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Characterization of expression quantitative trait loci in extensively phenotyped pedigrees from Colombia and Costa Rica

ABSTRACT: The observation that variants regulating gene expression (expression quantitative trait loci, eQTL) are at a high frequency among SNPs associated with complex traits has made the genome-wide characterization of gene expression an important tool in genetic mapping studies of such traits. As part of a study to identify genetic loci contributing to bipolar disorder and a wide range of BP-related quantitative traits in members of 26 pedigrees from Costa Rica and Colombia, we measured gene expression in lymphoblastoid cell lines derived from 786 pedigree members. The study design enabled us to comprehensively reconstruct the genetic regulatory network in these families, provide estimates of heritability, identify eQTL, evaluate missing heritability for the eQTL, and quantify the number of different alleles contributing to any given locus. Lymphoblastoid cell lines (LCLs) were established by in vitro infection of peripheral blood mononuclear cells with Epstein Barr virus, and RNA was extracted from these cell lines and its expression quantified using Illumina Human HT-12 v4.0 Expression BeadChips. Expression values were background corrected, quantile normalized, log2 transformed, and corrected for major known batch effects. The outcome of these procedures is what we refer to as â??probe expressionâ?? for all subsequent analyses. After quality control filters, the 34,030 probes included in the final set were uniquely aligned to hg19, contained no common SNPs (as defined in dbSNP 137 or 138), queried 24,385 unique genes, and their expression was detected in at least one individual. For a detailed description of the processing steps used at each site and the RNA quantification, normalization, and quality control procedures, see the supplementary note. Please note that charateristics FID, IID and DiagnosisBP1 represents family ID, individual ID and BP1 diagnosis (0= no BP1, 2= BP1), respectively.

ORGANISM(S): Homo sapiens

SUBMITTER: Giovanni Coppola

PROVIDER: E-GEOD-82042 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2,112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters, and enrichment of co-localised functional elements. We found eQTLs for about 85% of analysed genes, 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 MB to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might often be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels, and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. We show for strongly heritable transcripts that a considerable gap still exists between total heritability resulting from all trans-chromosomes and explained variance of all identified trans-eSNPs. In contrast, the vast majority of most cis-heritability of these genes is already explained. Dissection of co-localised functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene-expression, pathways and disease related processes. Gene expression from human blood mononuclear cells from individuals of the Leipzig LIFE Heart Study was analyzed applying Illumina HT-12 v4 Expression BeadChips. After preprocessing, 28,295 expression probes for 2,112 individuals remained for analysis. In a population-based analysis, we identified associations between DNA variants and RNA expression levels and characterized these findings.

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Characterization of expression quantitative trait loci in extensively phenotyped pedigrees from Colombia and Costa Rica

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