Rare EN1 Variants and Pediatric Bone Mass. Mitchell, J. A., Chesi, A., McCormack, S. E., Roy, S. M., Cousminer, D. L., Kalkwarf, H. J., Lappe, J. M., Gilsanz, V., Oberfield, S. E., Shepherd, J. A., Kelly, A., Zemel, B. S., & Grant, S. F. Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research, 31(8):1513–1517, 2016.
doi  abstract   bibtex   
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. © 2016 American Society for Bone and Mineral Research.
@article{mitchell_rare_2016,
	title = {Rare {EN}1 {Variants} and {Pediatric} {Bone} {Mass}},
	volume = {31},
	issn = {1523-4681},
	doi = {10.1002/jbmr.2833},
	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. © 2016 American Society for Bone and Mineral Research.},
	language = {eng},
	number = {8},
	journal = {Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research},
	author = {Mitchell, Jonathan A. and Chesi, Alessandra and McCormack, Shana E. and Roy, Sani M. and Cousminer, Diana L. and Kalkwarf, Heidi J. and Lappe, Joan M. and Gilsanz, Vicente and Oberfield, Sharon E. and Shepherd, John A. and Kelly, Andrea and Zemel, Babette S. and Grant, Struan Fa},
	year = {2016},
	pmid = {26970088},
	pmcid = {PMC4970877},
	keywords = {Alleles, Bone Density, Bone and Bones, CHILDHOOD, Child, DXA, Female, GENERAL POPULATION STUDIES, GENETIC RESEARCH, Genetic Association Studies, Genetic Loci, Genetic Variation, Humans, Male, Organ Size, PUBERTY, Polymorphism, Single Nucleotide},
	pages = {1513--1517}
}
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