Key Points
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Genetic factors are the cause of most common human diseases.
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Common human diseases are genetically complex.
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Genome-wide association (GWA) studies represent a new approach to identify common genetic variants that are associated with complex diseases.
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GWA studies seek statistically significant associations between a disease phenotype and genotypes of hundreds of thousands of common, single nucleotide variants that are distributed throughout the genome in hundreds or thousands of affected individuals and matched controls.
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During the past year and a half, GWA studies have had considerable success in identifying genetic risk factors for common diseases such as diabetes mellitus, inflammatory bowel disease and cancer.
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Independent replication of the findings of GWA studies is essential.
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GWA studies are anticipated to have a broad impact on drug discovery and development by providing a molecular understanding of common diseases and tools for molecular stratification of patients.
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The applicability of GWA studies is being increased by examination of copy-number variants, large scale resequencing of genes and genomic regions in populations and establishment of new, very large population genetics studies.
Abstract
Although genetic studies have been critically important for the identification of therapeutic targets in Mendelian disorders, genetic approaches aiming to identify targets for common, complex diseases have traditionally had much more limited success. However, during the past year, a novel genetic approach — genome-wide association (GWA) — has demonstrated its potential to identify common genetic variants associated with complex diseases such as diabetes, inflammatory bowel disease and cancer. Here, we highlight some of these recent successes, and discuss the potential for GWA studies to identify novel therapeutic targets and genetic biomarkers that will be useful for drug discovery, patient selection and stratification in common diseases.
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Acknowledgements
A Deo lumen, ab amicis auxilium. This work was partially supported by National Institutes of Health grants N01A000,064 and U01AI066,569, and by National Science Foundation grant 0524,775. The authors thank the reviewers for their helpful suggestions.
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DATABASES
OMIM
age-related macular degeneration
anterior uveitis/ankylosing spondylitis
FURTHER INFORMATION
Glossary
- Genetic linkage
-
Co-segregation (reduced recombination) of a trait and an allele in related subjects (pedigrees) more often than explicable by chance.
- Dominant
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An allele that confers a trait even when it is heterozygous (present as a single copy in a genome).
- Recessive
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An allele that confers a trait only when it is homozygous (present in two copies in a genome, one from each parent).
- Endophenotype
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A measurable component of a phenotype.
- Multifactorial
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Inheritance of a trait that is attributable to two or more genes and their interaction with the environment (also known as polygenic inheritance).
- Allele
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The DNA code at a given locus (position) on a chromosome.
- Genome-wide association study
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A comprehensive search of the human genome for genetic risk factors for a trait by a case-control association study involving comparisons of hundreds of thousands of alleles between unrelated subjects with and without a trait.
- Haplotype
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A combination of alleles at linked loci (on a single chromatid) that are transmitted together more often than explicable by chance.
- Linkage disequilibrium
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(LD). Combinations of alleles in a population that differ in frequency from that expected from random formation of haplotypes from alleles based on their frequencies.
- Minor-allele frequency
-
The allele frequency of the less frequently occurring allele of a polymorphism.
- Case–control association study
-
Comparison of the frequency of an allele between unrelated subjects with and without a trait. A difference in allele frequency between the two groups indicates that the allele might change the likelihood of the trait.
- Genetic association
-
Correlation of a trait and an allele in a population more often than explicable by chance.
- Genocopy
-
A genotype at a locus that produces a phenotype that is indistinguishable from that produced by a genotype at another locus.
- Phenocopy
-
An environmentally produced phenotype that simulates the effect of a particular genotype.
- Non-synonymous SNP
-
(nsSNP). A SNP that leads to a change in the amino-acid sequence of the gene's resulting protein and that might therefore affect its function.
- Odds ratio
-
A measure of risk that compares the probability of occurrence of a disease in a group with a risk allele with the probability in a control group.
- Pleiotropy
-
A single gene that influences multiple phenotypic traits.
- Epistasis
-
Modification of the action of a gene by another gene.
- Family-based association study
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Evaluation of the frequency of co-transmission of an allele and a trait from parents to offspring. Co-transmission of an allele and trait to offspring more often than expected by chance indicates that the allele might change the likelihood of the trait.
- Antagonistic pleiotropy
-
A single gene that influences multiple competing phenotypes such that beneficial effects of a trait created by the gene are offset by losses in other traits.
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Kingsmore, S., Lindquist, I., Mudge, J. et al. Genome-wide association studies: progress and potential for drug discovery and development. Nat Rev Drug Discov 7, 221–230 (2008). https://doi.org/10.1038/nrd2519
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DOI: https://doi.org/10.1038/nrd2519
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