A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women

Kira C. Taylor, Daniel S. Evans, Digna R.Velez Edwards, Todd L. Edwards, Tamar Sofer, Guo Li, Youfang Liu, Nora Franceschini, Rebecca D. Jackson, Ayush Giri, Macarius Donneyong, Bruce Psaty, Jerome I. Rotter, Andrea Z. LaCroix, Joanne M. Jordan, John A Robbins, Beth Lewis, Marcia L. Stefanick, Yongmei Liu, Melissa GarciaTamara Harris, Jane A. Cauley, Kari E. North

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50–70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis. Methods Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N = 8155), Cardiovascular Health Study (CHS) (N = 504), BioVU (N = 704), Health ABC (N = 651), and the Johnston County Osteoarthritis Project (JoCoOA) (N = 291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~ 2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P < 5 × 10− 8. Results One SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P = 4.0 × 10− 8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2 = 0). This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed. Conclusion This GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans.

Original languageEnglish (US)
Pages (from-to)233-242
Number of pages10
JournalBone Reports
Volume5
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

Fingerprint

Genome-Wide Association Study
African Americans
Meta-Analysis
Single Nucleotide Polymorphism
Health
Women's Health
Osteoarthritis
Osteoporosis
Blood Platelets
Genome
HapMap Project
Sternum
Osteoporotic Fractures
Toes
Proportional Hazards Models
Gene Frequency
Skull
Bone Density
Introns
Haplotypes

Keywords

  • African American
  • Fracture
  • Genetic association study
  • Genome-wide association study (GWAS)
  • Meta-analysis
  • Osteoporosis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Taylor, K. C., Evans, D. S., Edwards, D. R. V., Edwards, T. L., Sofer, T., Li, G., ... North, K. E. (2016). A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women. Bone Reports, 5, 233-242. https://doi.org/10.1016/j.bonr.2016.08.005

A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women. / Taylor, Kira C.; Evans, Daniel S.; Edwards, Digna R.Velez; Edwards, Todd L.; Sofer, Tamar; Li, Guo; Liu, Youfang; Franceschini, Nora; Jackson, Rebecca D.; Giri, Ayush; Donneyong, Macarius; Psaty, Bruce; Rotter, Jerome I.; LaCroix, Andrea Z.; Jordan, Joanne M.; Robbins, John A; Lewis, Beth; Stefanick, Marcia L.; Liu, Yongmei; Garcia, Melissa; Harris, Tamara; Cauley, Jane A.; North, Kari E.

In: Bone Reports, Vol. 5, 01.12.2016, p. 233-242.

Research output: Contribution to journalArticle

Taylor, KC, Evans, DS, Edwards, DRV, Edwards, TL, Sofer, T, Li, G, Liu, Y, Franceschini, N, Jackson, RD, Giri, A, Donneyong, M, Psaty, B, Rotter, JI, LaCroix, AZ, Jordan, JM, Robbins, JA, Lewis, B, Stefanick, ML, Liu, Y, Garcia, M, Harris, T, Cauley, JA & North, KE 2016, 'A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women', Bone Reports, vol. 5, pp. 233-242. https://doi.org/10.1016/j.bonr.2016.08.005
Taylor, Kira C. ; Evans, Daniel S. ; Edwards, Digna R.Velez ; Edwards, Todd L. ; Sofer, Tamar ; Li, Guo ; Liu, Youfang ; Franceschini, Nora ; Jackson, Rebecca D. ; Giri, Ayush ; Donneyong, Macarius ; Psaty, Bruce ; Rotter, Jerome I. ; LaCroix, Andrea Z. ; Jordan, Joanne M. ; Robbins, John A ; Lewis, Beth ; Stefanick, Marcia L. ; Liu, Yongmei ; Garcia, Melissa ; Harris, Tamara ; Cauley, Jane A. ; North, Kari E. / A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women. In: Bone Reports. 2016 ; Vol. 5. pp. 233-242.
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abstract = "Background Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50–70{\%} of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis. Methods Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N = 8155), Cardiovascular Health Study (CHS) (N = 504), BioVU (N = 704), Health ABC (N = 651), and the Johnston County Osteoarthritis Project (JoCoOA) (N = 291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~ 2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P < 5 × 10− 8. Results One SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P = 4.0 × 10− 8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2 = 0). This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed. Conclusion This GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans.",
keywords = "African American, Fracture, Genetic association study, Genome-wide association study (GWAS), Meta-analysis, Osteoporosis",
author = "Taylor, {Kira C.} and Evans, {Daniel S.} and Edwards, {Digna R.Velez} and Edwards, {Todd L.} and Tamar Sofer and Guo Li and Youfang Liu and Nora Franceschini and Jackson, {Rebecca D.} and Ayush Giri and Macarius Donneyong and Bruce Psaty and Rotter, {Jerome I.} and LaCroix, {Andrea Z.} and Jordan, {Joanne M.} and Robbins, {John A} and Beth Lewis and Stefanick, {Marcia L.} and Yongmei Liu and Melissa Garcia and Tamara Harris and Cauley, {Jane A.} and North, {Kari E.}",
year = "2016",
month = "12",
day = "1",
doi = "10.1016/j.bonr.2016.08.005",
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pages = "233--242",
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TY - JOUR

T1 - A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women

AU - Taylor, Kira C.

AU - Evans, Daniel S.

AU - Edwards, Digna R.Velez

AU - Edwards, Todd L.

AU - Sofer, Tamar

AU - Li, Guo

AU - Liu, Youfang

AU - Franceschini, Nora

AU - Jackson, Rebecca D.

AU - Giri, Ayush

AU - Donneyong, Macarius

AU - Psaty, Bruce

AU - Rotter, Jerome I.

AU - LaCroix, Andrea Z.

AU - Jordan, Joanne M.

AU - Robbins, John A

AU - Lewis, Beth

AU - Stefanick, Marcia L.

AU - Liu, Yongmei

AU - Garcia, Melissa

AU - Harris, Tamara

AU - Cauley, Jane A.

AU - North, Kari E.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Background Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50–70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis. Methods Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N = 8155), Cardiovascular Health Study (CHS) (N = 504), BioVU (N = 704), Health ABC (N = 651), and the Johnston County Osteoarthritis Project (JoCoOA) (N = 291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~ 2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P < 5 × 10− 8. Results One SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P = 4.0 × 10− 8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2 = 0). This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed. Conclusion This GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans.

AB - Background Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50–70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis. Methods Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N = 8155), Cardiovascular Health Study (CHS) (N = 504), BioVU (N = 704), Health ABC (N = 651), and the Johnston County Osteoarthritis Project (JoCoOA) (N = 291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~ 2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P < 5 × 10− 8. Results One SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P = 4.0 × 10− 8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2 = 0). This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed. Conclusion This GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans.

KW - African American

KW - Fracture

KW - Genetic association study

KW - Genome-wide association study (GWAS)

KW - Meta-analysis

KW - Osteoporosis

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U2 - 10.1016/j.bonr.2016.08.005

DO - 10.1016/j.bonr.2016.08.005

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JO - Bone Reports

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