An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits

被引：154

作者：

Hsu, Yi-Hsiang ^{[1
,2
,3
,4
]}

Zillikens, M. Carola ^{[5
,6
]}

Wilson, Scott G. ^{[7
,8
,9
,10
,11
]}

Farber, Charles R. ^{[12
,13
]}

Demissie, Serkalem ^{[4
,14
]}

Soranzo, Nicole ^{[7
,15
]}

Bianchi, Estelle N. ^{[16
]}

Grundberg, Elin ^{[15
,17
,18
]}

Liang, Liming ^{[19
]}

Richards, J. Brent ^{[17
,20
,21
,22
,23
]}

Estrada, Karol ^{[5
,6
]}

Zhou, Yanhua ^{[4
,14
]}

van Nas, Atila ^{[24
]}

Moffatt, Miriam F. ^{[25
]}

Zhai, Guangju ^{[7
]}

Hofman, Albert ^{[6
,26
]}

van Meurs, Joyce B. ^{[5
,6
]}

Pols, Huibert A. P. ^{[5
,26
]}

Price, Roger I. ^{[8
,9
,10
]}

Nilsson, Olle ^{[27
]}

Pastinen, Tomi ^{[17
,18
]}

Cupples, L. Adrienne ^{[4
,14
]}

Lusis, Aldons J. ^{[28
,29
,30
,31
,32
]}

Schadt, Eric E. ^{[33
]}

Ferrari, Serge ^{[16
]}

Uitterlinden, Andre G. ^{[5
,6
,26
]}

Rivadeneira, Fernando ^{[5
,6
,26
]}

Spector, Timothy D. ^{[7
]}

Karasik, David ^{[1
,2
,4
]}

Kiel, Douglas P. ^{[1
,2
,4
]}

机构：

[1] Hebrew SeniorLife Inst Aging Res, Boston, MA USA

[2] Harvard Univ, Sch Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Publ Hlth, Mol & Integrat Physiol Sci Program, Boston, MA 02115 USA

[4] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

[5] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[6] Netherlands Genom Initiat, The Hague, Netherlands

[7] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England

[8] Sir Charles Gairdner Hosp, Dept Endocrinol, Perth, WA 6000, Australia

[9] Sir Charles Gairdner Hosp, Dept Diabet, Perth, WA 6000, Australia

[10] Sir Charles Gairdner Hosp, Dept Med Technol & Phys, Perth, WA 6000, Australia

[11] Univ Western Australia, Sch Med & Pharmacol, Crawley, Australia

[12] Univ Virginia, Dept Med, Div Cardiovasc Med, Charlottesville, VA USA

[13] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[14] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA

[15] Wellcome Trust Sanger Inst, Cambridge, England

[16] Univ Hosp Geneva, Dept Rehabil & Geriatr, Serv Bone Dis, Geneva, Switzerland

[17] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[18] Genome Quebec Innovat Ctr, Montreal, PQ, Canada

[19] Harvard Univ, Sch Publ Hlth, Dept Biostat, Dept Epidemiol, Boston, MA 02115 USA

[20] McGill Univ, Dept Med, Montreal, PQ, Canada

[21] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[22] McGill Univ, Dept Epidemiol, Montreal, PQ, Canada

[23] McGill Univ, Dept Biostat, Montreal, PQ, Canada

[24] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[25] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England

[26] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[27] Uppsala Univ, Dept Surg Sci, Uppsala, Sweden

[28] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[29] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA

[30] Univ Calif Los Angeles, Dept Microbiol, Los Angeles, CA 90024 USA

[31] Univ Calif Los Angeles, Dept Immunol, Los Angeles, CA USA

[32] Univ Calif Los Angeles, Inst Mol Biol, David Geffen Sch Med, Dept Mol Genet, Los Angeles, CA 90024 USA

[33] Rosetta Inpharmat Merck, Seattle, WA USA

来源：

PLOS GENETICS | 2010年 / 6卷 / 06期

基金：

瑞典研究理事会;

关键词：

BONE-MINERAL DENSITY; DIFFERENT SKELETAL SITES; COMMON VARIANTS; CANDIDATE GENES; FEMORAL-NECK; METAANALYSIS; LINKAGE; GROWTH; BMD; DIFFERENTIATION;

D O I：

10.1371/journal.pgen.1000977

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 = 3.6 x 10(-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 = 2.6 x 10(-13); SOX6, p = 6.4 x 10(-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.

引用

页码：1 / 16

页数：16

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