Rare genetic variant analysis on blood pressure in related samples.

Han Chen,Jacqueline N Milton,Honghuang Lin,Seung Hoan Choi,Jaeyoung Hong,Chen Lu,Sean M Lacey,Josée Dupuis,Catherine Allard

doi:10.1186/1753-6561-8-s1-s35

Abstract

The genetic variants associated with blood pressure identified so far explain only a small proportion of the total heritability of this trait. With recent advances in sequencing technology and statistical methodology, it becomes feasible to study the association between blood pressure and rare genetic variants. Using real baseline phenotype data and imputed dosage data from Genetic Analysis Workshop 18, we performed a candidate gene association analysis. We focused on 8 genes shown to be associated with either systolic or diastolic blood pressure to identify the association with both common and rare genetic variants, and then did a genome-wide rare-variant analysis on blood pressure. We performed association analysis for rare coding and splicing variants within each gene region and all rare variants in each sliding window, using either burden tests or sequence kernel association tests accounting for familial correlation. With a sample size of only 747, we failed to find any novel associated genetic loci. Consequently, we performed analyses on simulated data, with knowledge of the underlying simulating model, to evaluate the type I error rate and power for the methods used in real data analysis.

Highlights

Despite the tremendous success of genome-wide association studies (GWAS) to uncover genetic variants influencing complex traits and diseases, only a fraction of the total heritability of these traits is explained by the loci identified so far
We investigate the association of rare variants in genomic regions that have been previously implicated by GWAS to identify the source of the original GWAS signal and to discover additional genetic loci influencing Blood pressure (BP) using either burden tests adjusting for familial correlation or sequence kernel association tests (SKAT) [3] for family samples [4,5]
Candidate gene analysis We chose 8 gene regions (CASZ1, MTHFR, ULK4, PLEKHA7, CSK, CSK-ULK3, PLCD3, ZNF652) that were previously reported to be associated with either systolic blood pressure (SBP) or diastolic blood pressure (DBP) [1,2]

Summary

Introduction

Despite the tremendous success of genome-wide association studies (GWAS) to uncover genetic variants influencing complex traits and diseases, only a fraction of the total heritability of these traits is explained by the loci identified so far. Because GWAS focuses on common variants, a possible source of the missing heritability might be rare variants that were not included in the earlier genotyping platforms. The logical step is to investigate rare variants, an endeavor that is possible because of the ever-decreasing cost of sequencing. Whole genome sequencing has the ability to uncover rare variants, but brings its own challenges. Despite a low error rate, the sheer number of base pairs sequenced makes it hard to distinguish very rare mutations from sequencing errors. Detecting association with rare variants requires very large sample sizes. Several methods to jointly analyze rare variants within a genomic

Methods

Results

Discussion

Conclusion