Abstract
Genic variants are more likely to alter gene function and affect disease risk than those that occur outside genes. Variants in genes, however, might not be sufficiently covered by the existing approaches to genome-wide association studies. Our analysis of the HapMap ENCODE data indicates that this concern is valid, and that an alternative approach that focuses on genic variants provides a more complete coverage of functionally important regions and a greater genotyping efficiency. We therefore argue that resources should be developed to make gene-centric genome-wide association studies feasible.
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. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).
Kruglyak, L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genet. 22, 139–144 (1999).
Collins, F. S., Brooks, L. D. & Chakravarti, A. A DNA polymorphism discovery resource for research on human genetic variation. Genome Res. 8, 1229–1231 (1998).
Olds, L. C. & Sibley, E. Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element. Hum. Mol. Genet. 12, 2333–2340 (2003).
The International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).
Altshuler, D. et al. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Ozaki, K. et al. Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction. Nature Genet. 32, 650–654 (2002).
Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).
Maraganore, D. M. et al. High-resolution whole-genome association study of Parkinson disease. Am. J. Hum. Genet. 77, 685–693 (2005).
Conley, Y. P. et al. Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy. Hum. Mol. Genet. 14, 1991–2002 (2005).
Rivera, A. et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum. Mol. Genet. 14, 3227–3236 (2005).
Terwilliger, J. D. & Hiekkalinna, T. An utter refutation of the “Fundamental Theorem of the HapMap”. Eur. J. Hum. Genet. 14, 426–437 (2006).
Botstein, D. & Risch, N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nature Genet. 33, 228–237 (2003).
Palmer L. J., Cardon, L. R. Shaking the tree: Mapping complex disease genes using linkage disequilibrium. Lancet 336, 1223–1234 (2005).
Tabor, H. K., Risch, N. J. & Myers, R. M. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nature Rev. Genet. 3, 391–397 (2002).
Smith, A. V., Thomas, D. J., Munro, H. M. & Abecasis, G. R. Sequence features in regions of weak and strong linkage disequilibrium. Genome Res. 15, 1519–1534 (2005).
McVean, G. A. et al. The fine-scale structure of recombination rate variation in the human genome. Science 304, 581–584 (2004).
Tsunoda, T. et al. Variation of gene-based SNPs and linkage disequilibrium patterns in the human genome. Hum. Mol. Genet. 13, 1623–1632 (2004).
Goddard, K. A., Hopkins, P. J., Hall, J. M. & Witte, J. S. Linkage disequilibrium and allele-frequency distributions for 114 single-nucleotide polymorphisms in five populations. Am. J. Hum. Genet. 66, 216–234 (2000).
Stephens, J. C. et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science 293, 489–493 (2001).
Hill, W. G. & Robertson, A. The effect of linkage on limits to artificial selection. Genet. Res. 8, 269–294 (1966).
Pe'er, I. et al. Evaluating and improving power in whole-genome association studies using fixed marker sets. Nature Genet. 38, 663–667 (2006).
Barrett, J. C. & Cardon, L. R. Evaluating coverage of genome-wide association studies. Nature Genet. 38, 659–662 (2006).
de Bakker, P. I. et al. Efficiency and power in genetic association studies. Nature Genet. 37, 1217–1223 (2005).
Jorgenson, E. & Witte, J. S. Coverage and power in genome-wide association studies. Am. J. Hum. Genet. 78, 884–889 (2006).
Pennisi, E. Human genome. A low number wins the GeneSweep Pool. Science 300, 1484 (2003).
Livingston, R. J. et al. Pattern of sequence variation across 213 environmental response genes. Genome Res. 14, 1821–1831 (2004).
Crawford, D. C. et al. Haplotype diversity across 100 candidate genes for inflammation, lipid metabolism, and blood pressure regulation in two populations. Am. J. Hum. Genet. 74, 610–622 (2004).
Pe'er, I. et al. Biases and reconciliation in estimates of linkage disequilibrium in the human genome. Am. J. Hum. Genet. 78, 588–603 (2006).
Acknowledgements
We thank N. Risch, D. Thomas, X. Liu and I. Cheng for their helpful comments, as well as L. Edblad and L. Woldin for assistance in the preparation of the manuscript. We also thank anonymous reviewers for their helpful suggestions. This work was supported by grants from the US National Institutes of Health.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Related links
Glossary
- Genome-wide significance criterion
-
The level of significance that an association must reach to reject the null hypothesis of no association, taking into account the large number of tests being conducted.
- Linkage analysis
-
A method for localizing genes that is based on the co-inheritance of genetic markers and phenotypes in families over several generations.
- Linkage disequilibrium
-
The non-random association of alleles of different linked polymorphisms in a population.
- Minor allele frequency
-
The frequency of the less-common allele at a polymorphic locus. It has a value that lies between 0 and 0.5, and can vary between populations.
- Multiple-hypothesis testing
-
The practice of testing more than one hypothesis within an experiment. As a result, the probability of an unusual result from within the entire experiment occurring by chance is higher than the individual probability for one test alone.
- Odds ratio
-
A measurement of association that is commonly used in case–control studies. It is defined as the odds of exposure to the susceptible genetic variant in cases compared with that in controls. If the odds ratio is statistically significantly greater or less than one, then the genetic variant is associated with the disease.
- Power
-
The probability of rejecting the null hypothesis when it is false. In genome-wide association studies, the null hypothesis is that there is no association between a variant and the phenotype of interest.
- HapMap
-
A catalogue of common genetic variation in the human genome that was developed by the International HapMap Project.
Rights and permissions
About this article
Cite this article
Jorgenson, E., Witte, J. A gene-centric approach to genome-wide association studies. Nat Rev Genet 7, 885–891 (2006). https://doi.org/10.1038/nrg1962
Issue Date:
DOI: https://doi.org/10.1038/nrg1962
This article is cited by
-
How to increase our belief in discovered statistical interactions via large-scale association studies?
Human Genetics (2019)
-
Genetic contributors to variation in alcohol consumption vary by race/ethnicity in a large multi-ethnic genome-wide association study
Molecular Psychiatry (2017)
-
Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder
Translational Psychiatry (2016)
-
Genome-wide association study using whole-genome sequencing rapidly identifies new genes influencing agronomic traits in rice
Nature Genetics (2016)
-
Genome-wide analysis correlates Ayurveda Prakriti
Scientific Reports (2015)