title: Common and rare variants in the exons and regulatory regions of osteoporosis-related genes improve osteoporotic fracture risk prediction.
abstract: BACKGROUND
  Osteoporotic fracture risk is highly heritable, but genome-wide association studies have explained only a small proportion of the heritability to date. Genetic data may improve prediction of fracture risk in osteopenic subjects and assist early intervention and management.
  
  
  OBJECTIVE
  To detect common and rare variants in coding and regulatory regions related to osteoporosis-related traits, and to investigate whether genetic profiling improves the prediction of fracture risk.
  
  
  METHODS
  This cross-sectional study was conducted in three clinical units in Korea.
  
  
  METHODS
  Postmenopausal women with extreme phenotypes (n = 982) were used for the discovery set, and 3895 participants were used for the replication set.
  
  
  METHODS
  We performed targeted resequencing of 198 genes. Genetic risk scores from common variants (GRS-C) and from common and rare variants (GRS-T) were calculated.
  
  
  RESULTS
  Nineteen common variants in 17 genes (of the discovered 34 functional variants in 26 genes) and 31 rare variants in five genes (of the discovered 87 functional variants in 15 genes) were associated with one or more osteoporosis-related traits. Accuracy of fracture risk classification was improved in the osteopenic patients by adding GRS-C to fracture risk assessment models (6.8%; P < .001) and was further improved by adding GRS-T (9.6%; P < .001). GRS-C improved classification accuracy for vertebral and nonvertebral fractures by 7.3% (P = .005) and 3.0% (P = .091), and GRS-T further improved accuracy by 10.2% (P < .001) and 4.9% (P = .008), respectively.
  
  
  CONCLUSIONS
  Our results suggest that both common and rare functional variants may contribute to osteoporotic fracture and that adding genetic profiling data to current models could improve the prediction of fracture risk in an osteopenic individual.
authors.affiliation: Division of Endocrinology and Metabolism (S.H.L., S.H.A., K.-H.L., B.-J.K., G.S.K., J.-M.K.), Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea; Department of Endocrinology and Metabolism (M.I.K., K.-H.Y.), The Catholic University of Korea, College of Medicine, Seoul 137-701, Korea; DNA Link (G.E.L., E.-S.S., J.-E.L.), Seoul 138-736, Korea; Department of Internal Medicine (E.-H.C., S.-W.K.), Kangwon National University College of Medicine, Chuncheon 200-722, Korea; Skeletal Diseases Genome Research Center and Department of Orthopedic Surgery (T.-H.K., H.-J.K., S.-Y.K.), Kyungpook National University School of Medicine, Daegu 702-701, Korea; and Department of Preventive Medicine (W.C.L.), The Catholic University of Korea, College of Medicine, Seoul 137-701, Korea.
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Lee
authors.forename: Moo Il
authors.initials: MI
authors.lastname: Kang
authors.forename: Seong Hee
authors.initials: SH
authors.lastname: Ahn
authors.forename: Kyeong-Hye
authors.initials: KH
authors.lastname: Lim
authors.forename: Gun Eui
authors.initials: GE
authors.lastname: Lee
authors.forename: Eun-Soon
authors.initials: ES
authors.lastname: Shin
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Beom-Jun
authors.initials: BJ
authors.lastname: Kim
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Cho
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kim
authors.forename: Tae-Ho
authors.initials: TH
authors.lastname: Kim
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Kim
authors.forename: Kun-Ho
authors.initials: KH
authors.lastname: Yoon
authors.forename: Won Chul
authors.initials: WC
authors.lastname: Lee
authors.forename: Ghi Su
authors.initials: GS
authors.lastname: Kim
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Koh
authors.forename: Shin-Yoon
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000368:Aged; D015519:Bone Density / Q000235:genetics; D003430:Cross-Sectional Studies; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D058866:Osteoporotic Fractures / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D018570:Risk Assessment