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Assessing the function of genetic variants in candidate gene association studies

Nature Reviews Genetics volume 5, pages 589–597 (2004)Cite this article

Key Points

  • A large proportion of genomic variation might be associated with human disease phenotypes. New approaches should improve our understanding of this variation and its functional significance.

  • Because there is insufficient guidance for molecular epidemiologists to optimally select variants for an epidemiology study, methods that prioritize the choice of genetic variants need to be included in molecular epidemiological studies.

  • Laboratory-based evidence about the functional significance of a genetic variant can provide the strongest evidence for the functional role of a genetic variant, but these studies are difficult to mount on the scale that may be required for characterizing all human genetic variants, and their results might not always reflect in vivo genotype function in humans.

  • Novel approaches to assessing the function of genetic variants are required to provide molecular epidemiological association studies with the information that is required to choose candidate genes and variants in these genes for association studies, and to optimally interpret the results of observed associations.

  • Novel experimental approaches that might be informative, include the HaploCHIP method, gene tagging, gene trapping, N-ethyl-N-nitrosourea (ENU) mutagenesis, proteomics methods and evaluation of epigenetic mechanisms that assess genotype function.

  • Non-laboratory-based approaches for assessing SNP function should also be considered. These approaches include those that use evolutionary similarity or structural effects of genetic variants, such as those implemented in the SIFT, PolyPhen or CODDLE algorithms.

  • Population and evolutionary genetics data can be directly incorporated into association studies to optimize the identification of genes that are causally related to disease risk. The 'set association' approach is one example of this method.

  • We propose an algorithm that can be useful in determining when a genetic variant might be functionally significant. This algorithm can be applied in the design and interpretation of molecular epidemiological association studies to maximize the potential that truly causative associations can be identified.

Abstract

Knowledge of inherited genetic variation has a fundamental impact on understanding human disease. Unfortunately, our understanding of the functional significance of many inherited genetic variants is limited. New approaches to assessing functional significance of inherited genetic variation, which combine molecular genetics, epidemiology and bioinformatics, promise to enhance reproducibility and plausibility of associations between genotypes and disease.

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Figure 1: In vitro studies of the effect of CYP3A4*1B compared with CYP3A4*1A.
Figure 2: Relationship of in silico indices of SNP function and associations (measured by log2-transformed odds ratios) taken from the literature.

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Acknowledgements

Some of the work discussed in this review was supported by grants from the Public Health Service and the University of Pennsylvania Cancer Center.

Author information

Authors and Affiliations

  1. Department of Biostatistics and Epidemiology, and Abramson Cancer Center, University of Pennsylvania School of Medicine, 904 Blockley Hall, 423 Guardian drive, Philadelphia, 19104, Pennsylvania, USA

    Timothy R. Rebbeck

  2. Department of Epidemiology, M. D. Anderson Cancer Center, 1515 Halcombe Boulevard, Houston, 77030, Texas, USA

    Margaret Spitz & Xifeng Wu

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  1. Timothy R. Rebbeck
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Corresponding author

Correspondence to Timothy R. Rebbeck.

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Related links

Related links

DATABASES

Entrez Gene

CYP3A4

TNF

FURTHER INFORMATION

CODDLE

PolyPhen

SIFT

Glossary

LINKAGE DISEQUILIBRIUM

The observation that two or more alleles, usually at loci that are physically close together on a chromosome, are not inherited independently but are observed to occur together more frequently than predicted under Mendel's law of independent assortment.

NIFEDIPINE

A calcium-blocker drug (also called Procardia) that was one of the first drugs recognized to be metabolized by CYP3A4, and for which a regulatory element specific to the CYP3A4 gene was named.

MENARCHE

The first occurrence of menstruation in a woman.

HARDY-WEINBERG PROPORTIONS

The binomial distribution of genotypes (that is, frequencies of genotypes AA, Aa and aa will be p2, 2pq, and q2, respectively, where p is the frequency of allele A, and q is the frequency of allele a) that result in a population when there are no external pressures that cause deviations from p2, 2pq and q2.

TEST STATISTIC

A quantity whose value is used to decide whether or not the null hypothesis should be rejected, usually based on quantities computed using observed data.

RESTENOSIS

The constriction, narrowing or blockage of a coronary artery after an initial treatment such as angioplasty aimed at removing this blockage.

ANGIOPLASTY

An operation that is used to repair a damaged blood vessel or unblock a coronary artery.

ADMIXTURE

Combining two or more populations into a single group. Combining two populations has implications for studies of genotype–disease associations if the component populations have different genotypic distributions.

CELL CYCLE CHECKPOINTS

Steps in the normal sequence of development and division in the cell. Disruption can lead to uncontrolled cell growth, and possibly cancer.

ODDS RATIO

A measure of relative risk that is usually estimated from case control studies.

TYPE I ERROR

Incorrectly rejecting a null hypothesis when the null hypothesis is correct. Similarly, the false positive rate.

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Rebbeck, T., Spitz, M. & Wu, X. Assessing the function of genetic variants in candidate gene association studies. Nat Rev Genet 5, 589–597 (2004). https://doi.org/10.1038/nrg1403

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