The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
Finding genes that underlie complex traits.
Abstract
Phenotypic variation among organisms is central to evolutionary adaptations underlying natural and artificial selection, and also determines individual susceptibility to common diseases. These types of complex traits pose special challenges for genetic analysis because of gene-gene and gene-environment interactions, genetic heterogeneity, low penetrance, and limited statistical power. Emerging genome resources and technologies are enabling systematic identification of genes underlying these complex traits. We propose standards for proof of gene discovery in complex traits and evaluate the nature of the genes identified to date. These proof-of-concept studies demonstrate the insights that can be expected from the accelerating pace of gene discovery in this field.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
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?
In the citing paper
“Complex traits including human altruism are molded by both environment and multiple genes and such phenotypes pose special challenges for genetic analysis due to gene-gene and gene-environment interactions, genetic heterogeneity, low penetrance, and limited statistical power [60].”
From The oxytocin receptor (OXTR) contributes to prosocial fund allocations in the dictator game and the social value orientations task (2009) · cites this paper as [60]
Citations
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
The Structure of Haplotype Blocks in the Human Genome
Gabriel, S. B., Schaffner, S. F., Nguyen, H., Moore, J. M., Roy, J., Blumenstiel, B., Higgins, J., DeFelice, M., Lochner, A., Faggart, M., et al. (2002) · Science · doi:10.1126/science.1069424 · Cited by 5,863
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
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
Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results
Lander, E. S., & Kruglyak, L. (1995) · Nature Genetics · doi:10.1038/ng1195-241 · Cited by 5,236
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease
Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., et al. (2001) · Nature · doi:10.1038/35079114 · Cited by 5,030
Genetic Dissection of Complex Traits
Lander, E. S., & Schork, N. J. (1994) · Science · doi:10.1126/science.8091226 · Cited by 3,425
King, M.-C., & Wilson, A. C. (1975) · Science · doi:10.1126/science.1090005 · Cited by 2,815
HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus
Todd, J. A., Bell, J. I., & McDevitt, H. O. (1987) · Nature · doi:10.1038/329599a0 · Cited by 2,036
Searching for genetic determinants in the new millennium
Risch, N. J. (2000) · Nature · doi:10.1038/35015718 · Cited by 1,839
Yano, M., Katayose, Y., Ashikari, M., Yamanouchi, U., Monna, L., Fuse, T., Baba, T., Yamamoto, K., Umehara, Y., Nagamura, Y., et al. (2000) · The Plant Cell · doi:10.1105/tpc.12.12.2473 · Cited by 1,609
Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus
Horikawa, Y., Oda, N., Cox, N. J., Li, X., Orho‐Melander, M., Hara, M., Hinokio, Y., Lindner, T. H., Mashima, H., Schwarz, P. E. H., et al. (2000) · Nature Genetics · doi:10.1038/79876 · Cited by 1,467
fw2.2 : A Quantitative Trait Locus Key to the Evolution of Tomato Fruit Size
Frary, A., Nesbitt, T. C., Frary, A., Grandillo, S., van der Knaap, E., Cong, B., Liu, J., Meller, J., Elber, R., Alpert, K. B., et al. (2000) · Science · doi:10.1126/science.289.5476.85 · Cited by 1,416
Permutation Tests for Multiple Loci Affecting a Quantitative Character
Doerge, R. W., & Churchill, G. A. (1996) · Genetics · doi:10.1093/genetics/142.1.285 · Cited by 1,126
Grisart, B., Coppieters, W. R., Farnir, F., Karim, L., Ford, C., Berzi, P., Cambisano, N., Mni, M., Reid, S., Simon, P., et al. (2002) · Genome Research · doi:10.1101/gr.224202 · Cited by 992
Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage.
(1991) · Europe PMC (PubMed Central) · Cited by 758
Aitman, T. J., Glazier, A. M., Wallace, C. A., Cooper, L. D., Norsworthy, P. J., Wahid, F. N., Al-Majali, K., Trembling, P. M., Mann, C. J., Shoulders, C. C., et al. (1999) · Nature Genetics · doi:10.1038/5013 · Cited by 733
Self-citationA Molecular Basis for MHC Class II—Associated Autoimmunity
Todd, J. A., Acha‐Orbea, H., Bell, J. I., Chao, N. J. A., Fronek, Z., Jacob, C. O., McDermott, M., Sinha, A. A., Timmerman, L., Steinman, L., et al. (1988) · Science · doi:10.1126/science.3368786 · Cited by 700
Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b
Bachmaier, K., Krawczyk, C. M., Kozieradzki, I., Kong, Y., Sasaki, T., Oliveira-dos-Santos, A., Mariathasan, S., Bouchard, D., Wakeham, A. C., Itié, A., et al. (2000) · Nature · doi:10.1038/35003228 · Cited by 674
Hanis, C. L., Boerwinkle, E., Chakraborty, R., Ellsworth, D. L., CONCANNON, P. J., Stirling, B., Morrison, V., Wapelhorst, B., Spielman, R. S., Gogolin-Ewens, K. J., et al. (1996) · Nature Genetics · doi:10.1038/ng0696-161 · Cited by 590
Modifier genes in mice and humans
Nadeau, J. H. (2001) · Nature Reviews Genetics · doi:10.1038/35056009 · Cited by 567
Self-citationMacPhee-Pellini, M., Chepenik, K. P., Liddell, R. A., Nelson, K. K., Siracusa, L. D., & Buchberg, A. M. (1995) · Cell · doi:10.1016/0092-8674(95)90015-2 · Cited by 564
Dissecting the architecture of a quantitative trait locus in yeast
Steinmetz, L. M., Sinha, H., Richards, D. R., Spiegelman, J. I., Oefner, P. J., McCusker, J. H., & Davis, R. W. (2002) · Nature · doi:10.1038/416326a · Cited by 530
Bales, K. R., Verina, T., Cummins, D. J., Du, Y., Dodel, R. C., Saura, J., Fishman, C. E., DeLong, C. A., Piccardo, P., Petegnief, V., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.15233 · Cited by 486
Takahashi, Y., Shomura, A., Sasaki, T., & Yano, M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111136798 · Cited by 483
Quantitative trait loci in Drosophila
Mackay, T. F. C. (2001) · Nature Reviews Genetics · doi:10.1038/35047544 · Cited by 421
Dissecting Human Disease in the Postgenomic Era
Peltonen, L., & McKusick, V. A. (2001) · Science · doi:10.1126/science.291.5507.1224 · Cited by 414
Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study
Hampe, J., Grebe, J., Nikolaus, S., Solberg, C., Croucher, P. J. P., Mascheretti, S., Jahnsen, J., Moum, B. A., Klump, B., Krawczak, M., et al. (2002) · The Lancet · doi:10.1016/s0140-6736(02)08590-2 · Cited by 409
Detection of regulatory variation in mouse genes
Cowles, C. R., Hirschhorn, J. N., Altshuler, D., & Lander, E. S. (2002) · Nature Genetics · doi:10.1038/ng992 · Cited by 381
Identification and Characterization of the Mouse Obesity Gene tubby: A Member of a Novel Gene Family
Kleyn, P. W., Fan, W., Kovats, S. G., Lee, J. J., Pulido, J. C., Wu, Y., Berkemeier, L. R., Misumi, D. J., Holmgren, L. M., Charlat, O., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81104-6 · Cited by 370
A candidate gene for the mouse mutation tubby
Noben‐Trauth, K., Naggert, J. K., North, M. A., & Nishina, P. M. (1996) · Nature · doi:10.1038/380534a0 · Cited by 356
Lund, T., O’Reilly, L. A., Hutchings, P. R., Kanagawa, O., Simpson, E., Gravely, R., Chandler, P., Dyson, J., PICARD, J. K., Edwards, A., et al. (1990) · Nature · doi:10.1038/345727a0 · Cited by 331
Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis
Cormier, R. T., Hong, K. H., Halberg, R. B., Hawkins, T. L., Richardson, P., Mulherkar, R., Dove, W. F., & Lander, E. S. (1997) · Nature Genetics · doi:10.1038/ng0997-88 · Cited by 324
Prevention of autoimmune insulitis by expression of I–E molecules in NOD mice
Nishimoto, H., Kikutani, H., Yamamura, K., & Kishimoto, T. (1987) · Nature · doi:10.1038/328432a0 · Cited by 300
From QTL to gene: the harvest begins
Korstanje, R., & Paigen, B. J. (2002) · Nature Genetics · doi:10.1038/ng0702-235 · Cited by 242
Genetic protection from the inflammatory disease type 1 diabetes in humans and animal models.
Todd, J. A., & Wicker, L. (2001) · Immunity · doi:10.1016/s1074-7613(01)00202-3 · Cited by 239
Todd, J. A., Mijovic, C. H., Fletcher, J., Jenkins, D. J. A., Bradwell, A. R., & Barnett, A. H. (1989) · Nature · doi:10.1038/338587a0 · Cited by 235
Parameters for reliable results in genetic association studies in common disease
Dahlman, I. A., Eaves, I. A., Kosoy, R., Morrison, V., Heward, J. M., Gough, S. C. L., Allahabadia, A., Franklyn, J. A., Tuomilehto, J., Tuomilehto‐Wolf, E., et al. (2002) · Nature Genetics · doi:10.1038/ng825 · Cited by 230
Miyazaki, T., Uno, M., Uehira, M., Kikutani, H., Kishimoto, T., Kimoto, M., Nishimoto, H., Miyazaki, J., & Yamamura, K. (1990) · Nature · doi:10.1038/345722a0 · Cited by 200
Pravenec, M., Landa, V., Zídek, Musilová, A., Křen, V., Kazdová, L., Aitman, T. J., Glazier, A. M., Ibrahimi, A., Abumrad, N. A., et al. (2001) · Nature Genetics · doi:10.1038/84777 · Cited by 195
Self-citationCblb is a major susceptibility gene for rat type 1 diabetes mellitus
Yokoi, N., Komeda, K., Wang, H., Yano, H., Kitada, K., Saitoh, Y., Seino, Y., Yasuda, K., Serikawa, T., & Seino, S. (2002) · Nature Genetics · doi:10.1038/ng927 · Cited by 176
Aitman, T. J., Gotoda, T., Evans, A. L., Imrie, H., Heath, K. E., Trembling, P. M., Truman, H., Wallace, C., Rahman, A., Doré, C. J., et al. (1997) · Nature Genetics · doi:10.1038/ng0697-197 · Cited by 151
Self-citationA QTL with major effect on milk yield and composition maps to bovine Chromosome 14
Coppieters, W. R., Riquet, J., Arranz, J.-J. X. E., Berzi, P., Cambisano, N., Grisart, B., Karim, L., Marcq, F., Moreau, L., Nezer, C., et al. (1998) · Mammalian Genome · doi:10.1007/s003359900815 · Cited by 150
Stam, L. F., & Laurie, C. C. (1996) · Genetics · doi:10.1093/genetics/144.4.1559 · Cited by 137
Deletion of cytosolic phospholipase A 2 suppresses Apc Min -induced tumorigenesis
Hong, K. H., Bonventre, J. C., O’Leary, E., Bonventre, J. V., & Lander, E. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051635898 · Cited by 127
A major effect QTL determined by multiple genes in epileptic EL mice.
Legare, M. E., Bartlett, F. S., & Frankel, W. N. (2000) · PubMed · Cited by 122
Microtubule-associated protein 1A is a modifier of tubby hearing (moth1)
Ikeda, A., Zheng, Q. Y., Zuberi, A. R., Johnson, K. R., Naggert, J. Κ., & Nishina, P. M. (2002) · Nature Genetics · doi:10.1038/ng838 · Cited by 100
Cassell, P. G., Jackson, A. E., North, B. V., Evans, J., Syndercombe‐Court, D., Phillips, C., Ramachandran, A., Snehalatha, C., Gelding, S. V., Vijayaravaghan, S., et al. (2002) · Diabetes · doi:10.2337/diabetes.51.5.1622 · Cited by 85
CARD15 gene and the classification of Crohn's disease
Murillo, L. S. (2002) · Immunogenetics · doi:10.1007/s00251-002-0440-1 · Cited by 82
Fingerlin, T., Erdos, M., Watanabe, R., Wiles, K., Stringham, H., Mohlke, K., Silander, K., Valle, T., Buchanan, T., Tuomilehto, J., et al. (2002) · Diabetes · doi:10.2337/diabetes.51.5.1644 · Cited by 75
Cell-specific expression of tubby gene family members (tub, Tulp1,2, and 3) in the retina.
Ikeda, S., He, W., Ikeda, A., Naggert, J. Κ., North, M. A., & Nishina, P. M. (1999) · PubMed · Cited by 71
Functional screening of an asthma QTL in YAC transgenic mice
Symula, D. J., Frazer, K. A., Ueda, Y., Denèfle, P., Stevens, M. E., Wang, Z., Locksley, R. M., & Rubin, E. M. (1999) · Nature Genetics · doi:10.1038/13880 · Cited by 60
Glazier, A. M., Scott, J., & Aitman, T. J. (2002) · Mammalian Genome · doi:10.1007/s00335-001-2132-9 · Cited by 56
Self-citation“Gene‐Swap Knock‐in” Cassette in Mice to Study Allelic Differences in Human Genes
Nebert, D. W., Dalton, T. P., Stuart, G. W., & Carvan, M. J. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06876.x · Cited by 53
A non-MHC locus essential for autoimmune type I diabetes in the Komeda Diabetes-Prone rat.
Yokoi, N., Kanazawa, M., Kitada, K., Tanaka, A., Kanazawa, Y., Suda, S., Ito, H., Serikawa, T., & Komeda, K. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119733 · Cited by 52
Choudhary, M., & Laurie, C. C. (1991) · Genetics · doi:10.1093/genetics/129.2.481 · Cited by 37
Sensitized polygenic trait analysis
Matin, A., & Nadeau, J. H. (2001) · Trends in Genetics · doi:10.1016/s0168-9525(01)02528-8 · Cited by 33
Self-citation
Flagged first, then by citations
Research works printed but not linked: 3
- Legare M. E., Bartlett F. S., Frankel W. N., Genome Res. 10, 42 (2000).
- Ikeda S., et al., Invest. Ophthalmol. Vis. Sci. 40, 2706 (1999).
- Pericak-Vance M. A., et al., Am. J. Hum. Genet. 48, 1034 (1991).
Cited by
Sorted by citations
The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions
Gottesman, I. I., & Gould, T. D. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.4.636 · Cited by 5,615
Walking the Interactome for Prioritization of Candidate Disease Genes
Köhler, S., Bauer, S., Horn, D., & Robinson, P. N. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.02.013 · Cited by 1,268
Discovering Endophenotypes for Major Depression
Hasler, G., Drevets, W. C., Manji, H. K., & Charney, D. S. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300506 · Cited by 1,123
Mammalian circadian biology: elucidating genome-wide levels of temporal organization
Lowrey, P. L., & Takahashi, J. S. (2004) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.5.061903.175925 · Cited by 976
A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig
Laere, A.-S. V., Nguyen, M. Q., Braunschweig, M., Nezer, C., Collette, C., Moreau, L., Archibald, A. L., Haley, C., Buys, N., Tally, M., et al. (2003) · Nature · doi:10.1038/nature02064 · Cited by 949
Metadata
- Authors
- Glazier, A. M., Nadeau, J. H., & Aitman, T. J.
- Affiliations
- Hammersmith Hospital (GB)
- Case Western Reserve University (US)
- Corresponding author
- Nadeau, Joseph H.
- Aitman, Timothy J.
- Venue
- Science
- Published
- 2002-12-20
- Volume
- 298
- Issue
- 5602
- Pages
- 2345-2349
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1838763289
- Cited by
- 855
- References
- 57
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 5 · 2023: 11 · 2022: 17 · 2021: 14 · 2020: 12 · 2019: 12 · 2018: 15 · 2017: 10 · 2016: 19 · 2015: 33 · 2014: 19 · 2013: 42 · 2012: 38
- FWCI
- 8.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (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
- complex traits, gene discovery, phenotypic variability, gene-environment interaction, genetic heterogeneity, low penetrance, statistical power, genomic resources, common diseases, natural selection, selective breeding
- MeSH terms
- Alleles, Animals, Chromosome Mapping, Humans, Genetic Linkage, Mutation, Phenotype, Plants, Saccharomyces cerevisiae, Genetic Variation, Sequence Analysis, DNA, Quantitative Trait, Heritable, Genetic Predisposition to Disease, Multifactorial Inheritance, Quantitative Trait 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