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Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics
Steve Horvath1, Xin Xu, Stephen L Lake
1Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA. shorvath@mednet.ucla.edu
Genetic Epidemiology
|December 24, 2003
Summary
A new family-based genetic testing strategy effectively links asthma to specific gene variations (haplotypes). This method is robust and handles missing genetic data, identifying significant associations missed by single-marker tests.
Area of Science:
- Genetics
- Statistical genetics
- Bioinformatics
Background:
- Family-based studies are crucial for genetic association analysis.
- Haplotype analysis offers higher resolution than single markers but faces challenges with ambiguous phase and missing parental data.
- Existing methods may not be robust to population structure or phenotype ascertainment.
Purpose of the Study:
- To develop a general-purpose, family-based statistical testing strategy for disease phenotype association with haplotypes.
- To extend existing methods to handle ambiguous phase and missing parental genotype data.
- To implement and apply the strategy to identify genetic associations with asthma.
Main Methods:
- Developed a weighted conditional approach extending previous methods to multiple markers.
- The strategy accommodates ambiguous phase and missing parental genotypes in offspring and parents.
- Implemented the approach in the freely available software, haplotype FBAT.
- Applied the software to analyze single nucleotide polymorphisms (SNPs) in the beta-2 adrenergic receptor gene for asthma association.
Main Results:
- The weighted conditional approach provides efficient and robust haplotype tests for family-based studies.
- The method is resilient to population admixture, phenotype distribution, and phenotype-based ascertainment.
- While no single SNP showed significant association with asthma, a haplotype-based global test revealed a highly significant association with asthma diagnosis (P < 0.00005).
- A significant association was also found with bronchodilator responsiveness (P = 0.016).
Conclusions:
- The developed haplotype-based testing strategy is effective for identifying genetic associations in family-based studies.
- The method successfully identified significant associations with asthma diagnosis and bronchodilator responsiveness, which were not detected by single SNP analysis.
- The haplotype FBAT software provides a valuable tool for genetic association studies, particularly for complex diseases and when dealing with data limitations.