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Family-based tests applied to extended pedigrees identify rare variants related to hypertension.

ABSTRACT: The application of family-based tests to whole-genome sequenced data provides a new window on the role of rare variant alleles in the etiology of disease. By applying family-based tests to these data, we can now identify rare variants associated with disease. Approaches for common variants, by contrast, require large sample sizes for power, and are powerless when faced with rare variants. When we tested Yip et al's 2011 family-based association tests for rare variants on pedigrees from the Genetic Analysis Workshop 18, we found that weighted collapsing methods generally have more power than unweighted methods, but are more prone to type I errors. We then evaluated a sliding window modification of the weighted family-based association tests for rare variants method. Although this modification inflates the rate of false positives, it significantly increases the power of family-based association tests for rare variants to identify causal rare variants.

SUBMITTER: Xu M

PROVIDER: S-EPMC4143699 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Family-based tests applied to extended pedigrees identify rare variants related to hypertension.

Xu Mengyuan M Wang Harold Z HZ Guo Wei W Qin Haide H Shugart Yin Y YY

BMC proceedings 20140617 Suppl 1

The application of family-based tests to whole-genome sequenced data provides a new window on the role of rare variant alleles in the etiology of disease. By applying family-based tests to these data, we can now identify rare variants associated with disease. Approaches for common variants, by contrast, require large sample sizes for power, and are powerless when faced with rare variants. When we tested Yip et al's 2011 family-based association tests for rare variants on pedigrees from the Genet ...[more]

PMID: 25519318

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Project description:BackgroundBoth common and rare genetic variants have been shown to contribute to the etiology of complex diseases. Recent genome-wide association studies (GWAS) have successfully investigated how common variants contribute to the genetic factors associated with common human diseases. However, understanding the impact of rare variants, which are abundant in the human population (one in every 17 bases), remains challenging. A number of statistical tests have been developed to analyze collapsed rare variants identified by association tests. Here, we propose a haplotype-based approach. This work inspired by an existing statistical framework of the pedigree disequilibrium test (PDT), which uses genetic data to assess the effects of variants in general pedigrees. We aim to compare the performance between the haplotype-based approach and the rare variant-based approach for detecting rare causal variants in pedigrees.ResultsExtensive simulations in the sequencing setting were carried out to evaluate and compare the haplotype-based approach with the rare variant methods that drew on a more conventional collapsing strategy. As assessed through a variety of scenarios, the haplotype-based pedigree tests had enhanced statistical power compared with the rare variants based pedigree tests when the disease of interest was mainly caused by rare haplotypes (with multiple rare alleles), and vice versa when disease was caused by rare variants acting independently. For most of other situations when disease was caused both by haplotypes with multiple rare alleles and by rare variants with similar effects, these two approaches provided similar power in testing for association.ConclusionsThe haplotype-based approach was designed to assess the role of rare and potentially causal haplotypes. The proposed rare variants-based pedigree tests were designed to assess the role of rare and potentially causal variants. This study clearly documented the situations under which either method performs better than the other. All tests have been implemented in a software, which was submitted to the Comprehensive R Archive Network (CRAN) for general use as a computer program named rvHPDT.

Dataset Information

Family-based tests applied to extended pedigrees identify rare variants related to hypertension.

Publications

Family-based tests applied to extended pedigrees identify rare variants related to hypertension.

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