A Genomewide Association Study Identifies Two Sex-Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Failure to achieve optimal bone mineral accretion during childhood and adolescence results in subsequent suboptimal peak bone mass, contributing to osteoporosis risk later in life. To identify novel genetic factors that influence pediatric bone mass at discrete skeletal sites, we performed a sex-stratified genomewide association study of areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry at the 1/3 distal radius, spine, total hip, and femoral neck in a cohort of 933 healthy European American children. We took forward signals with p < 5 × 10−5 and minor allele frequency (MAF) >5% into an independent cohort of 486 European American children in search of replication. In doing so, we identified five loci that achieved genome wide significance in the combined cohorts (nearest genes: CPED1, IZUMO3, RBFOX1, SPBT, and TBPL2), of which the last four were novel and two were sex-specific (SPTB in females and IZUMO3 in males), with all of them yielding associations that were particularly strong at a specific skeletal site. Annotation of potential regulatory function, expression quantitative trait loci (eQTL) effects and pathway analyses identified several potential target genes at these associated loci. This study highlights the importance of sex-stratified analyses at discrete skeletal sites during the critical period of bone accrual, and identifies novel loci for further functional follow-up to pinpoint key genes and better understand the regulation of bone development in children.

Original languageEnglish (US)
Pages (from-to)1274-1281
Number of pages8
JournalJournal of Bone and Mineral Research
Volume32
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Bone Density
Pediatrics
Bone and Bones
Genes
Quantitative Trait Loci
Bone Development
Femur Neck
Photon Absorptiometry
Osteoporosis
Minerals
Hip
Spine
Genome

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

A Genomewide Association Study Identifies Two Sex-Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites. / Chesi, Alessandra; Mitchell, Jonathan A.; Kalkwarf, Heidi J.; Bradfield, Jonathan P.; Lappe, Joan M.; Cousminer, Diana L.; Roy, Sani M.; McCormack, Shana E.; Gilsanz, Vicente; Oberfield, Sharon E.; Hakonarson, Hakon; Shepherd, John A.; Kelly, Andrea; Zemel, Babette S.; Grant, Struan F.A.

In: Journal of Bone and Mineral Research, Vol. 32, No. 6, 01.06.2017, p. 1274-1281.

Research output: Contribution to journalArticle

Chesi, A, Mitchell, JA, Kalkwarf, HJ, Bradfield, JP, Lappe, JM, Cousminer, DL, Roy, SM, McCormack, SE, Gilsanz, V, Oberfield, SE, Hakonarson, H, Shepherd, JA, Kelly, A, Zemel, BS & Grant, SFA 2017, 'A Genomewide Association Study Identifies Two Sex-Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites', Journal of Bone and Mineral Research, vol. 32, no. 6, pp. 1274-1281. https://doi.org/10.1002/jbmr.3097
Chesi, Alessandra ; Mitchell, Jonathan A. ; Kalkwarf, Heidi J. ; Bradfield, Jonathan P. ; Lappe, Joan M. ; Cousminer, Diana L. ; Roy, Sani M. ; McCormack, Shana E. ; Gilsanz, Vicente ; Oberfield, Sharon E. ; Hakonarson, Hakon ; Shepherd, John A. ; Kelly, Andrea ; Zemel, Babette S. ; Grant, Struan F.A. / A Genomewide Association Study Identifies Two Sex-Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites. In: Journal of Bone and Mineral Research. 2017 ; Vol. 32, No. 6. pp. 1274-1281.
@article{7782233634254203b8fd6ffc8f2c69a5,
title = "A Genomewide Association Study Identifies Two Sex-Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites",
abstract = "Failure to achieve optimal bone mineral accretion during childhood and adolescence results in subsequent suboptimal peak bone mass, contributing to osteoporosis risk later in life. To identify novel genetic factors that influence pediatric bone mass at discrete skeletal sites, we performed a sex-stratified genomewide association study of areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry at the 1/3 distal radius, spine, total hip, and femoral neck in a cohort of 933 healthy European American children. We took forward signals with p < 5 × 10−5 and minor allele frequency (MAF) >5{\%} into an independent cohort of 486 European American children in search of replication. In doing so, we identified five loci that achieved genome wide significance in the combined cohorts (nearest genes: CPED1, IZUMO3, RBFOX1, SPBT, and TBPL2), of which the last four were novel and two were sex-specific (SPTB in females and IZUMO3 in males), with all of them yielding associations that were particularly strong at a specific skeletal site. Annotation of potential regulatory function, expression quantitative trait loci (eQTL) effects and pathway analyses identified several potential target genes at these associated loci. This study highlights the importance of sex-stratified analyses at discrete skeletal sites during the critical period of bone accrual, and identifies novel loci for further functional follow-up to pinpoint key genes and better understand the regulation of bone development in children.",
author = "Alessandra Chesi and Mitchell, {Jonathan A.} and Kalkwarf, {Heidi J.} and Bradfield, {Jonathan P.} and Lappe, {Joan M.} and Cousminer, {Diana L.} and Roy, {Sani M.} and McCormack, {Shana E.} and Vicente Gilsanz and Oberfield, {Sharon E.} and Hakon Hakonarson and Shepherd, {John A.} and Andrea Kelly and Zemel, {Babette S.} and Grant, {Struan F.A.}",
year = "2017",
month = "6",
day = "1",
doi = "10.1002/jbmr.3097",
language = "English (US)",
volume = "32",
pages = "1274--1281",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - A Genomewide Association Study Identifies Two Sex-Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites

AU - Chesi, Alessandra

AU - Mitchell, Jonathan A.

AU - Kalkwarf, Heidi J.

AU - Bradfield, Jonathan P.

AU - Lappe, Joan M.

AU - Cousminer, Diana L.

AU - Roy, Sani 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.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Failure to achieve optimal bone mineral accretion during childhood and adolescence results in subsequent suboptimal peak bone mass, contributing to osteoporosis risk later in life. To identify novel genetic factors that influence pediatric bone mass at discrete skeletal sites, we performed a sex-stratified genomewide association study of areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry at the 1/3 distal radius, spine, total hip, and femoral neck in a cohort of 933 healthy European American children. We took forward signals with p < 5 × 10−5 and minor allele frequency (MAF) >5% into an independent cohort of 486 European American children in search of replication. In doing so, we identified five loci that achieved genome wide significance in the combined cohorts (nearest genes: CPED1, IZUMO3, RBFOX1, SPBT, and TBPL2), of which the last four were novel and two were sex-specific (SPTB in females and IZUMO3 in males), with all of them yielding associations that were particularly strong at a specific skeletal site. Annotation of potential regulatory function, expression quantitative trait loci (eQTL) effects and pathway analyses identified several potential target genes at these associated loci. This study highlights the importance of sex-stratified analyses at discrete skeletal sites during the critical period of bone accrual, and identifies novel loci for further functional follow-up to pinpoint key genes and better understand the regulation of bone development in children.

AB - Failure to achieve optimal bone mineral accretion during childhood and adolescence results in subsequent suboptimal peak bone mass, contributing to osteoporosis risk later in life. To identify novel genetic factors that influence pediatric bone mass at discrete skeletal sites, we performed a sex-stratified genomewide association study of areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry at the 1/3 distal radius, spine, total hip, and femoral neck in a cohort of 933 healthy European American children. We took forward signals with p < 5 × 10−5 and minor allele frequency (MAF) >5% into an independent cohort of 486 European American children in search of replication. In doing so, we identified five loci that achieved genome wide significance in the combined cohorts (nearest genes: CPED1, IZUMO3, RBFOX1, SPBT, and TBPL2), of which the last four were novel and two were sex-specific (SPTB in females and IZUMO3 in males), with all of them yielding associations that were particularly strong at a specific skeletal site. Annotation of potential regulatory function, expression quantitative trait loci (eQTL) effects and pathway analyses identified several potential target genes at these associated loci. This study highlights the importance of sex-stratified analyses at discrete skeletal sites during the critical period of bone accrual, and identifies novel loci for further functional follow-up to pinpoint key genes and better understand the regulation of bone development in children.

UR - http://www.scopus.com/inward/record.url?scp=85019090688&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019090688&partnerID=8YFLogxK

U2 - 10.1002/jbmr.3097

DO - 10.1002/jbmr.3097

M3 - Article

C2 - 28181694

AN - SCOPUS:85019090688

VL - 32

SP - 1274

EP - 1281

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 6

ER -