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Sökning: WFRF:(Funck Brentano Thomas) > Karolinska Institutet

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  • Nethander, Maria, 1980, et al. (författare)
  • An atlas of genetic determinants of forearm fracture.
  • 2023
  • Ingår i: Nature genetics. - : Springer Nature. - 1546-1718 .- 1061-4036. ; 55:11, s. 1820-1830
  • Tidskriftsartikel (refereegranskat)abstract
    • Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
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3.
  • Nethander, Maria, 1980, et al. (författare)
  • Evidence of a Causal Effect of Estradiol on Fracture Risk in Men.
  • 2019
  • Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 104:2, s. 433-442
  • Tidskriftsartikel (refereegranskat)abstract
    • Observational studies indicate that serum estradiol (E2) is more strongly associated with bone mineral density (BMD) than serum testosterone (T) while both E2 and T associate with fracture risk in men.To evaluate the possible causal effect of serum E2 and T on fracture risk in men.A Mendelian Randomization (MR) approach was undertaken using individual-level data of genotypes, BMD as estimated by quantitative ultrasound of the heel (eBMD), fractures (n=17,650), and relevant covariates of 175,583 unrelated men of European origin from the UK Biobank. The genetic instruments for serum E2 and T were taken from the most recent large scale GWAS meta-analyses on these hormones in men.MR analyses demonstrated a causal effect of serum E2 on eBMD and fracture risk. A 1 SD (or 9.6 pg/ml) genetically instrumented decrease in serum E2 was associated with a 0.38 SD decrease in eBMD (p-value 9.7 x 10-74) and an increased risk of any fracture (OR 1.35, 95% CI, 1.18-1.55), non-vertebral major osteoporotic fractures (OR 1.75, 95% CI, 1.35-2.27) and wrist fractures (OR 2.27, 95% CI, 1.62-3.16). These causal effects of serum E2 on fracture risk were robust in sensitivity analyses and remained unchanged in stratified analyses for age, BMI, eBMD, smoking status, and physical activity. MR analyses revealed no evidence of a causal effect of T levels on fracture risk.Our findings provide the first evidence of a robust causal effect of serum E2, but not T, on fracture risk in men.
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