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Genome-wide association studies reveal novel locus with sex-/therapy-specific fracture risk effects in childhood cancer survivors

By Cindy Im, Nan Li, Wonjong Moon, Qi Liu, Lindsay M Morton, Wendy M Leisenring, Rebecca M Howell, Eric J Chow, Charles A Sklar, Carmen L. Wilson, Zhaoming Wang, Yadav Sapkota, Wassim Chemaitilly, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, Smita Bhatia, Gregory T. Armstrong, Yutaka Yasui

Posted 23 Sep 2020
medRxiv DOI: 10.1101/2020.09.21.20196121

Survivors of childhood cancer treated with radiation therapy (RT) and osteotoxic chemotherapies are at increased risk for fractures. However, research focusing on how genetic and clinical susceptibility factors jointly contribute to fracture risk among long-term ([&ge;]5 years) survivors of childhood cancer has been limited. To address this gap, we conducted genome-wide association studies of fracture risk in 2,453 participants from the Childhood Cancer Survivor Study (CCSS) using Cox regression models and prioritized sex- and treatment-stratified genetic associations. Replication analyses were conducted in an independent survivor sample from the St. Jude Lifetime Cohort Study (SJLIFE). We identified a genome-wide significant (P<5x10-8) fracture risk locus, 16p13.3 (HAGHL), among female CCSS survivors (N=1,289) with strong evidence of sex-specific effects (Psex-heterogeneity<7x10-6). We found rs1406815 showed the strongest association with fracture risk after replication (HRmeta-analysis per risk allele=1.43, P=8.2x10-9; N=1,935 women). While the association between rs1406815 and fracture risk was weak among female survivors who did not receive radiation therapy (RT) (HRCCSS=1.22, P=0.11), the association strength increased with greater RT doses to the head or neck (HRCCSS=1.88, P=2.4x10-10 in those with any head/neck RT; HRCCSS=3.79, P=9.1x10-7 in those treated with >36 Gray). In silico bioinformatics analyses suggest these fracture risk alleles regulate HAGHL gene expression and related bone resorption pathways, and are plausibly moderated by head/neck RT. Genetic risk profiles integrating this locus may help identify young female survivors who would benefit from targeted interventions to reduce fracture risk.

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