The allelic architecture of human disease genes: common disease-common variant... or not?
Abstract
Linkage disequilibrium (LD) plays a central role in current and proposed methods for mapping complex disease genes. LD-based methods work best when there is a single susceptibility allele at any given disease locus, and generally perform very poorly if there is substantial allelic heterogeneity. The extent of allelic heterogeneity at typical complex disease loci is not yet known, but predictions about allelic heterogeneity have important implications for the design of future mapping studies, including the proposed genome-wide association studies. In this article, we review the available data and models relating to the number and frequencies of susceptibility alleles at complex disease loci-the 'allelic architecture' of human disease genes. We also show that the predicted frequency spectrum of disease variants at a gene depends crucially on the method of ascertainment, for example from prior linkage scans or from surveys of functional candidate loci.
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?
The common disease-common variant hypothesis has been refuted by the missing heritability problem.
“When GWAS began the field was dominated by the simple common disease-common variant (CD-CV) hypothesis1–4 has been refuted in light of the so-called ‘missing heritability problem’”
From Rare and common variants: twenty arguments (2012) · cites this paper as [3]
Because disease reduces fitness, variants that promote disease should be selected against and therefore should not be common.
“Since disease is deleterious to fitness, variants that promote disease should be selected against, and hence disease-promoting variants should not be common3,26,27.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [3]
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 · see citing works
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 · 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
Principles of Population Genetics.
Cormack, R. M., Hartl, D. L., & Clark, A. G. (1990) · Biometrics · doi:10.2307/2531471 · Cited by 5,283 · see citing works
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 · see citing works
Spielman, R. S., McGinnis, R. E., & Ewens, W. J. (1993) · PubMed · Cited by 3,679 · see citing works
Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?
Neel, J. V. (1962) · Europe PMC (PubMed Central) · Cited by 3,147 · see citing works
Searching for genetic determinants in the new millennium
Risch, N. J. (2000) · Nature · doi:10.1038/35015718 · Cited by 1,839 · see citing works
The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes
Altshuler, D., Hirschhorn, J. N., Klannemark, M., Lindgren, C. M., Vohl, M.-C., Nemesh, J., Lane, C. R., Schaffner, S. F., Bolk, S., Brewer, C., et al. (2000) · Nature Genetics · doi:10.1038/79216 · Cited by 1,766 · see citing works
Linkage disequilibrium in the human genome
Reich, D., Cargill, M., Gabriel, S., Ireland, J. S., Sabeti, P. C., Richter, D. J., Lavery, T., Kouyoumjian, R., Farhadian, S., Ward, R. H., et al. (2001) · Nature · doi:10.1038/35075590 · Cited by 1,763 · see citing works
Mathematical Population Genetics
Baake, E., Ewens, W. J., & Wakolbinger, A. (2006) · Oberwolfach Reports · doi:10.4171/owr/2005/40 · Cited by 1,683 · see citing works
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 · see citing works
Linkage disequilibrium in humans: models and data.
Pritchard, J., & Przeworski, M. (2001) · American Journal of Human Genetics · doi:10.1086/321275 · Cited by 1,340 · see citing works
Self-citationPopulation growth of human Y chromosomes: a study of Y chromosome microsatellites.
Pritchard, J., Seielstad, M., Pérez-Lezaun, A., & Feldman, M. (1999) · Molecular biology and evolution · doi:10.1093/oxfordjournals.molbev.a026091 · Cited by 1,201 · see citing works
Self-citationOn the allelic spectrum of human disease
Reich, D. E., & Lander, E. S. (2001) · Trends in Genetics · doi:10.1016/s0168-9525(01)02410-6 · Cited by 1,185 · see citing works
The New Genomics: Global Views of Biology
Lander, E. S. (1996) · Science · doi:10.1126/science.274.5287.536 · Cited by 1,174 · see citing works
Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young
Fajans, S. S., Bell, G. I., & Polonsky, K. S. (2001) · New England Journal of Medicine · doi:10.1056/nejmra002168 · Cited by 1,123 · see citing works
Bell, G. I., Horita, S., & Karam, J. H. (1984) · Diabetes · doi:10.2337/diab.33.2.176 · Cited by 744 · see citing works
Population genetics—making sense out of sequence
Chakravarti, A. (1999) · Nature Genetics · doi:10.1038/4482 · Cited by 643 · see citing works
The human gene mutation database
Cooper, D. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.1.285 · Cited by 604 · see citing works
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 · see citing works
Genomewide Scans of Complex Human Diseases: True Linkage Is Hard to Find
Altmüller, J., Palmer, L. J., Fischer, G., Scherb, H., & Wjst, M. (2001) · The American Journal of Human Genetics · doi:10.1086/324069 · Cited by 556 · see citing works
Cystic Fibrosis Heterozygote Resistance to Cholera Toxin in the Cystic Fibrosis Mouse Model
Gabriel, S. E., Brigman, K., Koller, B. H., Boucher, R. C., & Stutts, M. J. (1994) · Science · doi:10.1126/science.7524148 · Cited by 481 · see citing works
Fullerton, S. M., Clark, A. G., Weiss, K. M., Nickerson, D. A., Taylor, S. L., Stengård, J., Salomaa, V. V., Vartiainen, E. A., Perola, M., Boerwinkle, E., et al. (2000) · The American Journal of Human Genetics · doi:10.1086/303070 · Cited by 429 · see citing works
Population choice in mapping genes for complex diseases
Wright, A., Carothers, A., & Pirastu, M. (1999) · Nature Genetics · doi:10.1038/70501 · Cited by 377 · see citing works
Cox, N. J., Wapelhorst, B., Morrison, V., Johnson, L. N., Pinchuk, L. M., Spielman, R. S., Todd, J. A., & CONCANNON, P. J. (2001) · The American Journal of Human Genetics · doi:10.1086/323501 · Cited by 263 · see citing works
Genetic evidence for a Paleolithic human population expansion in Africa
Reich, D. E., & Goldstein, D. B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.8119 · Cited by 244 · see citing works
Signatures of Population Expansion in Microsatellite Repeat Data
Kimmel, M., Chakraborty, R., King, J. P., Bamshad, M. J., Watkins, W. S., & Jorde, L. B. (1998) · Genetics · doi:10.1093/genetics/148.4.1921 · Cited by 236 · see citing works
Mayr, E. (1981) · Bolletino di zoologia · doi:10.1080/11250008109439359 · Cited by 196 · see citing works
Risk models for familial ovarian and breast cancer
Antoniou, A. C., Gayther, S. A., Stratton, J. F., Ponder, B. A. J., & Easton, D. F. (2000) · Genetic Epidemiology · doi:10.1002/(sici)1098-2272(200002)18:2 · Cited by 192 · see citing works
Mismatch distributions of mtDNA reveal recent human population expansions.
Sherry, S. T., Rogers, A. R., Harpending, H. C., et al. (1994) · PubMed · Cited by 170 · see citing works
When Did the Human Population Size Start Increasing?
Wall, J. D., & Przeworski, M. (2000) · Genetics · doi:10.1093/genetics/155.4.1865 · Cited by 135 · see citing works
Genetics Moves Into the Medical Mainstream
Collins, F. S. (2001) · JAMA · doi:10.1001/jama.286.18.2322 · Cited by 98 · see citing works
Friedman, K. J., Heim, R. A., Knowles, M. R., & Silverman, L. M. (1997) · Human Mutation · doi:10.1002/(sici)1098-1004(1997)10:2 · Cited by 89 · see citing works
The Use of Intraallelic Variability for Testing Neutrality and Estimating Population Growth Rate
Slatkin, M., & Bertorelle, G. (2001) · Genetics · doi:10.1093/genetics/158.2.865 · Cited by 58 · see citing works
Green, P. M., Saad, S., Lewis, C. M., et al. (1999) · The American Journal of Human Genetics · doi:10.1086/302651 · Cited by 53 · see citing works
Do ΔF508 heterozygotes have a selective advantage?
Wiuf, C. (2001) · Genetics Research · doi:10.1017/s0016672301005195 · Cited by 49 · see citing works
Allele multiplicity in simple Mendelian disorders.
Hartl, D. L., & Campbell, R. B. (1982) · PubMed · Cited by 22 · see citing works
The Sampling Distribution of Disease-Associated Alleles
Slatkin, M., & Rannala, B. H. (1997) · Genetics · doi:10.1093/genetics/147.4.1855 · Cited by 18 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Finding 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
Integrative approaches for large-scale transcriptome-wide association studies
Gusev, A., Ko, A., Shi, H., Bhatia, G., Chung, W., Penninx, B. W. J. H., Jansen, R., de Geus, E. J. C., Boomsma, D. I., Wright, F. A., et al. (2016) · Nature Genetics · doi:10.1038/ng.3506 · Cited by 2,479 · see citing works
Nyholt, D. R. (2004) · The American Journal of Human Genetics · doi:10.1086/383251 · Cited by 1,699 · see citing works
Li, B., & Leal, S. M. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.06.024 · Cited by 1,527 · 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
The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease
Rogaeva, E., Meng, Y., Lee, J. H., Gu, Y., Kawarai, T., Zou, F., Katayama, T., Baldwin, C. T., Cheng, R., Hasegawa, H., et al. (2007) · Nature Genetics · doi:10.1038/ng1943 · Cited by 1,167 · see citing works
Uncovering the roles of rare variants in common disease through whole-genome sequencing
Cirulli, E. T., & Goldstein, D. B. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2779 · Cited by 1,136 · see citing works
A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic
Madsen, B. E., & Browning, S. R. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000384 · Cited by 1,113 · see citing works
Human genetic variation and its contribution to complex traits
Frazer, K. A., Murray, S. S., Schork, N. J., & Topol, E. J. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2554 · Cited by 1,073 · see citing works
Genetic Heterogeneity in Human Disease
McClellan, J., & King, M.-C. (2010) · Cell · doi:10.1016/j.cell.2010.03.032 · Cited by 981 · see citing works
A HapMap harvest of insights into the genetics of common disease
Manolio, T. A., Brooks, L. D., & Collins, F. S. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34772 · Cited by 889 · see citing works
Strong association of de novo copy number mutations with sporadic schizophrenia
Xu, B., Roos, J. L., Levy, S., van Rensburg, E. J., Gogos, J. A., & Karayiorgou, M. (2008) · Nature Genetics · doi:10.1038/ng.162 · Cited by 813 · see citing works
The genetics of asthma and allergic disease: a 21st century perspective
Ober, C., & Yao, T. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01029.x · Cited by 698 · see citing works
Haplotype blocks and linkage disequilibrium in the human genome
Wall, J. D., & Pritchard, J. K. (2003) · Nature Reviews Genetics · doi:10.1038/nrg1123 · Cited by 642 · see citing works
Self-citationKryukov, G. V., Pennacchio, L. A., & Sunyaev, S. R. (2007) · The American Journal of Human Genetics · doi:10.1086/513473 · Cited by 598 · see citing works
Morgenthaler, S., & Thilly, W. G. (2007) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/j.mrfmmm.2006.09.003 · Cited by 507 · see citing works
Genetics in Parkinson disease: Mendelian versus non‐Mendelian inheritance
Hernandez, D. G., Reed, X., & Singleton, A. B. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13593 · Cited by 448 · see citing works
Exome sequencing and the genetic basis of complex traits
Kiezun, A., Garimella, K., Do, R., Stitziel, N. O., Neale, B. M., McLaren, P. J., Gupta, N., Sklar, P., Sullivan, P. F., Moran, J. L., et al. (2012) · Nature Genetics · doi:10.1038/ng.2303 · Cited by 372 · see citing works
The COGENT Consortium, Houlston, R. S., The CORGI Consortium, The COIN Collaborative Group, The COINB Collaborative Group, Cheadle, J., Dobbins, S. E., Tenesa, A., Jones, A. M., Howarth, K., et al. (2010) · Nature Genetics · doi:10.1038/ng.670 · Cited by 360 · see citing works
Definition And Clinical Importance Of Haplotypes.
Crawford, D. C., & Nickerson, D. A. (2005) · Annual Review of Medicine · doi:10.1146/annurev.med.56.082103.104540 · Cited by 344 · see citing works
Shifting Paradigm of Association Studies: Value of Rare Single-Nucleotide Polymorphisms
Gorlov, I. P., Gorlova, O. Y., Sunyaev, S. R., Spitz, M. R., & Amos, C. I. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.09.006 · Cited by 338 · see citing works
Modeling madness in mice: one piece at a time
Arguello, P. A., & Gogos, J. A. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.023 · Cited by 309 · see citing works
A Data-Adaptive Sum Test for Disease Association with Multiple Common or Rare Variants
Han, F., & Pan, W. (2010) · Human Heredity · doi:10.1159/000288704 · Cited by 306 · see citing works
Multiple rare variants in the etiology of autism spectrum disorders
Buxbaum, J. D. (2009) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2009.11.1/jdbuxbaum · Cited by 158 · see citing works
Li, B., & Leal, S. M. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000481 · Cited by 142 · see citing works
Liu, L., Sabo, A., Neale, B. M., Nagaswamy, U., Stevens, C., Lim, E., Bodea, C. A., Muzny, D., Reid, J. G., Banks, E., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003443 · Cited by 135 · see citing works
Benn, M. (2009) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2009.01.004 · Cited by 119 · see citing works
Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder
Pickard, B. S., Christoforou, A., Thomson, P. A., Fawkes, A., Evans, K. L., Morris, S. W., Porteous, D. J., Blackwood, D. H., & Muir, W. J. (2009) · Molecular Psychiatry · doi:10.1038/mp.2008.24 · Cited by 101 · see citing works
The Role of DNA Copy Number Variation in Schizophrenia
Tam, G. W. C., Redon, R., Carter, N. P., & Grant, S. G. N. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.07.027 · Cited by 98 · see citing works
A Population Genetic Approach to Mapping Neurological Disorder Genes Using Deep Resequencing
Myers, R. A., Casals, F., Gauthier, J., Hamdan, F. F., Keebler, J., Boyko, A. R., Bustamante, C. D., Piton, A. M., Spiegelman, D., Henrion, E., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1001318 · Cited by 97 · see citing works
Macdonald, S. J., & Long, A. D. (2007) · Genetics · doi:10.1534/genetics.106.069641 · Cited by 61 · see citing works
Genetic Differential Sensitivity to Social Environments: Implications for Research
Mitchell, C., McLanahan, S., Brooks-Gunn, J., Garfinkel, I., Hobcraft, J., & Notterman, D. (2013) · American Journal of Public Health · doi:10.2105/ajph.2013.301382 · Cited by 42 · see citing works
The Evidence for Association of ATP2B2 Polymorphisms with Autism in Chinese Han Population
Yang, W., Liu, J., Zheng, F., Jia, M., Zhao, L., Lu, T., Ruan, Y., Zhang, J., Yue, W., Zhang, D., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061021 · Cited by 34 · see citing works
DNA Sequence‐Based Phenotypic Association Analysis
Schork, N. J., Wessel, J., & Malo, N. (2008) · Advances in Genetics · doi:10.1016/s0065-2660(07)00409-9 · Cited by 22 · see citing works
Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot
Palomino Doza, J., Topf, A., Bentham, J., Bhattacharya, S., Cosgrove, C., Brook, J. D., Granados-Riveron, J., Bu’Lock, F. A., O’Sullivan, J., Stuart, A. G., et al. (2013) · BMC Genetics · doi:10.1186/1471-2156-14-57 · Cited by 14 · see citing works
- Authors
- Pritchard, J. K.
- Affiliations
- University of Chicago (US)
- Corresponding author
- Pritchard, J. K.
- ORCID
- Pritchard, J. K.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-10-01
- Volume
- 11
- Issue
- 20
- Pages
- 2417-2423
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2157929834
- Cited by
- 711
- References
- 40
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 7 · 2023: 10 · 2022: 16 · 2021: 17 · 2020: 17 · 2019: 21 · 2018: 21 · 2017: 21 · 2016: 27 · 2015: 23 · 2014: 38 · 2013: 44 · 2012: 44
- FWCI
- 18.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (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 › Forensic and Genetic Research
- Keywords
- allelic heterogeneity, linkage disequilibrium, risk alleles, allele frequency spectrum, genome-wide association study, disease mapping, ascertainment bias
- MeSH terms
- Alleles, Humans, Models, Theoretical, Linkage Disequilibrium
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
