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dc.contributor.advisorDeng, Hong-Wenen_US
dc.contributor.authorXiong, Donghaien_US
dc.date.accessioned2014-11-17T15:35:39Z
dc.date.available2014-11-17T15:35:39Z
dc.date.issued2007-04en_US
dc.identifier.urihttp://hdl.handle.net/10504/63696
dc.description.abstractOsteoporosis is a common skeletal disease becoming one of the biggest public health menaces with the consequence of millions of fractures annually around the world. Osteoporosis is mainly characterized by compromised bone strength that is determined by many skeletal factors such as bone mineral density (BMD), bone geometry, bone microarchitecture, and intrinsic material properties. The BMD and bone geometry all have strong genetic determinations. Identifying their genetic determinants has both biological and clinical importance. I first performed a remarkably large-scale whole genome linkage scan involving 3,998 individuals from 434 pedigrees for four FNCS (femoral neck cross-sectional) geometry parameters, namely buckling ratio (BR), cross-sectional area (CSA), cortical thickness (CT), and section modulus (Z). Significant linkage evidence (Threshold LOD = 3.72 after correction for tests of multiple phenotypes) was found in the regions of 20ql2 and Xq25 for CT (LOD = 4.28 and 3.90, respectively). I also identified 8 suggestive linkage signals (Threshold LOD = 2.31 after correction for multiple tests) for the respective geometry traits. Particularly, 20ql2 was of prime interest because it was linked to multiple FNCS geometry traits and significantly interacted with 5 other genomic loci to influence CSA variation. The effects of 20ql2 on FNCS geometry were present in both male and female subgroups. There are also sex-specific QTLs for FNCS traits in the regions such as 2pl4, 3q26, 7q21 and 15q21. Second, I conducted a large-scale family-based association study by screening 20 important and novel osteoporosis candidate genes with 277 SNPs (single nucleotide polymorphisms) for the quantitative trait - BMD (bone mineral density) variation and the qualitative trait - osteoporosis (OP) at three clinically important skeletal sites - spine, hip and ultradistal radius (UD). 1873 subjects from 405 Caucasian nuclear families were genotyped and analyzed with an average density of 1 SNP per 4 kb across the 20 genes. I detected four genes (DBP, LRP5, CYP17 and RANK) that showed 'highly suggestive' association (10,000-permutation derived empirical global P values < .01) with spine BMD/OP; four genes (CYP19, RANK, RANKL and CYP17) highly suggestive for hip BMD/OP; and four genes (CYP19, BMP2, RANK, TNFR2) highly suggestive for UD BMD/OP. Some of these findings supported previous results while the others were novel discoveries. The associations between BMP2 with UD BMD, and those between RANK with OP at spine, hip and UD also met the experimentwide stringent criterion (empirical global P values <.0007). In addition, I identified and validated a two-locus gene-gene interaction model involving GCR and ESR2, for which prior biological evidence exists. My results suggested the prioritization of osteoporosis candidate genes from among the many proposed in recent years and revealed the significant gene-gene interaction effects influencing osteoporosis risk. Taken together, my linkage and association studies for bone geometry and bone mass have further delineated the genetic basis of osteoporosis-related skeletal traits and laid a solid foundation for downstream functional and molecular studies.en_US
dc.language.isoen_USen_US
dc.publisherCreighton Universityen_US
dc.rightsCopyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.en_US
dc.subject.meshBone Density--geneticsen_US
dc.subject.meshGenetic Linkageen_US
dc.titleGenetic Linkage and Association Studies for Bone Geometry and Bone Mineral Densityen_US
dc.typeDissertation
dc.rights.holderDonghai Xiongen_US
dc.publisher.locationOmaha, Nebraskaen_US
dc.description.noteProQuest Traditional Publishing Optionen_US
dc.description.pagesix, 163 pagesen_US
dc.contributor.cuauthorXiong, Donghaien_US
dc.degree.levelPhD (Doctor of Philosophy)en_US
dc.degree.disciplineBiomedical Sciences (graduate program)en_US
dc.degree.namePh.D. in Biomedical Sciencesen_US
dc.degree.grantorGraduate Schoolen_US
dc.degree.committeeMurphy, Richard F.en_US
dc.degree.committeeCheng, Shih-Chuanen_US
dc.degree.committeeWatson, Patrice A.en_US
dc.degree.committeeLappe, Joan M.en_US
dc.degree.committeeKimberling, William J.en_US


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