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Evaluating shared genetic influences on nonsyndromic cleft lip/palate and oropharyngeal neoplasms.

Authors
  • Howe, Laurence J1, 2, 3
  • Hemani, Gibran1
  • Lesseur, Corina4
  • Gaborieau, Valérie4
  • Ludwig, Kerstin U5
  • Mangold, Elisabeth5
  • Brennan, Paul4
  • Ness, Andy R6, 7
  • St Pourcain, Beate1, 3
  • Davey Smith, George1
  • Lewis, Sarah J1
  • 1 Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.
  • 2 Institute of Cardiovascular Science, University College London, London, UK.
  • 3 Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands. , (Netherlands)
  • 4 Section of Genetics, International Agency for Research on Cancer, Lyon, France. , (France)
  • 5 Institute of Human Genetics, University of Bonn, Bonn, Germany. , (Germany)
  • 6 NIHR Bristol Biomedical Research Centre, University Hospitals Bristol, Bristol, UK.
  • 7 Weston NHS Foundation Trust, University of Bristol, Bristol, UK.
Type
Published Article
Journal
Genetic Epidemiology
Publisher
Wiley (John Wiley & Sons)
Publication Date
Nov 01, 2020
Volume
44
Issue
8
Pages
924–933
Identifiers
DOI: 10.1002/gepi.22343
PMID: 32710482
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC. © 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC.

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