Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 May;35(5):875-882.
doi: 10.1002/jbmr.3956. Epub 2020 Jan 28.

Increased Burden of Common Risk Alleles in Children With a Significant Fracture History

Despoina Manousaki  1   2 , Anders Kämpe  3   4 , Vincenzo Forgetta  1 , Riikka E Makitie  5   6   7 , Ghalib Bardai  8 , Alexandre Belisle  9 , Rui Li  9 , Sture Andersson  10 , Outi Makitie  3   5   6   10 , Frank Rauch  8 , J Brent Richards  1   2   11   12
Affiliations
Free article

Increased Burden of Common Risk Alleles in Children With a Significant Fracture History

Despoina Manousaki et al. J Bone Miner Res. 2020 May.
Free article

Abstract

Extreme presentations of common disease in children are often presumed to be of Mendelian etiology, but their polygenic basis has not been fully explored. We tested whether children with significant fracture history and no osteogenesis imperfecta (OI) are at increased polygenic risk for fracture. A childhood significant fracture history was defined as the presence of low-trauma vertebral fractures or multiple long bone fractures. We generated a polygenic score of heel ultrasound-derived speed of sound, termed "gSOS," which predicts risk of osteoporotic fracture. We tested if individuals from three cohorts with significant childhood fracture history had lower gSOS. A Canadian cohort included 94 children with suspected Mendelian osteoporosis, of which 68 had negative OI gene panel. Two Finnish cohorts included 59 children with significant fracture history and 22 with suspected Mendelian osteoporosis, among which 18 had no OI. After excluding individuals with OI and ancestral outliers, we generated gSOS estimates and compared their mean to that of a UK Biobank subset, representing the general population. The average gSOS across all three cohorts (n = 131) was -0.47 SD lower than that in UK Biobank (n = 80,027, p = 1.1 × 10-5 ). The gSOS of 78 individuals with suspected Mendelian osteoporosis was even lower (-0.76 SD, p = 5.3 × 10-10 ). Among the 131 individuals with a significant fracture history, we observed 8 individuals with gSOS below minus 2 SD from the mean; their mean lumbar spine DXA-derived bone mineral density Z-score was -1.7 (SD 0.8). In summary, children with significant fracture history but no OI have an increased burden of common risk alleles. This suggests that a polygenic contribution to disease should be considered in children with extreme presentations of fracture. © 2020 American Society for Bone and Mineral Research.

Keywords: FRACTURE RISK ASSESSMENT; OSTEOGENESIS IMPERFECTA; POLYGENIC FRACTURE RISK.

PubMed Disclaimer

References

    1. Pettersson M, Viljakainen H, Loid P, et al. Copy number variants are enriched in individuals with early-onset obesity and highlight novel pathogenic pathways. J Clin Endocrinol Metab. 2017;102(8):3029-39.
    1. Katsanis N. The continuum of causality in human genetic disorders. Genome Biol. 2016;17(1):233.
    1. Gaugler T, Klei L, Sanders SJ, et al. Most genetic risk for autism resides with common variation. Nat Genet. 2014;46(8):881-5.
    1. Kalsner L, Twachtman-Bassett J, Tokarski K, et al. Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: findings and implications. Mol Genet Genomic Med. 2018;6(2):171-85.
    1. Timpson NJ, Greenwood CMT, Soranzo N, Lawson DJ, Richards JB. Genetic architecture: the shape of the genetic contribution to human traits and disease. Nat Rev Genet. 2018;19(2):110-24.

Publication types