Abstract
There is growing evidence that genetic risk factors for common disease are caused by hereditary changes of gene regulation acting in complex pathways. Clearly understanding the molecular genetic relationships between genetic control of gene expression and its effect on complex diseases is essential. Here we describe the Brisbane Systems Genetics Study (BSGS), a family-based study that will be used to elucidate the genetic factors affecting gene expression and the role of gene regulation in mediating endophenotypes and complex diseases.BSGS comprises of a total of 962 individuals from 314 families, for which we have high-density genotype, gene expression and phenotypic data. Families consist of combinations of both monozygotic and dizygotic twin pairs, their siblings, and, for 72 families, both parents. A significant advantage of the inclusion of parents is improved power to disentangle environmental, additive genetic and non-additive genetic effects of gene expression and measured phenotypes. Furthermore, it allows for the estimation of parent-of-origin effects, something that has not previously been systematically investigated in human genetical genomics studies. Measured phenotypes available within the BSGS include blood phenotypes and biochemical traits measured from components of the tissue sample in which transcription levels are determined, providing an ideal test case for systems genetics approaches.We report results from an expression quantitative trait loci (eQTL) analysis using 862 individuals from BSGS to test for associations between expression levels of 17,926 probes and 528,509 SNP genotypes. At a study wide significance level approximately 15,000 associations were observed between expression levels and SNP genotypes. These associations corresponded to a total of 2,081 expression quantitative trait loci (eQTL) involving 1,503 probes. The majority of identified eQTL (87%) were located within cis-regions.
Highlights
Dissection of the genetic architecture underlying quantitative traits and complex disease is essential to our understanding of the aetiology of complex diseases that cause most of the disease burden in society
As has been well discussed, Genome-wide association studies (GWAS) have struggled to discover loci that collectively explain large proportions of the heritability of most complex traits [3], [4]. It has been proposed [5,6,7] that the nature of genetic variance for complex disease may be different to that of Mendelian disease that are caused by protein coding mutations, in that it may result from hereditary changes in gene regulation rather than gene variants that alter protein function
Understanding the genetic basis of gene expression is likely to lead to a better understanding of genetic variation of quantitative traits and risk factors for common diseases
Summary
Dissection of the genetic architecture underlying quantitative traits and complex disease is essential to our understanding of the aetiology of complex diseases that cause most of the disease burden in society. As has been well discussed, GWAS have struggled to discover loci that collectively explain large proportions of the heritability of most complex traits [3], [4] It has been proposed [5,6,7] that the nature of genetic variance for complex disease may be different to that of Mendelian disease that are caused by protein coding mutations, in that it may result from hereditary changes in gene regulation rather than gene variants that alter protein function. Genetic differences between individuals in quantitative traits, endophenotypes (phenotypes that are risk factors for disease) and susceptibility to common diseases may be caused by differences in gene expression at a number of interacting loci [11]. Understanding the genetic basis of gene expression is likely to lead to a better understanding of genetic variation of quantitative traits and risk factors for common diseases
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