Abstract
Homozygosity disequilibrium (HD), a nonrandom sizable run of homozygosity in the genome, may be related to the evolution of populations and may also confer susceptibility to disease. No studies have investigated HD using whole genome sequencing (WGS) analysis. In this study, we used an enhanced version of Loss-Of-Heterozygosity Analysis Suite (LOHAS) software to investigate HD through analysis of real and simulated WGS data sets provided by Genetic Analysis Workshop 18. Using a local polynomial model, we derived whole-genome profiles of homozygosity intensities for 959 individuals and characterized the patterns of HD. Generalized estimating equation analysis for 855 related samples was performed to examine the association between patterns of HD and 3 phenotypes of interest, namely diastolic blood pressure, systolic blood pressure, and hypertension status, with covariate adjustments for age and gender. We found that 4.48% of individuals in this study carried sizable runs of homozygosity (ROHs). Distributions of the length of ROHs were derived and revealed a familial aggregation of HD. Genome-wide homozygosity association analysis identified 5 and 3 ROHs associated with diastolic blood pressure and hypertension, respectively. These regions contain genes associated with calcium channels (CACNA1S), renin catalysis (REN), blood groups (ABO), apolipoprotein (APOA5), and cardiovascular diseases (RASGRP1). Simulation studies showed that our homozygosity association tests controlled type 1 error well and had a promising power. This study provides a useful analysis tool for studying HD and allows us to gain a deeper understanding of HD in the human genome.
Highlights
Homozygosity disequilibrium (HD) describes a phenomenon in which a nonrandom pattern is observed for a sizable run of homozygosity (ROH) in the human genome, where runs of homozygosity (ROHs) indicates a contiguous set of homozygous genotypes in an intact genomic region or allows to be interrupted by a small proportion of heterozygous genotypes arising from genotyping errors, missing genotypes, or mutations [1]
We observed a familial aggregation of ROHs
We characterized the patterns of HD by analyzing a large whole genome sequencing (WGS) data set of 959 individuals from 20 pedigrees
Summary
Homozygosity disequilibrium (HD) describes a phenomenon in which a nonrandom pattern is observed for a sizable run of homozygosity (ROH) in the human genome, where ROH indicates a contiguous set of homozygous genotypes in an intact genomic region or allows to be interrupted by a small proportion of heterozygous genotypes arising from genotyping errors, missing genotypes, or mutations [1]. HD can result from autozygosity [2], natural selection [3], and chromosomal aberrations [4]. Previous studies suggested that HD may confer susceptibility to neurodevelopment-related disorders [5,6] and autoimmune diseases [1,7]. No studies have investigated HD with whole genome sequencing (WGS) analysis. This study analyzed a real human WGS data set and simulated
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