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Collapsing singletons may boost signal for associating rare variants in sequencing study.

ABSTRACT: Advances in next-generation sequencing technology have made it possible to comprehensively interrogate the entire spectrum of genomic variations including rare variants. They may help capture the remaining genetic heritability which has not been fully explained by previous genome-wide association studies. Here we performed a gene-based genome-wide scan to identify hypertension susceptibility loci in analysis of a whole genome sequencing cohort of 103 unrelated individuals. We found that collapsing singletons may boost signals for associating rare variants and identified SETX statistically significant by a genome-wide gene-based threshold (p value <5.0 × 10(-6)). The function of SETX in hypertension may be worthy of further investigation.

SUBMITTER: Wang W

PROVIDER: S-EPMC4143730 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Collapsing singletons may boost signal for associating rare variants in sequencing study.

Wang Wei W Wei Zhi Z

BMC proceedings 20140617 Suppl 1

Advances in next-generation sequencing technology have made it possible to comprehensively interrogate the entire spectrum of genomic variations including rare variants. They may help capture the remaining genetic heritability which has not been fully explained by previous genome-wide association studies. Here we performed a gene-based genome-wide scan to identify hypertension susceptibility loci in analysis of a whole genome sequencing cohort of 103 unrelated individuals. We found that collapsi ...[more]

PMID: 25519331

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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

Collapsing singletons may boost signal for associating rare variants in sequencing study.

Publications

Collapsing singletons may boost signal for associating rare variants in sequencing study.

Similar Datasets

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