RT Journal
A1 Grundberg, Elin
A1 Kwan, Tony
A1 Ge, Bing
A1 Lam, Kevin C.L.
A1 Koka, Vonda
A1 Kindmark, Andreas
A1 Mallmin, Hans
A1 Dias, Joana
A1 Verlaan, Dominique J.
A1 Ouimet, Manon
A1 Sinnett, Daniel
A1 Rivadeneira, Fernando
A1 Estrada, Karol
A1 Hofman, Albert
A1 van Meurs, Joyce M.
A1 Uitterlinden, André
A1 Beaulieu, Patrick
A1 Graziani, Alexandru
A1 Harmsen, Eef
A1 Ljunggren, Östen
A1 Ohlsson, Claes
A1 Mellström, Dan
A1 Karlsson, Magnus K.
A1 Nilsson, Olle
A1 Pastinen, Tomi
T1 Population genomics in a disease targeted primary cell model
JF Genome Research 
JO Genome Research 
YR 2009 
FD November 01 
VO 19 
IS 11 
SP 1942 
OP 1952 
DO 10.1101/gr.095224.109 
UL http://genome.cshlp.org/content/19/11/1942.abstract 
AB 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 < ∼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 × 10−10 − 7 × 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 (Pcombined = 5.6 × 10−5). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r2 = 0.5, P = 2.6 × 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.