Rare EN1 Variants and Pediatric Bone Mass

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

A recent whole-genome sequencing study in search of variation associated with adult areal bone mineral density (aBMD) identified rare variants near EN1, with markedly large effect sizes, and a common variant near SOX6. To understand the developmental effects of these loci, we sought to determine if they were associated with pediatric dual-energy X-ray absorptiometry–derived aBMD and bone mineral content (BMC) and if the associations were modified by sex. Our sample comprised 733 females and 685 males of European ancestry enrolled in the longitudinal Bone Mineral Density in Childhood Study (up to 7 annual study visits). Sex- and age-specific Z-scores, adjusted for height, were calculated for the total hip, femoral neck, spine, and distal radius. Total body less head (TBLH) BMC Z-scores were also calculated. The previously reported single nucleotide polymorphisms (SNPs) near EN1 and SOX6 were derived from our imputed data set. Linear mixed-effects models were used to test associations between each SNP and bone Z-scores, plus interactions with sex were explored. The rare T allele of lead EN1 SNP rs11692564 was associated with higher aBMD Z-score for total hip (beta = 0.62, p = 9.0 × 10−4) and femoral neck (beta = 0.53, p = 0.010). In sex-stratified analyses, this variant was associated with higher bone Z-scores in females only, with the associations being strongest for total hip (sex interaction p = 1.9 × 10−4; beta females = 0.86, p = 6.6 × 10−6) and femoral neck (sex interaction p = 0.016; beta females = 0.73, p = 0.001). The common G allele of SOX6 SNP rs11024028 was associated with higher aBMD Z-score for total hip (beta = 0.12, p = 0.009), femoral neck (beta = 0.13, p = 0.003), and TBLH-BMC (beta = 0.09, p = 0.007); furthermore, this association strengthened in males in the sex-stratified analyses. Our findings reveal that rare genetic variation near EN1 and common variation near SOX6 operates in childhood and has implications for the lifelong risk of osteoporosis and fracture. The sex differences observed need to be independently replicated.

Original languageEnglish (US)
Pages (from-to)1513-1517
Number of pages5
JournalJournal of Bone and Mineral Research
Volume31
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Bone Density
Pediatrics
Bone and Bones
Femur Neck
Single Nucleotide Polymorphism
Hip
Alleles
Head
Sex Characteristics
Osteoporosis
Spine
X-Rays
Genome

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Mitchell, J. A., Chesi, A., McCormack, S. E., Roy, S. M., Cousminer, D. L., Kalkwarf, H. J., ... Grant, S. F. A. (2016). Rare EN1 Variants and Pediatric Bone Mass. Journal of Bone and Mineral Research, 31(8), 1513-1517. https://doi.org/10.1002/jbmr.2833

Rare EN1 Variants and Pediatric Bone Mass. / Mitchell, Jonathan A.; Chesi, Alessandra; McCormack, Shana E.; Roy, Sani M.; Cousminer, Diana L.; Kalkwarf, Heidi J.; Lappe, Joan M.; Gilsanz, Vicente; Oberfield, Sharon E.; Shepherd, John A.; Kelly, Andrea; Zemel, Babette S.; Grant, Struan F A.

In: Journal of Bone and Mineral Research, Vol. 31, No. 8, 01.08.2016, p. 1513-1517.

Research output: Contribution to journalArticle

Mitchell, JA, Chesi, A, McCormack, SE, Roy, SM, Cousminer, DL, Kalkwarf, HJ, Lappe, JM, Gilsanz, V, Oberfield, SE, Shepherd, JA, Kelly, A, Zemel, BS & Grant, SFA 2016, 'Rare EN1 Variants and Pediatric Bone Mass', Journal of Bone and Mineral Research, vol. 31, no. 8, pp. 1513-1517. https://doi.org/10.1002/jbmr.2833
Mitchell JA, Chesi A, McCormack SE, Roy SM, Cousminer DL, Kalkwarf HJ et al. Rare EN1 Variants and Pediatric Bone Mass. Journal of Bone and Mineral Research. 2016 Aug 1;31(8):1513-1517. https://doi.org/10.1002/jbmr.2833
Mitchell, Jonathan A. ; Chesi, Alessandra ; McCormack, Shana E. ; Roy, Sani M. ; Cousminer, Diana L. ; Kalkwarf, Heidi J. ; Lappe, Joan M. ; Gilsanz, Vicente ; Oberfield, Sharon E. ; Shepherd, John A. ; Kelly, Andrea ; Zemel, Babette S. ; Grant, Struan F A. / Rare EN1 Variants and Pediatric Bone Mass. In: Journal of Bone and Mineral Research. 2016 ; Vol. 31, No. 8. pp. 1513-1517.
@article{3e5af56ace8f4a51ac64b534c416e8ec,
title = "Rare EN1 Variants and Pediatric Bone Mass",
abstract = "A recent whole-genome sequencing study in search of variation associated with adult areal bone mineral density (aBMD) identified rare variants near EN1, with markedly large effect sizes, and a common variant near SOX6. To understand the developmental effects of these loci, we sought to determine if they were associated with pediatric dual-energy X-ray absorptiometry–derived aBMD and bone mineral content (BMC) and if the associations were modified by sex. Our sample comprised 733 females and 685 males of European ancestry enrolled in the longitudinal Bone Mineral Density in Childhood Study (up to 7 annual study visits). Sex- and age-specific Z-scores, adjusted for height, were calculated for the total hip, femoral neck, spine, and distal radius. Total body less head (TBLH) BMC Z-scores were also calculated. The previously reported single nucleotide polymorphisms (SNPs) near EN1 and SOX6 were derived from our imputed data set. Linear mixed-effects models were used to test associations between each SNP and bone Z-scores, plus interactions with sex were explored. The rare T allele of lead EN1 SNP rs11692564 was associated with higher aBMD Z-score for total hip (beta = 0.62, p = 9.0 × 10−4) and femoral neck (beta = 0.53, p = 0.010). In sex-stratified analyses, this variant was associated with higher bone Z-scores in females only, with the associations being strongest for total hip (sex interaction p = 1.9 × 10−4; beta females = 0.86, p = 6.6 × 10−6) and femoral neck (sex interaction p = 0.016; beta females = 0.73, p = 0.001). The common G allele of SOX6 SNP rs11024028 was associated with higher aBMD Z-score for total hip (beta = 0.12, p = 0.009), femoral neck (beta = 0.13, p = 0.003), and TBLH-BMC (beta = 0.09, p = 0.007); furthermore, this association strengthened in males in the sex-stratified analyses. Our findings reveal that rare genetic variation near EN1 and common variation near SOX6 operates in childhood and has implications for the lifelong risk of osteoporosis and fracture. The sex differences observed need to be independently replicated.",
author = "Mitchell, {Jonathan A.} and Alessandra Chesi and McCormack, {Shana E.} and Roy, {Sani M.} and Cousminer, {Diana L.} and Kalkwarf, {Heidi J.} and Lappe, {Joan M.} and Vicente Gilsanz and Oberfield, {Sharon E.} and Shepherd, {John A.} and Andrea Kelly and Zemel, {Babette S.} and Grant, {Struan F A}",
year = "2016",
month = "8",
day = "1",
doi = "10.1002/jbmr.2833",
language = "English (US)",
volume = "31",
pages = "1513--1517",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "8",

}

TY - JOUR

T1 - Rare EN1 Variants and Pediatric Bone Mass

AU - Mitchell, Jonathan A.

AU - Chesi, Alessandra

AU - McCormack, Shana E.

AU - Roy, Sani M.

AU - Cousminer, Diana L.

AU - Kalkwarf, Heidi J.

AU - Lappe, Joan M.

AU - Gilsanz, Vicente

AU - Oberfield, Sharon E.

AU - Shepherd, John A.

AU - Kelly, Andrea

AU - Zemel, Babette S.

AU - Grant, Struan F A

PY - 2016/8/1

Y1 - 2016/8/1

N2 - A recent whole-genome sequencing study in search of variation associated with adult areal bone mineral density (aBMD) identified rare variants near EN1, with markedly large effect sizes, and a common variant near SOX6. To understand the developmental effects of these loci, we sought to determine if they were associated with pediatric dual-energy X-ray absorptiometry–derived aBMD and bone mineral content (BMC) and if the associations were modified by sex. Our sample comprised 733 females and 685 males of European ancestry enrolled in the longitudinal Bone Mineral Density in Childhood Study (up to 7 annual study visits). Sex- and age-specific Z-scores, adjusted for height, were calculated for the total hip, femoral neck, spine, and distal radius. Total body less head (TBLH) BMC Z-scores were also calculated. The previously reported single nucleotide polymorphisms (SNPs) near EN1 and SOX6 were derived from our imputed data set. Linear mixed-effects models were used to test associations between each SNP and bone Z-scores, plus interactions with sex were explored. The rare T allele of lead EN1 SNP rs11692564 was associated with higher aBMD Z-score for total hip (beta = 0.62, p = 9.0 × 10−4) and femoral neck (beta = 0.53, p = 0.010). In sex-stratified analyses, this variant was associated with higher bone Z-scores in females only, with the associations being strongest for total hip (sex interaction p = 1.9 × 10−4; beta females = 0.86, p = 6.6 × 10−6) and femoral neck (sex interaction p = 0.016; beta females = 0.73, p = 0.001). The common G allele of SOX6 SNP rs11024028 was associated with higher aBMD Z-score for total hip (beta = 0.12, p = 0.009), femoral neck (beta = 0.13, p = 0.003), and TBLH-BMC (beta = 0.09, p = 0.007); furthermore, this association strengthened in males in the sex-stratified analyses. Our findings reveal that rare genetic variation near EN1 and common variation near SOX6 operates in childhood and has implications for the lifelong risk of osteoporosis and fracture. The sex differences observed need to be independently replicated.

AB - A recent whole-genome sequencing study in search of variation associated with adult areal bone mineral density (aBMD) identified rare variants near EN1, with markedly large effect sizes, and a common variant near SOX6. To understand the developmental effects of these loci, we sought to determine if they were associated with pediatric dual-energy X-ray absorptiometry–derived aBMD and bone mineral content (BMC) and if the associations were modified by sex. Our sample comprised 733 females and 685 males of European ancestry enrolled in the longitudinal Bone Mineral Density in Childhood Study (up to 7 annual study visits). Sex- and age-specific Z-scores, adjusted for height, were calculated for the total hip, femoral neck, spine, and distal radius. Total body less head (TBLH) BMC Z-scores were also calculated. The previously reported single nucleotide polymorphisms (SNPs) near EN1 and SOX6 were derived from our imputed data set. Linear mixed-effects models were used to test associations between each SNP and bone Z-scores, plus interactions with sex were explored. The rare T allele of lead EN1 SNP rs11692564 was associated with higher aBMD Z-score for total hip (beta = 0.62, p = 9.0 × 10−4) and femoral neck (beta = 0.53, p = 0.010). In sex-stratified analyses, this variant was associated with higher bone Z-scores in females only, with the associations being strongest for total hip (sex interaction p = 1.9 × 10−4; beta females = 0.86, p = 6.6 × 10−6) and femoral neck (sex interaction p = 0.016; beta females = 0.73, p = 0.001). The common G allele of SOX6 SNP rs11024028 was associated with higher aBMD Z-score for total hip (beta = 0.12, p = 0.009), femoral neck (beta = 0.13, p = 0.003), and TBLH-BMC (beta = 0.09, p = 0.007); furthermore, this association strengthened in males in the sex-stratified analyses. Our findings reveal that rare genetic variation near EN1 and common variation near SOX6 operates in childhood and has implications for the lifelong risk of osteoporosis and fracture. The sex differences observed need to be independently replicated.

UR - http://www.scopus.com/inward/record.url?scp=84980006590&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84980006590&partnerID=8YFLogxK

U2 - 10.1002/jbmr.2833

DO - 10.1002/jbmr.2833

M3 - Article

VL - 31

SP - 1513

EP - 1517

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 8

ER -