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

Laurence J. Howe, Gibran Hemani, Corina Lesseur, Valérie Gaborieau, Kerstin U. Ludwig, Elisabeth Mangold, Paul Brennan, Andy R. Ness, Beate St Pourcain, George Davey Smith, Sarah J. Lewis

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish
Pages (from-to)924-933
Number of pages10
JournalGenetic Epidemiology
Issue number8
StatePublished - Nov 2020
Externally publishedYes


  • Mendelian randomization
  • birth defects
  • genetic epidemiology
  • oral cancers
  • orofacial clefts
  • polygenic risk scores


Dive into the research topics of 'Evaluating shared genetic influences on nonsyndromic cleft lip/palate and oropharyngeal neoplasms'. Together they form a unique fingerprint.

Cite this