BACKGROUND: Osteoporosis is characterized by low bone mass and compromised bone structure, heritable traits that contribute to fracture risk. There have been no genome-wide association and linkage studies for these traits using high-density genotyping platforms. METHODS: We used the Affymetrix 100K SNP GeneChip marker set in the Framingham Heart Study (FHS) to examine genetic associations with ten primary quantitative traits: bone mineral density (BMD), calcaneal ultrasound, and geometric indices of the hip. To test associations with multivariable-adjusted residual trait values, we used additive generalized estimating equation (GEE) and family-based association tests (FBAT) models within each sex as well as sexes combined. We evaluated 70,987 autosomal SNPs with genotypic call rates > or =80%, HWE p > or = 0.001, and MAF > or =10% in up to 1141 phenotyped individuals (495 men and 646 women, mean age 62.5 yrs). Variance component linkage analysis was performed using 11,200 markers. RESULTS: Heritability estimates for all bone phenotypes were 30-66%. LOD scores > or =3.0 were found on chromosomes 15 (1.5 LOD confidence interval: 51,336,679-58,934,236 bp) and 22 (35,890,398-48,603,847 bp) for femoral shaft section modulus. The ten primary phenotypes had 12 associations with 100K SNPs in GEE models at p < 0.000001 and 2 associations in FBAT models at p < 0.000001. The 25 most significant p-values for GEE and FBAT were all less than 3.5 x 10(-6) and 2.5 x 10(-5), respectively. Of the 40 top SNPs with the greatest numbers of significantly associated BMD traits (including femoral neck, trochanter, and lumbar spine), one half to two-thirds were in or near genes that have not previously been studied for osteoporosis. Notably, pleiotropic associations between BMD and bone geometric traits were uncommon. Evidence for association (FBAT or GEE p < 0.05) was observed for several SNPs in candidate genes for osteoporosis, such as rs1801133 in MTHFR; rs1884052 and rs3778099 in ESR1; rs4988300 in LRP5; rs2189480 in VDR; rs2075555 in COLIA1; rs10519297 and rs2008691 in CYP19, as well as SNPs in PPARG (rs10510418 and rs2938392) and ANKH (rs2454873 and rs379016). All GEE, FBAT and linkage results are provided as an open-access results resource at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. CONCLUSION: The FHS 100K SNP project offers an unbiased genome-wide strategy to identify new candidate loci and to replicate previously suggested candidate genes for osteoporosis.
BACKGROUND:Osteoporosis is characterized by low bone mass and compromised bone structure, heritable traits that contribute to fracture risk. There have been no genome-wide association and linkage studies for these traits using high-density genotyping platforms. METHODS: We used the Affymetrix 100K SNP GeneChip marker set in the Framingham Heart Study (FHS) to examine genetic associations with ten primary quantitative traits: bone mineral density (BMD), calcaneal ultrasound, and geometric indices of the hip. To test associations with multivariable-adjusted residual trait values, we used additive generalized estimating equation (GEE) and family-based association tests (FBAT) models within each sex as well as sexes combined. We evaluated 70,987 autosomal SNPs with genotypic call rates > or =80%, HWE p > or = 0.001, and MAF > or =10% in up to 1141 phenotyped individuals (495 men and 646 women, mean age 62.5 yrs). Variance component linkage analysis was performed using 11,200 markers. RESULTS: Heritability estimates for all bone phenotypes were 30-66%. LOD scores > or =3.0 were found on chromosomes 15 (1.5 LOD confidence interval: 51,336,679-58,934,236 bp) and 22 (35,890,398-48,603,847 bp) for femoral shaft section modulus. The ten primary phenotypes had 12 associations with 100K SNPs in GEE models at p < 0.000001 and 2 associations in FBAT models at p < 0.000001. The 25 most significant p-values for GEE and FBAT were all less than 3.5 x 10(-6) and 2.5 x 10(-5), respectively. Of the 40 top SNPs with the greatest numbers of significantly associated BMD traits (including femoral neck, trochanter, and lumbar spine), one half to two-thirds were in or near genes that have not previously been studied for osteoporosis. Notably, pleiotropic associations between BMD and bone geometric traits were uncommon. Evidence for association (FBAT or GEE p < 0.05) was observed for several SNPs in candidate genes for osteoporosis, such as rs1801133 in MTHFR; rs1884052 and rs3778099 in ESR1; rs4988300 in LRP5; rs2189480 in VDR; rs2075555 in COLIA1; rs10519297 and rs2008691 in CYP19, as well as SNPs in PPARG (rs10510418 and rs2938392) and ANKH (rs2454873 and rs379016). All GEE, FBAT and linkage results are provided as an open-access results resource at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. CONCLUSION: The FHS 100K SNP project offers an unbiased genome-wide strategy to identify new candidate loci and to replicate previously suggested candidate genes for osteoporosis.
Authors: Douglas P Kiel; Serge L Ferrari; L Adrienne Cupples; David Karasik; Danielle Manen; Alma Imamovic; Alan G Herbert; Josée Dupuis Journal: Bone Date: 2006-11-28 Impact factor: 4.398
Authors: Serge L Ferrari; David Karasik; Jun Liu; Samev Karamohamed; Alan G Herbert; L Adrienne Cupples; Douglas P Kiel Journal: J Bone Miner Res Date: 2004-01-05 Impact factor: 6.741
Authors: Amanda M Shearman; David Karasik; Kristen M Gruenthal; Serkalem Demissie; L Adrienne Cupples; David E Housman; Douglas P Kiel Journal: J Bone Miner Res Date: 2003-12-22 Impact factor: 6.741
Authors: Robert R McLean; David Karasik; Jacob Selhub; Katherine L Tucker; Jose M Ordovas; Giuseppina T Russo; L Adrienne Cupples; Paul F Jacques; Douglas P Kiel Journal: J Bone Miner Res Date: 2003-12-22 Impact factor: 6.741
Authors: L Adrienne Cupples; Heather T Arruda; Emelia J Benjamin; Ralph B D'Agostino; Serkalem Demissie; Anita L DeStefano; Josée Dupuis; Kathleen M Falls; Caroline S Fox; Daniel J Gottlieb; Diddahally R Govindaraju; Chao-Yu Guo; Nancy L Heard-Costa; Shih-Jen Hwang; Sekar Kathiresan; Douglas P Kiel; Jason M Laramie; Martin G Larson; Daniel Levy; Chun-Yu Liu; Kathryn L Lunetta; Matthew D Mailman; Alisa K Manning; James B Meigs; Joanne M Murabito; Christopher Newton-Cheh; George T O'Connor; Christopher J O'Donnell; Mona Pandey; Sudha Seshadri; Ramachandran S Vasan; Zhen Y Wang; Jemma B Wilk; Philip A Wolf; Qiong Yang; Larry D Atwood Journal: BMC Med Genet Date: 2007 Impact factor: 2.103
Authors: Nicole Hoppman; John C McLenithan; Daniel J McBride; Haiqing Shen; Jan Bruder; Richard L Bauer; John R Shaffer; Jie Liu; Elizabeth A Streeten; Alan R Shuldiner; Candace M Kammerer; Braxton D Mitchell Journal: Bone Date: 2010-05-05 Impact factor: 4.398
Authors: José A Riancho; Yongjun Liu; Jesús Sainz; Miguel A García-Pérez; José M Olmos; Alfonso Bolado-Carrancio; Carmen Valero; Javier Pérez-López; Antonio Cano; Tielin Yang; Carolina Sañudo; Hong-Wen Deng; José C Rodríguez-Rey Journal: Eur J Endocrinol Date: 2011-11-02 Impact factor: 6.664
Authors: Péter Horváth; Bernadett Balla; János P Kósa; Bálint Tóbiás; Balázs Szili; Gyöngyi Kirschner; Gabriella Győri; Karina Kató; Péter Lakatos; István Takács Journal: J Bone Miner Metab Date: 2015-03-12 Impact factor: 2.626