Synthetic Associations Are Unlikely to Account for Many Common Disease Genome-Wide Association Signals
Open accessAbstract
The Perspective section provides experts with a forum to comment
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Synthetic association is not expected to account for most missing heritability.
“Synthetic association is not expected to account for most of the missing heritability19, 51”
From Rare and common variants: twenty arguments (2012) · cites this paper as [51]
The Procrustean theory that common variant signals inevitably reflect "synthetic associations" to rare, high penetrance mutations is not credible.
“The Procrustean theory that common variant signals inevitably reflect “synthetic associations” 124 to rare, high penetrance mutations is not credible. 77,125–127”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [127]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
The Wellcome Trust Case Control Consortium, Management Committee, Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., et al. (2007) · Nature · doi:10.1038/nature05911 · Cited by 9,442 · see citing works
Self-citationFinding the missing heritability of complex diseases
Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J., McCarthy, M. I., Ramos, E. M., Cardon, L. R., Chakravarti, A., et al. (2009) · Nature · doi:10.1038/nature08494 · Cited by 8,336 · see citing works
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease
Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cézard, J.-P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C. A., Gassull, M., et al. (2001) · Nature · doi:10.1038/35079107 · Cited by 5,591 · see citing works
The Future of Genetic Studies of Complex Human Diseases
Risch, N., & Merikangas, K. (1996) · Science · doi:10.1126/science.273.5281.1516 · Cited by 5,355 · see citing works
The Wellcome Trust Case Control Consortium, U.K.
Mossman, K. (2008) · Scientific American · doi:10.1038/scientificamerican0108-42a · Cited by 2,714 · 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-citationComplement factor H variant increases the risk of age-related macular degeneration
Haines, J. L., Hauser, M. A., Schmidt, S., Scott, W. K., Olson, L. M., Gallins, P., Spencer, K. L., Kwan, S. Y., Noureddine, M., Gilbert, J. R., et al. (2005) · Science · doi:10.1126/science.1110359 · Cited by 2,424 · see citing works
Rioux, J. D., Xavier, R. J., Taylor, K. D., Silverberg, M. S., Goyette, P., Huett, A., Green, T., Kuballa, P., Barmada, M. M., Datta, L. W., et al. (2007) · Nature Genetics · doi:10.1038/ng2032 · Cited by 1,769 · see citing works
Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis
The MAGIC investigators, Voight, B. F., The GIANT Consortium, Scott, L. J., Steinthorsdottir, V., Morris, A. P., Dina, C., Welch, R. P., Zeggini, E., Huth, C., et al. (2010) · Nature Genetics · doi:10.1038/ng.609 · Cited by 1,761 · see citing works
Self-citationThe Type 1 Diabetes Genetics Consortium, Barrett, J. C., Clayton, D. G., Concannon, P., Akolkar, B., Cooper, J. D., Erlich, H. A., Julier, C., Morahan, G., Nerup, J., et al. (2009) · Nature Genetics · doi:10.1038/ng.381 · Cited by 1,746 · see citing works
Self-citationParkes, M., Barrett, J. C., Prescott, N. J., Tremelling, M., Anderson, C. A., Fisher, S. A., Roberts, R. G., Nimmo, E. R., Cummings, F. J. R., Soars, D., et al. (2007) · Nature Genetics · doi:10.1038/ng2061 · Cited by 1,144 · see citing works
Self-citationNejentsev, S., Walker, N., Riches, D., Egholm, M., & Todd, J. A. (2009) · Science · doi:10.1126/science.1167728 · Cited by 958 · see citing works
Mapping of a susceptibility locus for Crohn's disease on chromosome 16
Hugot, J., Laurent‐Puig, P., Gower‐Rousseau, C., Olson, J. M., Lee, J. C., Beaugerie, L., Naom, I., Dupas, J., Gossum, A. V., Af, G. D. T. D., et al. (1996) · Nature · doi:10.1038/379821a0 · Cited by 950 · see citing works
Rare Variants Create Synthetic Genome-Wide Associations
Dickson, S. P., Wang, K., Krantz, I., Hakonarson, H., & Goldstein, D. B. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000294 · Cited by 857 · see citing works
Barrett, J., Lee, J. C., Lees, C., Prescott, N., Anderson, C., Phillips, A., Wesley, E., Parnell, K. S., Zhang, H., Drummond, H., et al. (2009) · Nature Genetics · doi:10.1038/ng.483 · Cited by 602 · see citing works
Self-citationDetecting shared pathogenesis from the shared genetics of immune-related diseases
Zhernakova, A., van Diemen, C. C., & Wijmenga, C. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2489 · Cited by 551 · see citing works
Lack of common NOD2 variants in Japanese patients with Crohn's disease
Inoue, N., Tamura, K., Kinouchi, Y., Fukuda, Y., Takahashi, S., Ogura, Y., Inohara, N., Núñez, G., Kishi, Y., Koike, Y., et al. (2002) · Gastroenterology · doi:10.1053/gast.2002.34155 · Cited by 483 · see citing works
Raychaudhuri, 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
Cho, J. H., Nicolae, D. L., Gold, L. H., Fields, C. T., LaBuda, M. C., Rohal, P. M., Pickles, M., Li, Q., Fu, Y., Mann, J., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7502 · Cited by 380 · see citing works
Human genetics illuminates the paths to metabolic disease
O’Rahilly, S. (2009) · Nature · doi:10.1038/nature08532 · Cited by 324 · see citing works
Croucher, P. J. P., Mascheretti, S., Hampe, J., Huse, K., Frenzel, H., Stoll, M., Lu, T. T., Nikolaus, S., Yang, S., Krawczak, M., et al. (2003) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5200897 · Cited by 226 · see citing works
Yamazaki, K., Onouchi, Y., Takazoe, M., Kubo, M., Nakamura, Y., & Hata, A. (2007) · Journal of Human Genetics · doi:10.1007/s10038-007-0156-z · Cited by 203 · see citing works
Waters, K. M., Stram, D. O., Hassanein, M. T., Le Marchand, L., Wilkens, L. R., Maskarinec, G., Monroe, K. R., Kolonel, L. N., Altshuler, D., Henderson, B. E., et al. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001078 · Cited by 191 · see citing works
Wang, K., Dickson, S. P., Stolle, C. A., Krantz, I. D., Goldstein, D. B., & Hakonarson, H. H. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.04.003 · Cited by 153 · see citing works
Brant, S. R., Fu, Y., Fields, C. T., Baltazar, R. F., Ravenhill, G., Pickles, M., Rohal, P. M., Mann, J., Kirschner, B. S., Jabs, E. W., et al. (1998) · Gastroenterology · doi:10.1016/s0016-5085(98)70073-3 · Cited by 135 · see citing works
CONCANNON, P. J., Chen, W., Julier, C., Morahan, G., Akolkar, B., Erlich, H. A., Hilner, J. E., Nerup, J., Nierras, C. R., Pociot, F., et al. (2009) · Diabetes · doi:10.2337/db08-1551 · Cited by 103 · see citing works
Anderson, C. A., Pettersson, F. H., Barrett, J. C., Zhuang, J. J., Ragoussis, J., Cardon, L. R., & Morris, A. P. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.06.008 · Cited by 93 · see citing works
Self-citationAnnese, V., Latiano, A., Bovio, P., et al. (1999) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5200328 · Cited by 87 · see citing works
Mirza, M. M., Lee, J., Teare, M. D., et al. (1998) · Journal of Medical Genetics · doi:10.1136/jmg.35.3.218 · Cited by 77 · see citing works
Tan, J. T., Ng, D. P. K., Yaakub, S. N., Ye, S., Lim, X. L., Leong, H., Seet, L. T., Siew, W. F., Kon, W. Y. C., Wong, T. Y., et al. (2009) · Endocrine Reviews · doi:10.1210/edrv.30.7.9999 · Cited by 77 · see citing works
Tan, J. T., Ng, D. P. K., Yaakub, S. N., Ye, S., Lim, X. L., Leong, H., Seet, L. T., Siew, W. F., Kon, W. Y. C., Wong, T. Y., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0688 · Cited by 76 · see citing works
Common NOD2 mutations are absent in patients with Crohn's disease in India.
Pugazhendhi, S., Amte, A., Ramadass, B., Subramanian, V., & Ramakrishna, B. S. (2008) · PubMed · Cited by 51 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Liu, J. Z., van Sommeren, S., Huang, H., Ng, S. C., Alberts, R., Takahashi, A., Ripke, S., Lee, J. C., Jostins, L., Shah, T., et al. (2015) · Nature Genetics · doi:10.1038/ng.3359 · Cited by 2,603 · see citing works
Self-citationVisscher, P. M., Brown, M. A., McCarthy, M. I., & Yang, J. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.11.029 · Cited by 2,425 · see citing works
Rare and common variants: twenty arguments
Gibson, G. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3118 · Cited by 1,278 · see citing works
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
The genetic architecture of type 2 diabetes
Fuchsberger, C., Flannick, J., Teslovich, T. M., Mahajan, A., Agarwala, V., Gaulton, K. J., Ma, C., Fontanillas, P., Moutsianas, L., McCarthy, D. J., et al. (2016) · Nature · doi:10.1038/nature18642 · Cited by 1,051 · see citing works
Self-citationMapping cis- and trans-regulatory effects across multiple tissues in twins
The Multiple Tissue Human Expression Resource (MuTHER) Consortium, Grundberg, E., Small, K. S., Hedman, Å. K., Nica, A. C., Buil, A., Keildson, S., Bell, J. T., Yang, T.-P., Meduri, E., et al. (2012) · Nature Genetics · doi:10.1038/ng.2394 · Cited by 729 · see citing works
Self-citationGenetic architecture: the shape of the genetic contribution to human traits and disease
Timpson, N. J., Greenwood, C. M. T., Soranzo, N., Lawson, D. J., & Richards, J. B. (2018) · Nature Reviews Genetics · doi:10.1038/nrg.2017.101 · Cited by 434 · see citing works
Self-citationSynthetic associations in the context of genome-wide association scan signals
Orozco, G., Barrett, J. C., & Zeggini, E. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq368 · Cited by 61 · see citing works
Self-citation
- Authors
- Anderson, C. A., Soranzo, N., Zeggini, E., & Barrett, J. C.
- Affiliations
- Wellcome Sanger Institute (GB)
- Corresponding author
- Anderson, Carl A.
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-01-18
- Volume
- 9
- Issue
- 1
- Pages
- e1000580
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC3022527
- OpenAlex
- W2136173868
- Cited by
- 114
- References
- 32
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 7 · 2018: 2 · 2017: 3 · 2016: 9 · 2015: 6 · 2014: 13 · 2013: 12 · 2012: 31
- FWCI
- 13.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Wellcome Trust (WT091745/Z/10/Z, WT089120/Z/09/Z)
- 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 › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- common diseases, genetic architecture of disease
- MeSH terms
- Computer Simulation, Crohn Disease, Genetics, Population, Humans, Genetic Linkage, Models, Genetic, Genetic Variation, Nod2 Signaling Adaptor Protein, Genome-Wide Association Study, Genetic Loci
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
