Abstract
We apply a multiphase strategy for pedigree-based genetic analysis of systolic blood pressure data collected in a longitudinal study of large Mexican American pedigrees. In the first phase, we conduct variance-components linkage analysis to identify regions that may harbor quantitative trait loci. In the second phase, we carry out pedigree-based association analysis in a selected region with common and low-frequency variants from genome-wide association studies and whole genome sequencing data. Using sequencing data, we compare approaches to pedigree analysis in a 10 megabase candidate region on chromosome 3 harboring a gene previously identified by a consortium for blood pressure genome-wide association studies. We observe that, as expected, the measured genotype analysis tends to provide larger signals than the quantitative transmission disequilibrium test. We also observe that while linkage signals are contributed by common variants, strong associations are found mainly at rare variants. Multiphase analysis can improve computational efficiency and reduce the multiple testing burden.
Highlights
In pedigree-based studies, discovery of genomic regions harboring genetic determinants of quantitative traits such as systolic blood pressure (SBP) has conventionally been conducted using linkage analysis based on identity-bydescent allele sharing
We demonstrate that multiphase analysis in pedigrees can be an efficient strategy for identifying genetic variants underlying a quantitative trait, in which region discovery by linkage analysis of genome-wide association studies (GWAS) single-nucleotide polymorphism (SNP) markers with high minor allele frequency (MAF) is followed by region refinement with densely distributed GWAS SNPs and/or fine mapping with sequence variants in identified regions
Using a summary phenotype derived from longitudinal measurements of SBP together with GWAS and whole genome sequencing genotype data from the San Antonio Family Studies (SAFS) as provided by Genetic Analysis Workshop 18 (GAW18), we report pedigree-based linkage and association analysis conducted to identify genetic variants underlying SBP
Summary
In pedigree-based studies, discovery of genomic regions harboring genetic determinants of quantitative traits such as systolic blood pressure (SBP) has conventionally been conducted using linkage analysis based on identity-bydescent allele sharing. We demonstrate that multiphase analysis in pedigrees can be an efficient strategy for identifying genetic variants underlying a quantitative trait, in which region discovery by linkage analysis of GWAS single-nucleotide polymorphism (SNP) markers with high minor allele frequency (MAF) is followed by region refinement with densely distributed GWAS SNPs and/or fine mapping with sequence variants in identified regions. Using a summary phenotype derived from longitudinal measurements of SBP together with GWAS and whole genome sequencing genotype data from the San Antonio Family Studies (SAFS) as provided by Genetic Analysis Workshop 18 (GAW18), we report pedigree-based linkage and association analysis conducted to identify genetic variants underlying SBP. In step 3, we conduct pedigree-based association analysis using sequence data to fine-map the MECOM genomic region
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