Abstract
Association studies with candidate genes have been widely used for the study of complex diseases. However, this approach has been criticized because of non-replication of results and limits on its ability to include all possible causative genes and polymorphisms. These challenges have led to pessimism about the candidate-gene approach and about the genetic analysis of complex diseases in general. We believe that these criticisms can be usefully countered with an appeal to the principles of epidemiological investigation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Risch, N. J. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).
Potter, J. D. At the interfaces of epidemiology, genetics and genomics. Nature Rev. Genet. 2, 142–147 (2001).
Khoury, M. J., Beaty, T. & Cohen, B. H. Fundamentals of Genetic Epidemiology (Oxford Univ. Press, New York, 1993).
Hennekens, C. H. & Buring, J. E. Epidemiology in Medicine (Little, Brown & Co., Boston, Massachusetts, 1987).
Hulley, S. B. et al. Designing Clinical Research: an Epidemiologic Approach (Lippincott, Williams & Wilkins, Baltimore, Maryland, 2001).
Hugot, J.-P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).
Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).
Ioannidis, J. P. A. et al. Replication validity of genetic association studies. Nature Genet. 29, 306–309 (2001).
Noble, E. P. The D2 dopamine receptor gene: a review of association studies in alcoholism and phenotypes. Alcohol 16, 33–45 (1998).
Palmer, L. J. & Cookson, W. O. Genomic approaches to understanding asthma. Genome Res. 10, 1280–1287 (2000).
Cardon, L. R. & Bell, J. I. Association study designs for complex diseases. Nature Rev. Genet. 2, 91–99 (2001).
Tu, I. P. & Whittemore, A. S. Power of association and linkage tests when the disease alleles are unobserved. Am. J. Hum. Genet. 64, 641–649 (1999).
Lindpaintner, K. et al. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N. Engl. J. Med. 332, 706–711 (1995).
O'Donnell, C. J. et al. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study. Circulation 97, 1766–1772 (1998).
Ensrud, K. E. et al. Vitamin D receptor gene polymorphisms and the risk of fractures in older women. For the Study of Osteoporotic Fractures Research Group. J. Bone Miner. Res. 14, 1637–1645 (1999).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
The International SNP Working Group. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409, 928–933 (2001).
Syvänen, A. Accessing genetic variation: genotyping single-nucleotide polymorphisms. Nature Rev. Genet. 2, 930–942 (2001).
Ng, P. C. & Henikoff, S. Accounting for human polymorphisms predicted to affect protein function. Genome Res. 12, 436–446 (2002).
Sunyaev, S. et al. Prediction of deleterious human alleles. Hum. Mol. Genet. 10, 591–597 (2001).
Chasman, D. & Adams, R. M. Predicting the functional consequences of non-synonymous single nucleotide polymorphisms: structure-based assessment of amino acid variation. J. Mol. Biol. 307, 683–706 (2001).
Terwilliger, J. D. & Goring, H. H. Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design. Hum. Biol. 72, 63–132 (2000).
Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).
Scherf, U. et al. A gene expression database for the molecular pharmacology of cancer. Nature Genet. 24, 236–244 (2000).
Welsh, J. B. et al. Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. Proc. Natl Acad. Sci. USA 98, 1176–1181 (2001).
Long, A. D. & Langley, C. H. The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits. Genome Res. 9, 720–731 (1999).
Cavalli-Sforza, L. L. & Bodmer, B. The Genetics of Human Populations (W. H. Freeman, San Francisco, California, 1971).
Nickerson, D. A. et al. Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene. Genome Res. 10, 1531–1545 (2000).
Kwok, P.-Y. et al. Increasing the information content of STS-based genome maps: identifying polymorphisms in mapped STSs. Genomics 31, 123–136 (1996).
Cargill, M. et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature Genet. 22, 231–238 (1999).
Halushka, M. D. et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood pressure homeostasis. Nature Genet. 22, 239–247 (1999).
Marth, G. T. et al. A general approach to single nucleotide polymorphism discovery. Nature Genet. 23, 452–456 (1999).
Taillon-Miller, P., Gu, Z., Li, Q., Hillier, L. & Kwok, P. Overlapping genomic sequences: a treasure trove of single-nucleotide polymorphisms. Genome Res. 8, 748–754 (1998).
Drysdale, C. M. et al. Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc. Natl Acad. Sci. USA 97, 10483–10488 (2000).
Myers, R. M., Tilly, K. & Maniatis, T. Fine structure genetic analysis of a β-globin promoter. Science 232, 613–618 (1986).
Liu, H. et al. Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression. Proc. Natl Acad. Sci. USA 96, 4581–4585 (1999).
Theuns, J. et al. Genetic variability in the regulatory region of presenillin 1 associated with risk for Alzheimer's disease and variable expression. Hum. Mol. Genet. 200, 325–331 (2000).
Cartegni, L., Chew, S. L. & Krainer, A. R. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nature Rev. Genet. 3, 285–298 (2002).
Risch, N. J. Searching for genetic determinants in the new millennium. Nature 405, 847–856 (2000).
Buyse, I. M. et al. Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms. Am. J. Hum. Genet. 67, 1428–1436 (2000).
Couch, F. J. & Weber, B. L. Mutations and polymorphisms in the familial early-onset breast cancer (BRCA1) gene. Breast Cancer Information Core. Hum. Mutat. 8, 8–18 (1996).
Stephens, J. C. et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science 293, 489–493 (2001).
Lalouel, J. M. & Rohrwasser, A. Power and replication in case–control studies. Am. J. Hypertens. 15, 201–205 (2002).
Lewontin, R. C. On measures of gametic disequilibrium. Genetics 120, 849–852 (1988).
Subrahmanyan, L. et al. Sequence variation and linkage disequilibrium in the human T-cell receptor β (TCRB) locus. Am. J. Hum. Genet. 69, 381–395 (2001).
Patil, N. et al. Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 294, 1719–1723 (2001).
Goddard, K. A. B. et al. Linkage disequilibrium and allele-frequency distributions for 114 single-nucleotide polymorphisms in five populations. Am. J. Hum. Genet. 66, 216–234 (2000).
Ardlie, K. G., Kruglyak, L. & Seielstad, M. Patterns of linkage disequilibrium in the human genome. Nature Rev. Genet. 3, 299–309 (2002).
Long, J. C., Williams, R. C. & Urbanek, M. An E-M algorithm and testing strategy for multiple-locus haplotypes. Am. J. Hum. Genet. 56, 799–810 (1995).
Zhao, J. H., Curtis, D. & Sham, P. C. Model-free analysis and permutation tests for allelic association. Hum. Hered. 50, 133–139 (1999).
Altshuler, D., Daly, M. & Kruglyak, L. Guilt by association. Nature Genet. 26, 135–137 (2000).
Kwok, P.-Y. Genetic association by whole-genome analysis? Science 294, 1669–1670 (2001).
Rothman, K. J. & Greenland, S. Modern Epidemiology, 2nd edn (Lippincott Raven, Philadelphia, 1998).
Marth, G. et al. Single-nucleotide polymorphisms in the public domain: how useful are they? Nature Genet. 27, 371–372 (2001).
Sherry, S. T., Ward, M. & Sirotkin, K. Use of molecular variation in the NCBI dbSNP database. Hum. Mutat. 15, 68–75 (2000).
Pruitt, K. D. & Maglott, D. R. RefSeq and LocusLink: NCBI gene-centered resources. Nucleic Acids Res. 29, 137–140 (2001).
Brookes, A. J. et al. HGBASE: a database of SNPs and other variations in and around human genes. Nucleic Acids Res. 28, 356–360 (2000).
Krawczak, M. & Cooper, D. N. The Human Gene Mutation Database. Trends Genet. 13, 121–122 (1997).
Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).
Grantham, R. Amino acid difference formula to help explain protein evolution. Science 185, 862–864 (1974).
Acknowledgements
We thank members of the Myers laboratory and the Stanford Human Genome Center for their support. H.K.T., N.J.R. and R.M.M are supported by the National Institutes of Health and the Reynolds Foundation.
Author information
Authors and Affiliations
Corresponding author
Related links
Glossary
- CONFOUNDING
-
The distortion of a measure of association, because of the association of other non-intermediate factors with both the variable of interest and the outcome of interest.
- HAPLOTYPE
-
A combination of alleles at different sites on a single chromosome.
- HERITABILITY
-
The proportion of the phenotypic variance due to genetic variance.
- LINKAGE DISEQUILIBRIUM
-
A population association among alleles at two or more loci. It is a measure of co-segregation of alleles in a population.
- MISCLASSIFICATION
-
Errors in the classification of individuals by phenotype, exposures or genotype that can lead to errors in results. The probability of misclassification can be the same across all groups in a study (non-differential) or vary among groups (differential).
- RECALL BIAS
-
Bias in results due to systematic differences in the accuracy or completeness of recall of past exposures or family history.
- RELATIVE RISK
-
The ratio of the risk of the phenotype among individuals with a particular exposure, genotype or haplotype to the risk among those without that exposure, genotype or haplotype.
- SELECTION BIAS
-
A bias in results due to systematic differences between those who are selected for study and those who are not selected.
Rights and permissions
About this article
Cite this article
Tabor, H., Risch, N. & Myers, R. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet 3, 391–397 (2002). https://doi.org/10.1038/nrg796
Issue Date:
DOI: https://doi.org/10.1038/nrg796
This article is cited by
-
Cortical thickness is differently associated with ALDH2 rs671 polymorphism according to level of amyloid deposition
Scientific Reports (2021)
-
Genetic modifiers in rare disorders: the case of fragile X syndrome
European Journal of Human Genetics (2021)
-
Genomics of body fat distribution
Journal of Genetics (2021)
-
Principles and approaches of association mapping in plant breeding
Tropical Plant Biology (2020)
-
Correlations between CYP3A4 polymorphism and susceptibility to breast cancer in Chinese Han population
International Journal of Clinical Oncology (2019)