Population genomics in a disease targeted primary cell model.
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.
Grundberg
Elin
E
Department of Human Genetics, McGill University, Montréal H3A 1B1, Canada.
Kwan
Tony
T
Ge
Bing
B
Lam
Kevin C L
KC
Koka
Vonda
V
Kindmark
Andreas
A
Mallmin
Hans
H
Dias
Joana
J
Verlaan
Dominique J
DJ
Ouimet
Manon
M
Sinnett
Daniel
D
Rivadeneira
Fernando
F
Estrada
Karol
K
Hofman
Albert
A
van Meurs
Joyce M
JM
Uitterlinden
André
A
Beaulieu
Patrick
P
Graziani
Alexandru
A
Harmsen
Eef
E
Ljunggren
Osten
O
Ohlsson
Claes
C
Mellström
Dan
D
Karlsson
Magnus K
MK
Nilsson
Olle
O
Pastinen
Tomi
T
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