@article{01JCMWMPE8B3WH6G6PA2J3HBHV,
  abstract     = {{Background and purpose: We aimed to the genetic components and susceptibility variants associated with acute radiation-induced toxicities (RITs) in patients with head and neck cancer (HNC). Materials and methods: We performed the largest meta-GWAS of seven European cohorts (n = 4,042). Patients were scored weekly during radiotherapy for acute RITs including dysphagia, mucositis, and xerostomia. We analyzed the effect of variants on the average burden (measured as area under curve, AUC) per each RIT, and standardized total average acute toxicity (STATacute) score using a multivariate linear regression. We tested suggestive variants (p < 1.0x10-5) in discovery set (three cohorts; n = 2,640) in a replication set (four cohorts; n = 1,402). We meta-analysed all cohorts to calculate RITs specific SNPbased heritability, and effect of polygenic risk scores (PRSs), and genetic correlations among RITS. Results: From 393 suggestive SNPs identified in discovery set; 37 were nominally significant (preplication < 0.05) in replication set, but none reached genome-wide significance (pcombined < 5 x 10-8). Insilico functional analyses identified "3'-5'-exoribonuclease activity" (FDR = 1.6e-10) for dysphagia, "inositol phosphate-mediated signalling" for mucositis (FDR = 2.20e-09), and "drug catabolic process" for STATacute (FDR = 3.57e-12) as the most enriched pathways by the RIT specific suggestive genes. The SNP-based heritability (+/- standard error) was 29 +/- 0.08 % for dysphagia, 9 +/- 0.12 % (mucositis) and 27 +/- 0.09 % (STATacute). Positive genetic correlation was rg = 0.65 (p = 0.048) between dysphagia and STATacute. PRSs explained limited variation of dysphagia (3 %), mucositis (2.5 %), and STATacute (0.4 %). Conclusion: In HNC patients, acute RITs are modestly heritable, sharing 10 % genetic susceptibility, when PRS explains < 3 % of their variance. We identified numerus suggestive SNPs, which remain to be repli-cated in larger studies. (c) 2022 The Author(s). Published by Elsevier B.V. Radiotherapy and Oncology 176 (2022) 138-148 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).}},
  author       = {{Naderi, Elnaz and Schack, Line M. H. and Welsh, Ceilidh and Sim, Adelene Y. L. and Aguado-Barrera, Miguel E. and Dudding, Tom and Summersgil, Holly and Martinez-Calvo, Laura and Ong, Enya H. W. and Odding, Yasmin and Varela-Pazos, Ana and Steenbakkers, Roel J. H. M. and Crijns, Anne P. G. and Jena, Rajesh and Pring, Miranda and Dennis, Joe and Lobato-Busto, Ramon and Alsner, Jan and Ness, Andy and Nutting, Christopher and Thomson, David J. and Gomez-Caamano, Antonio and Eriksen, Jesper G. and Thomas, Steve J. and Bates, Amy M. and Overgaard, Jens and Cascallar-Caneda, Luis M. and Duprez, Fréderic and Barnett, Gillian C. and Dorling, Leila and Chua, Melvin L. K. and Vega, Ana and West, Catharine M. L. and Langendijk, Johannes A. and Andreassen, Christian Nicolaj and Alizadeh, Behrooz Z. and Radiogenomics Consortium, [missing]}},
  issn         = {{0167-8140}},
  journal      = {{RADIOTHERAPY AND ONCOLOGY}},
  keywords     = {{Head and neck cancer,Radiation-induced acute toxicity,Meta-GWAS,SNP-based heritability,Polygenic risk score,ASSOCIATION,RADIOSENSITIVITY,METAANALYSIS,IMPUTATION,DISEASE,BREAST,GENES,DEATH,SNP}},
  language     = {{eng}},
  pages        = {{138--148}},
  title        = {{Meta-GWAS identifies the heritability of acute radiation-induced toxicities in head and neck cancer}},
  url          = {{http://doi.org/10.1016/j.radonc.2022.09.016}},
  volume       = {{176}},
  year         = {{2022}},
}

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