Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes

Abstract

Quantitative differences in gene expression are thought to contribute to phenotypic differences between individuals. We generated genome-wide transcriptional profiles of lymphocyte samples from 1,240 participants in the San Antonio Family Heart Study. The expression levels of 85% of the 19,648 detected autosomal transcripts were significantly heritable. Linkage analysis uncovered >1,000 cis-regulated transcripts at a false discovery rate of 5% and showed that the expression quantitative trait loci with the most significant linkage evidence are often located at the structural locus of a given transcript. To highlight the usefulness of this much-enlarged map of cis-regulated transcripts for the discovery of genes that influence complex traits in humans, as an example we selected high-density lipoprotein cholesterol concentration as a phenotype of clinical importance, and identified the cis-regulated vanin 1 (VNN1) gene as harboring sequence variants that influence high-density lipoprotein cholesterol concentrations.

RNA-Seq and human complex diseases: recent accomplishments and future perspectives

“…Nonetheless, several evidences have unequivocally demonstrated that SNPs, identified by GWAS, and falling outside the coding regions of genes, may account for gene expression perturbation, pointing out to a crucial role of transcriptome studies for several complex diseases. [4][5][6]43 Human genetics research has drawn particular benefit by the introduction of NGS platforms and, particularly of RNA-Seq, which has significantly improved the way of looking at cell transcriptome in physiological and pathological conditions. 8,9 It is reasonable to believe that massive analysis of transcriptomes, as well as large-scale NGS studies, will become a routine in the next future, within just a few years, and that not only cancer and ND research will benefit this technology.…”

“…Since then, GWAS have unequivocally shown that SNPs affect gene expression. 4,5,75 A common finding of eQTL studies is that cis-acting SNPs (ie, in close proximity to a gene) have a strong influence on gene expression and a greater replicability in different populations and by independent detection methods. On the opposite, trans-acting variations 76 with subtle effects on expression are less replicable and their causal association to traits/diseases is not trivial.…”

“…Loci with such a property are referred to as expression quantitative trait loci (eQTL). A growing number of studies has unequivocally shown that such inherited polymorphisms account for gene expression variation in the population 4,5 and that global gene expression studies -not requiring a priori hypothesis -provide a large-scale way to investigate complex traits and the pathogenesis of common disorders. 6 Thus, despite a deep genetic knowledge for many human genetic diseases, to date most of the studies do not provide relevant clues about the real contribution, or the functional role, of such DNA variations to disease onset.…”

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

“…The San Antonio Family Heart Study (SAFHS) dataset23 is publicly available through ArrayExpress (http://www.ebi.ac.uk/arrayexpress) under the accession E‐TABM‐305. This cohort is composed of 1240 peripheral blood lymphocyte samples hybridized to Illumina Human‐6 v1 Expression BeadChip microarrays.…”

Intermediate phenotypes in schizophrenia genetics redux: is it a no brainer?

“…On the other hand, a substantial percentage of human proteins have expression levels that are highly heritable, strongly map onto genetic variation also implicated in complex diseases, and therefore have characteristics of intermediate phenotypes with the potential to link susceptibility alleles and the genetic regulation of key disease-related proteins within physiological networks. 29,30 Ultimately, the answer to the question of the relative genetic complexity of promising intermediate phenotypes awaits further study. The current evidence showing clear effects of genes associated with schizophrenia at the level of heritable phenotypes based on brain structure and function in the absence of a clinical diagnosis is consistent with the prediction that these phenotypes should be less complex.…”