An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility loci for osteoporosis-related traits

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An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility loci for osteoporosis-related traits


نویسنده	hsu y. ,zillikens m.c. ,wilson s.g. ,farber c.r. ,demissie s. ,soranzo n. ,bianchi e.n. ,grundberg e. ,liang l. ,richards j.b. ,estrada k. ,zhou y. ,van nas a. ,moffatt m.f. ,zhai g. ,hofman a. ,van meurs j.b. ,pols h.a.p. ,price r.i. ,nilsson o. ,pastinen t. ,cupples l.a. ,lusis a.j. ,schadt e.e. ,ferrari s. ,uitterlinden a.g. ,rivadeneira f. ,spector t.d. ,karasik d. ,kiel d.p.
منبع	plos genetics - 2010 - دوره : 6 - شماره : 6 - صفحه:1 -16
چکیده	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=3.610-8),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=2.610-13; sox6,p=6.4*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. © 2010 hsu et al.

آدرس	hebrew seniorlife institute for aging research and harvard medical school,boston,ma,united states,harvard school of public health,boston,ma,united states,framingham heart study,framingham,ma, United States, department of internal medicine,erasmus medical center,rotterdam,netherlands,netherlands genomics initiative,the hague, Netherlands, department of twin research and genetic epidemiology,king's college london,london,united kingdom,departments of endocrinology,diabetes,and medical technology and physics,sir charles gairdner hospital,perth,australia,school of medicine and pharmacology,university of western australia,crawley, Australia, department of medicine,division of cardiovascular medicine and center for public health genomics,university of virginia,charlottesville,va, United States, framingham heart study,framingham,ma,united states,department of biostatistics,school of public health,boston university,boston,ma, United States, department of twin research and genetic epidemiology,king's college london,london,united kingdom,wellcome trust sanger institute,hinxton,cambridge, United Kingdom, service of bone diseases,department of rehabilitation and geriatrics,university geneva hospital,geneva, Switzerland, wellcome trust sanger institute,hinxton,cambridge,united kingdom,department of human genetics,mcgill university,montreal,canada,mcgill university and genome quebec innovation center,montreal, Canada, department of epidemiology,department of biostatistics,harvard school of public health,boston,ma, United States, department of twin research and genetic epidemiology,king's college london,london,united kingdom,department of human genetics,mcgill university,montreal,canada,departments of medicine,human genetics,and epidemiology and biostatistics,jewish general hospital,mcgill university,montreal, Canada, department of internal medicine,erasmus medical center,rotterdam,netherlands,netherlands genomics initiative,the hague, Netherlands, framingham heart study,framingham,ma,united states,department of biostatistics,school of public health,boston university,boston,ma, United States, department of human genetics,david geffen school of medicine,university of california los angeles,los angeles,ca, United States, national heart and lung institute,imperial college london,london, United Kingdom, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, netherlands genomics initiative,the hague,netherlands,department of epidemiology,erasmus medical center,rotterdam, Netherlands, department of internal medicine,erasmus medical center,rotterdam,netherlands,netherlands genomics initiative,the hague, Netherlands, department of internal medicine,erasmus medical center,rotterdam,netherlands,department of epidemiology,erasmus medical center,rotterdam, Netherlands, departments of endocrinology,diabetes,and medical technology and physics,sir charles gairdner hospital,perth, Australia, department of surgical sciences,uppsala university,uppsala, Sweden, department of human genetics,mcgill university,montreal,canada,mcgill university and genome quebec innovation center,montreal, Canada, framingham heart study,framingham,ma,united states,department of biostatistics,school of public health,boston university,boston,ma, United States, departments of medicine,human genetics,microbiology,immunology,and molecular genetics,david geffen school of medicine,molecular biology institute,university of california los angeles,los angeles,ca, United States, rosetta inpharmatics/merck,seattle,wa, United States, service of bone diseases,department of rehabilitation and geriatrics,university geneva hospital,geneva, Switzerland, department of internal medicine,erasmus medical center,rotterdam,netherlands,netherlands genomics initiative,the hague,netherlands,department of epidemiology,erasmus medical center,rotterdam, Netherlands, department of internal medicine,erasmus medical center,rotterdam,netherlands,netherlands genomics initiative,the hague,netherlands,department of epidemiology,erasmus medical center,rotterdam, Netherlands, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, hebrew seniorlife institute for aging research and harvard medical school,boston,ma,united states,framingham heart study,framingham,ma, United States, hebrew seniorlife institute for aging research and harvard medical school,boston,ma,united states,framingham heart study,framingham,ma, United States



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