title: Population genomics in a disease targeted primary cell model.
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 < approximately 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.
authors: Department of Human Genetics, McGill University, Montréal H3A 1B1, Canada.
authors: Elin
authors: E
authors: Grundberg
authors: Tony
authors: T
authors: Kwan
authors: Bing
authors: B
authors: Ge
authors: Kevin C L
authors: KC
authors: Lam
authors: Vonda
authors: V
authors: Koka
authors: Andreas
authors: A
authors: Kindmark
authors: Hans
authors: H
authors: Mallmin
authors: Joana
authors: J
authors: Dias
authors: Dominique J
authors: DJ
authors: Verlaan
authors: Manon
authors: M
authors: Ouimet
authors: Daniel
authors: D
authors: Sinnett
authors: Fernando
authors: F
authors: Rivadeneira
authors: Karol
authors: K
authors: Estrada
authors: Albert
authors: A
authors: Hofman
authors: Joyce M
authors: JM
authors: van Meurs
authors: André
authors: A
authors: Uitterlinden
authors: Patrick
authors: P
authors: Beaulieu
authors: Alexandru
authors: A
authors: Graziani
authors: Eef
authors: E
authors: Harmsen
authors: Osten
authors: O
authors: Ljunggren
authors: Claes
authors: C
authors: Ohlsson
authors: Dan
authors: D
authors: Mellström
authors: Magnus K
authors: MK
authors: Karlsson
authors: Olle
authors: O
authors: Nilsson
authors: Tomi
authors: T
authors: Pastinen
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002874:Chromosome Mapping; D005269:Femur / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D023281:Genomics / Q000379:methods*; D006239:Haplotypes; D006367:HeLa Cells; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010024:Osteoporosis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D040641:Quantitative Trait Loci / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction