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Genetic epidemiology of single-nucleotide polymorphisms.
A Collins1, C Lonjou, N E Morton
1Human Genetics, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom.
Summary
Genetic association studies can identify disease-causing single-nucleotide polymorphisms (SNPs) through linkage disequilibrium. Contrary to simulations, useful associations extend beyond 3 kb, enabling cost-effective genome scans with fewer SNPs.
Area of Science:
- Population Genetics
- Human Genetics
- Genomic Research
Background:
- Positional cloning relies on genetic markers like single-nucleotide polymorphisms (SNPs) to identify disease determinants.
- Two hypotheses exist: causal (SNPs are disease determinants) and proximity (determinants are near markers detected via linkage disequilibrium).
Purpose of the Study:
- To investigate the extent of linkage disequilibrium between SNPs.
- To evaluate its implications for cost-effective genome-wide association studies (GWAS).
Main Methods:
- Analysis of over 1,000 locus pairs to assess linkage disequilibrium.
- Comparison of simulation data with empirical data on SNP associations.
Main Results:
- Significant linkage disequilibrium extends beyond the 3 kb predicted by monotonic population expansion models.
- Cyclical population expansions may explain long-range disequilibria, with most tracing to the Neolithic era.
- Highly polymorphic alleles across ethnic groups show weaker disequilibrium, potentially limiting their utility in positional cloning.
Conclusions:
- Long-range linkage disequilibrium reduces the number of SNPs needed for genome scans to approximately 30,000.
- Understanding linkage disequilibrium patterns is crucial for efficient genetic association studies and positional cloning of disease genes.