A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius

Alessandra Chesi, Jonathan A. Mitchell, Heidi J. Kalkwarf, Jonathan P. Bradfield, Joan M. Lappe, Shana E. McCormack, Vicente Gilsanz, Sharon E. Oberfield, Hakon Hakonarson, John A. Shepherd, Andrea Kelly, Babette S. Zemel, Struan F A Grant

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Abstract

Childhood fractures are common, with the forearm being the most common site. Genome-wide association studies (GWAS) have identified more than 60 loci associated with bone mineral density (BMD) in adults but less is known about genetic influences specific to bone in childhood. To identify novel genetic factors that influence pediatric bone strength at a common site for childhood fractures,we performed a sex-stratified trans-ethnic genome-wide association study of areal BMD(aBMD) and bone mineral content (BMC) Z-scores measured by dual energy X-ray absorptiometry at the one-third distal radius, in a cohort of 1399 children without clinical abnormalities in bone health. We tested signals with P <5 × 10-6 for replication in an independent, same-age cohort of 486 Caucasian children. Two loci yielded a genome-wide significant combined P-value: rs7797976 within CPED1 in females [P = 2.4 × 10-11, ß =- 0.30 standard deviations (SD) per T allele; aBMD-Z] and rs7035284 at 9p21.3 in males (P = 1.2 × 10-8, β = 0.28 SD per G allele; BMC-Z). Signals at the CPED1-WNT16-FAM3C locus have been previously associated with BMD at other skeletal sites in adults and children. Our result at the distal radius underscores the importance of this locus at multiple skeletal sites. The 9p21.3 locus is within a gene desert, with the nearest gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC previously. These findings suggest that genetic determinants of childhood bone accretion at the radius, a skeletal site that is primarily cortical bone, exist and also differ by sex.

Original languageEnglish
Pages (from-to)5053-5059
Number of pages7
JournalHuman Molecular Genetics
Volume24
Issue number17
DOIs
StatePublished - 2015

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Genome-Wide Association Study
Bone Density
Pediatrics
Bone and Bones
Alleles
Photon Absorptiometry
Forearm
Genes
Genome
Health

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius. / Chesi, Alessandra; Mitchell, Jonathan A.; Kalkwarf, Heidi J.; Bradfield, Jonathan P.; Lappe, Joan M.; McCormack, Shana E.; Gilsanz, Vicente; Oberfield, Sharon E.; Hakonarson, Hakon; Shepherd, John A.; Kelly, Andrea; Zemel, Babette S.; Grant, Struan F A.

In: Human Molecular Genetics, Vol. 24, No. 17, 2015, p. 5053-5059.

Research output: Contribution to journalArticle

Chesi, A, Mitchell, JA, Kalkwarf, HJ, Bradfield, JP, Lappe, JM, McCormack, SE, Gilsanz, V, Oberfield, SE, Hakonarson, H, Shepherd, JA, Kelly, A, Zemel, BS & Grant, SFA 2015, 'A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius', Human Molecular Genetics, vol. 24, no. 17, pp. 5053-5059. https://doi.org/10.1093/hmg/ddv210
Chesi, Alessandra ; Mitchell, Jonathan A. ; Kalkwarf, Heidi J. ; Bradfield, Jonathan P. ; Lappe, Joan M. ; McCormack, Shana E. ; Gilsanz, Vicente ; Oberfield, Sharon E. ; Hakonarson, Hakon ; Shepherd, John A. ; Kelly, Andrea ; Zemel, Babette S. ; Grant, Struan F A. / A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 17. pp. 5053-5059.
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abstract = "Childhood fractures are common, with the forearm being the most common site. Genome-wide association studies (GWAS) have identified more than 60 loci associated with bone mineral density (BMD) in adults but less is known about genetic influences specific to bone in childhood. To identify novel genetic factors that influence pediatric bone strength at a common site for childhood fractures,we performed a sex-stratified trans-ethnic genome-wide association study of areal BMD(aBMD) and bone mineral content (BMC) Z-scores measured by dual energy X-ray absorptiometry at the one-third distal radius, in a cohort of 1399 children without clinical abnormalities in bone health. We tested signals with P <5 × 10-6 for replication in an independent, same-age cohort of 486 Caucasian children. Two loci yielded a genome-wide significant combined P-value: rs7797976 within CPED1 in females [P = 2.4 × 10-11, {\ss} =- 0.30 standard deviations (SD) per T allele; aBMD-Z] and rs7035284 at 9p21.3 in males (P = 1.2 × 10-8, β = 0.28 SD per G allele; BMC-Z). Signals at the CPED1-WNT16-FAM3C locus have been previously associated with BMD at other skeletal sites in adults and children. Our result at the distal radius underscores the importance of this locus at multiple skeletal sites. The 9p21.3 locus is within a gene desert, with the nearest gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC previously. These findings suggest that genetic determinants of childhood bone accretion at the radius, a skeletal site that is primarily cortical bone, exist and also differ by sex.",
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AU - Chesi, Alessandra

AU - Mitchell, Jonathan A.

AU - Kalkwarf, Heidi J.

AU - Bradfield, Jonathan P.

AU - Lappe, Joan M.

AU - McCormack, Shana E.

AU - Gilsanz, Vicente

AU - Oberfield, Sharon E.

AU - Hakonarson, Hakon

AU - Shepherd, John A.

AU - Kelly, Andrea

AU - Zemel, Babette S.

AU - Grant, Struan F A

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N2 - Childhood fractures are common, with the forearm being the most common site. Genome-wide association studies (GWAS) have identified more than 60 loci associated with bone mineral density (BMD) in adults but less is known about genetic influences specific to bone in childhood. To identify novel genetic factors that influence pediatric bone strength at a common site for childhood fractures,we performed a sex-stratified trans-ethnic genome-wide association study of areal BMD(aBMD) and bone mineral content (BMC) Z-scores measured by dual energy X-ray absorptiometry at the one-third distal radius, in a cohort of 1399 children without clinical abnormalities in bone health. We tested signals with P <5 × 10-6 for replication in an independent, same-age cohort of 486 Caucasian children. Two loci yielded a genome-wide significant combined P-value: rs7797976 within CPED1 in females [P = 2.4 × 10-11, ß =- 0.30 standard deviations (SD) per T allele; aBMD-Z] and rs7035284 at 9p21.3 in males (P = 1.2 × 10-8, β = 0.28 SD per G allele; BMC-Z). Signals at the CPED1-WNT16-FAM3C locus have been previously associated with BMD at other skeletal sites in adults and children. Our result at the distal radius underscores the importance of this locus at multiple skeletal sites. The 9p21.3 locus is within a gene desert, with the nearest gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC previously. These findings suggest that genetic determinants of childhood bone accretion at the radius, a skeletal site that is primarily cortical bone, exist and also differ by sex.

AB - Childhood fractures are common, with the forearm being the most common site. Genome-wide association studies (GWAS) have identified more than 60 loci associated with bone mineral density (BMD) in adults but less is known about genetic influences specific to bone in childhood. To identify novel genetic factors that influence pediatric bone strength at a common site for childhood fractures,we performed a sex-stratified trans-ethnic genome-wide association study of areal BMD(aBMD) and bone mineral content (BMC) Z-scores measured by dual energy X-ray absorptiometry at the one-third distal radius, in a cohort of 1399 children without clinical abnormalities in bone health. We tested signals with P <5 × 10-6 for replication in an independent, same-age cohort of 486 Caucasian children. Two loci yielded a genome-wide significant combined P-value: rs7797976 within CPED1 in females [P = 2.4 × 10-11, ß =- 0.30 standard deviations (SD) per T allele; aBMD-Z] and rs7035284 at 9p21.3 in males (P = 1.2 × 10-8, β = 0.28 SD per G allele; BMC-Z). Signals at the CPED1-WNT16-FAM3C locus have been previously associated with BMD at other skeletal sites in adults and children. Our result at the distal radius underscores the importance of this locus at multiple skeletal sites. The 9p21.3 locus is within a gene desert, with the nearest gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC previously. These findings suggest that genetic determinants of childhood bone accretion at the radius, a skeletal site that is primarily cortical bone, exist and also differ by sex.

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