · doi:10.1097/icu.0b013e32834bbe7a · Cited by 81 · see citing works
Tan, A., Sun, J., Xia, N., Qin, X. Y., Hu, Y., Zhang, S., Tao, S., Gao, Y., Yang, X., Zhang, H., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr587 · Cited by 77 · see citing works
Cornes, B. K., Khor, C. C., Nongpiur, M. E., Xu, L., Tay, W.-T., Zheng, Y., Lavanya, R., Li, Y., Wu, R., Sim, X., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr463 · Cited by 74 · see citing works
Ophthalmological Features Associated With COL4A1 Mutations
Coupry, I. (2010) · Archives of Ophthalmology · doi:10.1001/archophthalmol.2010.42 · Cited by 73 · see citing works
Genome-Wide Scan for Loci of Adolescent Obesity and Their Relationship with Blood Pressure
Melka, M. G., Bernard, M., Mahboubi, A., Abrahamowicz, M., Paterson, A. D., Syme, C. A., Lourdusamy, A., Schumann, G., Leonard, G. T., Perron, M., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1801 · Cited by 58 · see citing works
Proteomic Analysis of Human Age-related Nuclear Cataracts and Normal Lens Nuclei
Su, S., Liu, P., Zhang, H., et al. (2011) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.10-7094 · Cited by 56 · see citing works
Gupta, V., Awasthi, N., & Wagner, B. J. (2007) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.06-0889 · Cited by 54 · see citing works
Population-based study on prevalence and risk factors of age-related cataracts in Peitou, Taiwan.
Cheng, C., Liu, J. H., Chen, S. J., et al. (2000) · PubMed · Cited by 41 · see citing works
Tan, A. C. S., Tan, A. C. S., Wang, J. J., et al. (2011) · Ophthalmic Epidemiology · doi:10.3109/09286586.2011.594205 · Cited by 39 · see citing works
Fujita, Y., Ezura, Y., Emi, M., et al. (2003) · Journal of Human Genetics · doi:10.1007/s10038-003-0101-8 · Cited by 31 · see citing works
Novel mutation in the gamma-S crystallin gene causing autosomal dominant cataract.
Vanita, V., Singh, J. R., Singh, D., et al. (2009) · PubMed · Cited by 28 · see citing works
KCNQ1 Haplotypes Associate with Type 2 Diabetes in Malaysian Chinese Subjects
Saif-Ali, R., Ismail, I. S., Al-Hamodi, Z. H., et al. (2011) · International Journal of Molecular Sciences · doi:10.3390/ijms12095705 · Cited by 23 · see citing works
Introduction to Linkage Disequilibrium, the HapMap, and ImputationPreprint
Neale, B. M. (2010) · Cold Spring Harbor Protocols · doi:10.1101/pdb.top74 · Cited by 22 · see citing works
Self-citationYang, G., Zhai, X., & Zhao, J. (2011) · PubMed · Cited by 14 · see citing works
Determination of the correct reference frame from an atomic coordinate list
Yeates, T. O. (1990) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390002793 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Genetic architectures of psychiatric disorders: the emerging picture and its implications
Sullivan, P. F., Daly, M. J., & O'Donovan, M. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3240 · Cited by 1,177 · see citing works
Self-citationYang, L., Neale, B. M., Liu, L., Lee, S. H., Wray, N. R., Ji, N., Li, H., Qian, Q., Wang, D., Li, J., et al. (2013) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32169 · Cited by 171 · see citing works
Self-citationSharp, S. I., McQuillin, A., Marks, M., Hunt, S. P., Stanford, S. C., Lydall, G. J., Morgan, M. Y., Asherson, P., Curtis, D., & Gurling, H. M. D. (2014) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32241 · Cited by 52 · see citing works
- Authors
- de Bakker, P. I. W., Neale, B. M., & Daly, M. J.
- Venue
- Cold Spring Harbor Protocols
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-06
- Volume
- 2010
- Issue
- 6
- Pages
- pdb.top81
- ISSN
- 1559-6095 (ISSN-L)
- 1940-3402
- OpenAlex
- W2031957244
- Cited by
- 48
- References
- 73
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 7 · 2014: 6 · 2013: 5 · 2012: 4
- Type
- posted content
- Language
- en
- Open access
- closed
- Locations
- Cold Spring Harbor Protocols (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- single nucleotide polymorphisms, imputation uncertainty, complex traits, common diseases, genetic susceptibility loci, genotype-phenotype correlation
- MeSH terms
- Genotype, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
