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Population genomics in a disease targeted primary cell model

ABSTRACT: The common genetic variants associated with complex traits typically lie in non-coding DNA and may alter gene regulation in a cell-type specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an eQTL study of primary human osteoblasts (HOb) derived from unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top BMD-associated SNPs were tested for cis-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment of converging cis-eQTLs as compared to LCLs. The top BMD loci with SNPs showing strong cis-effects on gene expression in HObs were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All variants were tested in the Swedish MrOs Cohort (n=3014), providing evidence for two novel BMD loci. These variants were then tested in the Rotterdam Study (n=2100), yielding converging evidence for BMD association at one locus. The cis-regulatory effect was further fine-mapped to the proximal promoter of the gene. Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE15678 | GEO | 2009/04/16

SECONDARY ACCESSION(S): PRJNA115621

REPOSITORIES: GEO

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Project description:Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the M-bM-^@M-^\missing heritability problem.M-bM-^@M-^] Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complementary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines (LCLs) from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility, as well as novel candidate genes enriched for functions related to T cell receptor signaling and ATP synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility. 96 RNA samples were collected (1 subsequently excluded) from lymphoblastoid cell lines derived from Hutterite subjects chosen to represent the extremes of absolute lymphocyte count. The high and low absolute lymphocyte count groups were balanced with respect to age, gender, and relatedness.

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Population genomics in a disease targeted primary cell model

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