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Genome-wide association filtering using a highly locus-specific transmission/disequilibrium test
María M Abad-Grau1, Nuria Medina-Medina, Rosana Montes-Soldado
1Departamento de Lenguajes y Sistemas Informáticos, CITIC, Universidad de Granada, Spain. mabad@ugr.es
Human Genetics
|July 7, 2010
Summary
We developed a new statistical test, the multimarker proportional transmission/disequilibrium test (mTDT(P)), to pinpoint disease-related genetic regions more precisely. This method improves locus specificity for complex diseases while maintaining high statistical power, aiding in genetic research.
Area of Science:
- Genetics
- Statistical Genetics
- Genomic Association Studies
Background:
- Multimarker transmission/disequilibrium tests (TDTs) are crucial for genome-wide filtering to identify disease susceptibility loci.
- While TDTs minimize false positives from population stratification, they often identify large genomic regions due to linkage disequilibrium (LD).
Purpose of the Study:
- To introduce a novel statistical test, the multimarker proportional TDT (mTDT(P)), designed to enhance locus specificity in complex disease association studies.
- To evaluate the power and specificity of mTDT(P) compared to existing multimarker TDTs.
Main Methods:
- The mTDT(P) test is a generalization of standard multimarker TDTs, incorporating haplotype frequencies to weight individual haplotype contributions.
- The method leverages the 'common disease, common variant' hypothesis and the principle that LD decreases with physical distance.
- Haplotype frequencies are used to weight their contribution, reflecting the expected decrease in frequency of risk haplotypes with increasing distance from a disease locus.
Main Results:
- Simulations and real data analyses demonstrate that mTDT(P) achieves good statistical power, comparable to the most powerful existing multimarker TDTs.
- mTDT(P) exhibits significantly higher locus specificity, leading to a more rapid decrease in association signal with increasing distance from the true disease locus.
- This improved specificity allows for more precise localization of disease-associated genetic regions.
Conclusions:
- The mTDT(P) offers a powerful and more specific approach for fine-mapping disease susceptibility loci in complex diseases.
- Its ability to improve locus specificity makes it a valuable tool for genetic association studies, potentially reducing the size of candidate regions.
- The mTDT(P) provides a refined method for navigating the challenges posed by linkage disequilibrium in complex trait genetics.
