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Population genomics in a disease targeted primary cell model

Grundberg, Elin; Kwan, Tony; Ge, Bing; Lam, Kevin C. L.; Koka, Vonda; Kindmark, Andreas; Mallmin, Hans; Dias, Joana; Verlaan, Dominique J. and Ouimet, Manon, et al. (2009) In Genome Research 19(11). p.1942-1952
Abstract
The common genetic variants associated with complex traits typically lie in noncoding 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 expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 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 2000 BMD-associated SNPs (P < similar to 10(-3)) were tested for cis-association of gene expression... (More)
The common genetic variants associated with complex traits typically lie in noncoding 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 expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 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 2000 BMD-associated SNPs (P < similar to 10(-3)) 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 ( threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs (P = 6 x 10(-10) - 7 x 10(-16)) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study ( n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (P-combined = 5.6 x 10(-5)). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r(2) = 0.5, P = 2.6 x 10 (15)). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies. (Less)
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publication status
published
subject
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Genome Research
volume
19
issue
11
pages
1942 - 1952
publisher
Cold Spring Harbor Laboratory Press
external identifiers
  • wos:000271426600003
  • scopus:70350724550
ISSN
1549-5469
DOI
10.1101/gr.095224.109
language
English
LU publication?
yes
id
517c41de-73c5-4561-a6c2-269381e05759 (old id 1520209)
date added to LUP
2009-12-28 10:15:32
date last changed
2017-12-10 04:16:24
@article{517c41de-73c5-4561-a6c2-269381e05759,
  abstract     = {The common genetic variants associated with complex traits typically lie in noncoding 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 expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 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 2000 BMD-associated SNPs (P &lt; similar to 10(-3)) 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 ( threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs (P = 6 x 10(-10) - 7 x 10(-16)) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study ( n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (P-combined = 5.6 x 10(-5)). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r(2) = 0.5, P = 2.6 x 10 (15)). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.},
  author       = {Grundberg, Elin and Kwan, Tony and Ge, Bing and Lam, Kevin C. L. and Koka, Vonda and Kindmark, Andreas and Mallmin, Hans and Dias, Joana and Verlaan, Dominique J. and Ouimet, Manon and Sinnett, Daniel and Rivadeneira, Fernando and Estrada, Karol and Hofman, Albert and van Meurs, Joyce M. and Uitterlinden, Andre and Beaulieu, Patrick and Graziani, Alexandru and Harmsen, Eef and Ljunggren, Osten and Ohlsson, Claes and Mellstrom, Dan and Karlsson, Magnus and Nilsson, Olle and Pastinen, Tomi},
  issn         = {1549-5469},
  language     = {eng},
  number       = {11},
  pages        = {1942--1952},
  publisher    = {Cold Spring Harbor Laboratory Press},
  series       = {Genome Research},
  title        = {Population genomics in a disease targeted primary cell model},
  url          = {http://dx.doi.org/10.1101/gr.095224.109},
  volume       = {19},
  year         = {2009},
}