An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits.
Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6x10(-8)), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6x10(-13); SOX6, p = 6.4x10(-10)) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation.
Hsu
Yi-Hsiang
YH
Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, Massachusetts, USA.
Zillikens
M Carola
MC
Wilson
Scott G
SG
Farber
Charles R
CR
Demissie
Serkalem
S
Soranzo
Nicole
N
Bianchi
Estelle N
EN
Grundberg
Elin
E
Liang
Liming
L
Richards
J Brent
JB
Estrada
Karol
K
Zhou
Yanhua
Y
van Nas
Atila
A
Moffatt
Miriam F
MF
Zhai
Guangju
G
Hofman
Albert
A
van Meurs
Joyce B
JB
Pols
Huibert A P
HA
Price
Roger I
RI
Nilsson
Olle
O
Pastinen
Tomi
T
Cupples
L Adrienne
LA
Lusis
Aldons J
AJ
Schadt
Eric E
EE
Ferrari
Serge
S
Uitterlinden
André G
AG
Rivadeneira
Fernando
F
Spector
Timothy D
TD
Karasik
David
D
Kiel
Douglas P
DP
D000818:Animals; D015519:Bone Density; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010024:Osteoporosis / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D014158:Transcription, Genetic