Detecting rare variants for complex traits using family and unrelated data
- 21 October 2009
- journal article
- research article
- Published by Wiley in Genetic Epidemiology
- Vol. 34 (2), 171-187
- https://doi.org/10.1002/gepi.20449
Abstract
Large genome‐wide association studies (GWAS) have been performed to detect common genetic variants involved in common diseases, but most of the variants found this way account for only a small portion of the trait variance. Furthermore, candidate gene‐based resequencing suggests that many rare genetic variants contribute to the trait variance of common diseases. Here we propose two designs, sibpair and unrelated‐case designs, to detect rare genetic variants in either a candidate gene‐based or genome‐wide association analysis. First we show that we can detect and classify together rare risk haplotypes using a relatively small sample with either of these designs, and then have increased power to test association in a larger case‐control sample. This method can also be applied to resequencing data. Next we apply the method to the Wellcome Trust Case Control Consortium (WTCCC) coronary artery disease (CAD) and hypertension (HT) data, the latter being the only trait for which no genome‐wide association evidence was reported in the original WTCCC study, and identify one interesting gene associated with HT and four associated with CAD at a genome‐wide significance level of 5%. These results suggest that searching for rare genetic variants is feasible and can be fruitful in current GWAS, candidate gene studies or resequencing studies. Genet. Epidemiol . 34: 171–187, 2010.Keywords
This publication has 54 references indexed in Scilit:
- Methods for Detecting Associations with Rare Variants for Common Diseases: Application to Analysis of Sequence DataAmerican Journal of Human Genetics, 2008
- Estimating coverage and power for genetic association studies using near-complete variation dataNature Genetics, 2008
- Common and rare variants in multifactorial susceptibility to common diseasesNature Genetics, 2008
- Rapid and Accurate Haplotype Phasing and Missing-Data Inference for Whole-Genome Association Studies By Use of Localized Haplotype ClusteringAmerican Journal of Human Genetics, 2007
- New susceptibility locus for hypertension on chromosome 8q by efficient pedigree-breaking in an Italian isolateHuman Molecular Genetics, 2006
- A haplotype map of the human genomeNature, 2005
- Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9Nature Genetics, 2005
- Multiple Rare Alleles Contribute to Low Plasma Levels of HDL CholesterolScience, 2004
- Merlin—rapid analysis of dense genetic maps using sparse gene flow treesNature Genetics, 2001
- Population genetics—making sense out of sequenceNature Genetics, 1999