Abstract
In this paper, we propose a novel mixed-effects model for longitudinal changes of systolic blood pressure (SBP) over time that can estimate the joint effect of multiple sequence variants on SBP after accounting for familial correlation and the time dependencies within individuals. First we carried out agenome-wide association study (GWAS) using chromosome 3 single-nucleotide polymorphisms(SNPs) to identify regions associated with SBP levels. In a second step, we examined the sequence data to fine-map additional variants in these regions. Four SNPs from two intergenic regions (PLXNA1-TPRA1, BPESC1-PISTR1) and one gene (NLGN1) were detected to be significantly associated with SBP after adjusting for multiple testing. These SNPs were used to capture the multilocus genotype diversity in the regions. The multilocus genotypes derived from these four variants were then treated as random effects in the mixed-effects model, and the corresponding confidence intervals (Cis) were built to assess the significance of the joint effect of the sequence variants on SBP. We found that multilocus genotypes (GG,TT,AG,GG), (GG,TT,GG,GG), and (GG,TT,AA,AG) are associated with higher SBPand (GG,CT,AA,AA), (AA,TT,AA,AA), and (AG,CT,AA,AG) are associated with lower SBP. The linear mixed-effects models provide a powerful tool for GWAS and the analysis of joint modeling of multilocus genotypes.
Highlights
The Genetic Analysis Workshop 18 (GAW 18) data set [1] is drawn from the San Antonio Family Study with a total of 959 participants from 20 families, and it includes genome-wide association study (GWAS) and whole genome sequencing(WGS) data on all individuals
The GWAS on chromosome 3 has identified two intergenic regions,PLXNA1-TPRA1and BPESC1-PISTR1, and one gene,NLGN1, to be most significantly associated with systolic blood pressure (SBP) (Figure 2)
We chose the SNPs that are most significantly associated with SBP for the joint modeling analysis
Summary
The Genetic Analysis Workshop 18 (GAW 18) data set [1] is drawn from the San Antonio Family Study with a total of 959 participants from 20 families, and it includes genome-wide association study (GWAS) and whole genome sequencing(WGS) data on all individuals. The participants had 1to 4systolic blood pressure (SBP) measurements. Current use of antihypertensive medications, hypertension diagnosis, and current tobacco smoking status were recorded. This study provides a unique resource for elucidating genetic factors associated with longitudinal SBP after accounting for heterogeneity between individuals and families. The mixed-effects model was used to analyze the longitudinal GWAS data and to estimate the joint effects of multiple sequence variants while accounting for familial correlation and the time dependencies within individuals. A real phenotype data set, along with GWAS and dosage
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